Abstract
Background
Despite the extensive research in recent years, the current treatment modalities for neurological disorders are suboptimal. Curcumin, a polyphenol found in Curcuma genus, has been shown to mitigate the pathophysiology and clinical sequalae involved in neuroinflammation and neurodegenerative diseases.
Methods
We searched PubMed database for relevant publications on curcumin and its uses in treating neurological diseases. We also reviewed relevant clinical trials which appeared on searching PubMed database using ‘Curcumin and clinical trials’.
Results
This review details the pleiotropic immunomodulatory functions and neuroprotective properties of curcumin, its derivatives and formulations in various preclinical and clinical investigations. The effects of curcumin on neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), brain tumors, epilepsy, Huntington's disorder (HD), ischemia, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI) with a major focus on associated signalling pathways have been thoroughly discussed.
Conclusion
This review demonstrates curcumin can suppress spinal neuroinflammation by modulating diverse astroglia mediated cascades, ensuring the treatment of neurological disorders.
Keywords: Alzheimer's disease, Curcumin, Inflammation, Neurological disorders, Parkinson's disease
1. Introduction
Neurological diseases (NDs) are characterized by progressive deterioration of preferentially susceptible neurons in various regions of central nervous system (CNS).1, 2 Numerous factors, including the excessive accumulation of misfolded proteins, inadequate clearance by proteasomal complexes, oxidative stress, deficiency in endogenous antioxidant enzymes activity, mitochondrial dysfunction, depletion of neurotrophin, neuro-inflammation, and various genetic perturbations contribute to the development and progression of NDs.3 Depending on the location, neuronal loss, gliosis, or demyelination can cause cognitive decline, behavioural issues, and motor abnormalities.4 NDs can be mainly characterized as memory loss/dementia or personality disorders—AD, impaired mobility, motor functions and attention deficits—PD, progressive weakness and decline in cognitive functions—ALS, auto-immune mediated neuronal loss— MS.4,2,5 NDs have a significant negative influence on quality of life (QoL), as evidenced by their high disability-adjusted life years (DALYs), which measures loss of years of healthy life due to illness. Epidemiological studies have indicated that incidence of these diseases including AD and PD is increasing globally with rising life expectancies.6,7 Progressive neuronal loss, associated stroke, ischemia and immense pain due to NDs have been the major cause of disabilities and mortality in the aged-adults.4,2,5 The majority of treatments for NDs now on the market are aimed at providing temporary symptom alleviation. Certain conventional pharmacological compounds used to treat NDs exhibit inevitable side effects.4 Besides, most of these drugs are expensive. As a result, there is a great need for the development of innovative treatments and neuroprotective substances with higher efficacy and fewer off-target effects to prevent and halt the development of NDs.
Natural compounds from the plant origin have been extensively explored to obtain the more effective and safer alternate therapeutic agent against various chronic diseases including cardiovascular diseases, cancers, diabetes, and NDs.4, 8, 9, 10, 11, 12, 13 In-depth investigations have provided the evidence that phytochemicals including alkaloids, flavonoids, polyphenols and terpenes have remarkable potential in alleviating NDs in vitro, in vivo and clinical studies. Suppression of oxidative stress, inflammatory responses, cell death, neuronal activation along with stimulation of angiogenesis and neurogenesis are the well-known NDs progression preventing processes that can be accomplished by the primary bioactive substances isolated from plants.4, 5 Considerable research conducted over the past fifty years have shown that curcumin, a potential bioactive compound isolated from turmeric, aid in the treatment of practically most of the human diseases. This phytochemical is known to possess anti-arthritis, anti-atherosclerosis, anti-bacterial, anti-diabetic, anti-fungal, anti-hypertensive, anti-hyperlipidemic, anti-inflammatory, anti-tumor, antiphlogistic, anti-psoriasis, antithrombotic, and anti-hepatotoxic effects.5,14, 15, 16 In addition to its organ protective properties such as cardioprotective, hepatoprotective, nephron protective, and pulmonary protective effects, this phytochemical is also known to have neuroprotective activities.17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Curcumin has been shown in animal experiments to accelerate adult hippocampus neurogenesis by augmenting the density of newly formed cells in the dentate gyrus areas of the brain.29 Additionally, it is a strong inhibitor of reactive astrocyte and glial cells activation, preventing the death of hippocampus cells driven by kainic acid.30 Moreover, curcumin was found to be potential in the treatment of AD due to its ability to disaggregate β-amyloid and prevent the production of fibrils and oligomers.5, 31 Curcumin has been proven to be neuroprotective in animal models of seizures, migraine, ALS, PD, MS and neuroinflammation in a number of experimental studies.5 With all of this background information, the current review aims to describe the potential of curcumin in various cell lines, animal models of NDs and in clinical trials. We have also illustrated the molecular mechanisms behind the protective activities of curcumin. Further, the safety, adverse side effects, disadvantages and future prospective have been thoroughly discussed.
2. Methods
This is a review article which provide the update on uses of curcumin in treating various chronic neurological diseases. Publications that provide the evidence of effectiveness of curcumin in preventing and reducing the symptoms of neurological diseases were collected from PubMed database by searching the keyword of curcumin plus name of the diseases, for instance, ‘curcumin and Alzheimer's disease’, ‘curcumin and amyotrophic lateral sclerosis’, ‘curcumin and epilepsy’, etc. The review articles, retracted manuscripts, short notes and editorial communications and manuscripts on turmeric were considered irrelevant articles for the current study. The remaining research articles were further thoroughly screened for dose, time and effects in both in vitro and in vivo studies. In addition, we also conducted the search for clinical trials on curcumin using ‘curcumin and clinical trials’ as a keyword. The number of articles screened and criteria for considering relevant articles are provided in the supplementary figure.
3. Effect of curcumin on various NDs
NDs occur primarily due to inflammation, oxidative stress, aging, trauma, vascular dysfunction, mitochondrial dysfunction, metabolic and genetic perturbations. Damaged mitochondria at the location of injury generate a huge amount of reactive oxygen species (ROS).32 To reduce this oxidative load and provide some protection for the neurons, autophagy plays a key role and destroys these dysfunctional mitochondria.33,34 By preventing mitochondrial apoptosis and neuroinflammation, autophagy has restorative benefits and plays a crucial role in re-establishing neuronal homeostasis. Controlled stimulation of the PI3K/Akt/mTOR signalling pathway can prevent post-injury mediated apoptosis as well as help regulate neuronal degeneration.35 Both endogenous and exogenous ligands can activate NF-κB, and activated protein is reported to be involved in neuronal and glial cells functional deregulation under a variety of inflammatory circumstances. Additionally, activated NF-κB promotes the release of inflammatory substances including IL-6, which leads to secondary brain injury.32, 36 Increasing lines of evidence suggest that neurodegenerative processes are initiated by oxidative damage and free radicals. Nuclear factor erythroid 2 (Nrf2) controls the expression of genes linked to oxidative stress. It activates antioxidant enzymes including glutathione peroxidase (GSH-Px), heme oxygenase-1 (HO-1), malondialdehyde (MDA), nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase-1 (NQO1), and superoxide dismutase (SOD).34 Curcumin has been shown to cross BBB and activate Nrf2 and its associated genes, inhibit NF-κB and inflammatory cytokines thereby reducing the neuroinflammation. Moreover, curcumin is a known free radical and ROS scavenger.32 This section details the major pathways which are dysregulated in NDs. The potential of curcumin in reversing the events have also been highlighted (Fig. 1). Anti-NDs effect of curcumin in vitro and in vivo models (Table 1) and the effect of various curcumin and its derivatives in clinical trials (Table 2) have been explained.
Fig. 1.
Major inflammatory pathways associated with neurological disorders and potential of curcumin in restoring these deregulated pathways have been shown.
Table 1.
In vitro/in vivo studies that show the effect of curcumin on various neurological diseases.
| Disease/Condition | Curcumin formulation | Cell line / Animal model | Dose | Duration | Effects | Refs. |
|---|---|---|---|---|---|---|
| Alzheimer's disease | ||||||
| Curcumin | Primary hippocampal neurons | 1, 5, 10 μM | – | ↑Cell viability in presence of Aβ42, ↑SIRT3 deacetylation, ↑NAD/NADH, ↑ATP, ↑Thrb | 37 | |
| SH-SY5Y cells | 0.625–5μmol/L | 4 hours | ↓TG-induced cell toxicity, ↓TG-induced apoptosis, ↓TG-induced ROS, ↓GRP78, ↓pSer981-PERK, ↓pSer51-eIF2α, ↓TG induced MFN2, ↓TG-induced mitochondrial stress, ↓TG-induced ERS | 38 | ||
| BV2, SH-SY5Y cells | 1, 2.5, 5, 10, 20 μM | 24 hours | No cytotoxicity, No effect on cell viability, ↑Nrf2, ↑IL-10, ↓TREM1, ↓DAP12, ↓NF-κB, ↓COX-2, ↓iNOS, ↓TNF-α, ↓IL-1, ↓C3A, ↓C5A, ↓TLR4, ↓MYD88, ↓IL-6, ↓NLRP3, ↓Caspase-1, ↓IL-1α, ↓IL-1β, ↓ROS, ↓AGE, ↓p-Tau, ↓β-amyloid, ↓GSK-3β | 39 | ||
| Microglia | 10 μM | 1 hour before Aβ 25–35 treatment | ↓HMGB1, ↓RAGE, ↓TLR4, ↓IL-1β, ↓TNF-α, ↓Cytotoxicity of Aβ 25–35 | 40 | ||
| Rat microglia cells & primary cortical neurons | 1-50 μM | 0–30 days | ↓HMW Aβ42O-induced IL-1β & TNF-α release, ↓Neurite damage, ↓Neuronal cell death | 41 | ||
| APP/PS1 mice | 100 mg/kg/day | 5 months | ↑Time spent in target quadrant, ↑Short term working memory, ↓Escape latency, ↓GFAP, ↓COX-2, ↓CD68, ↓HMGB1, ↓TLR4, ↓RAGE, ↓NF-κB | 42 | ||
| APP/PS1 mice | 0.16, 1 g/kg | 6 months | ↑Spatial memory retention, ↑ABCA1, ↑HDL, ↑ApoA1, ↑RXR-α, ↑LXR-β, ↓TC, ↓Platform crossing frequency, ↓Amyloid protein plaques | 43 | ||
| APP/PS1 mice | 100, 200, 300 mg/kg/day | 2 weeks | ↑JMJD3, ↑BDNF, ↑Time spent in target quadrant, ↑Swimming speed, ↑No. of platform crossings, ↓H3K27me3 BDNF, ↓Escape latency | 44 | ||
| APPTG mice | 100 mg/kg/day | 3 months | ↑SIRT3 deacetylation, ↑NAD/NADH, ↑Thrb, ↑Time spent in the target quadrant, ↓Escape latency | 37 | ||
| Wistar Albino rats | 200 mg/kg/day | 7 days | ↓Length to reach the platform, ↓Time to reach the platform, ↓IL-6 | 45 | ||
| ApoE4 transgenic mice | 40 mg/kg/day | 3 weeks | ↑Time spent in the platform, ↑Number of times mice crossed the platform, ↑Improvement in neuronal morphology, ↓ApoE4, ↓TNF-α, ↓IL-1β, ↓Spatial learning deficits, ↓Neuronal cell death, ↓Nuclear translocation of NF-κB, ↓Number of GRP78+ cells, ↓Number of IRE1α+ cells | 46 | ||
| Curcumin α- and β-d-glucoside | Wistar rats | 12.5, 25 mg/kg | 10 days | ↑GSH, ↑FRAP, ↓Memory impairment, ↓Protein carbonyls | 47 | |
| Curcumin, THC | SH-SY5Y cells | 1 μM | 24-48 hours | ↑HSP90, ↑HSP70, ↑Akt, ↓Caspase-3 | 48 | |
| Curcumin derivatives | SH-SY5Y cells | 0.1–10 μM | – | ↑Neuroprotection, ↑GSH, ↓Inflammation, ↓Oxidative stress, ↓p-Tau, ↓ROS, ↓ Nitrites | 49 | |
| Curcumin, Cur-2GE | BV2 | 10 μM | 24 hours | ↓NO production, ↓TNF-α, ↓IL-6 | 50 | |
| Curcugreen | 3xTg, 5xFAD mice | 100 mg/kg | 2 months | Restored spleen & liver cytoarchitecture, ↓Spleen size, ↓Bronchiolar degeneration, ↓Granulomatous inflammation, ↓Apoptotic death, ↓Amyloid deposits, ↓p-Tau | 51 | |
| Cur ME, CurDHA ME | Acute oAβ25–35 C57B1/6 J, J20 transgenic mice | 2 mg/kg | 4 days, 4 weeks (3 times/week) | Restored spatial memory deficits, anxiety & depression, ↑Short-term memory, ↓GFAP, ↓p-Tau, ↓p-JNK2 | 52 | |
| Cur-MNPs | APP/PS1 mice | 25mg/kg | 4 days for 3 consecutive months | ↑Memory, ↑Spatial learning, ↓Escape latency, ↑BDNF, ↑DCX, ↑Neuron generation, ↓Finding the blind platform time, ↓Aβ in brain, ↓Microglia, ↓Inflammation, ↓NLRP3 inflammasome, ↓IL-18, ↓CD68 | 53 | |
| Curcumin nanoparticles | Wistar rats | 10, 50 mg/kg | 6 weeks | ↑GST, ↑CAT, ↑GPx, ↑SOD, ↑IDE, ↑BDNF, ↑ADAM-10, ↑Bcl-2, ↑Normal architecture of pyramidal cells, ↓Memory deficits, ↓NO, ↓Swim time & distance, ↓AGEs, ↓TBARS, ↓TNF-α, ↓IL-1β, ↓Aβ−42, ↓AChE, ↓Bax, ↓p-p38 MAPK, ↓p-ERK, ↓p-MEK, ↓p-Tau, ↓Pyknotic pyramidal cells | 54 | |
| Wistar Albino rats | 50 mg/kg/day | 15 days | ↑GSH, ↑Restoration of NO, ↑Na+-K+- ATPase, ↑Restoration of glutamate, glycine, taurine & GABA, ↓Latency to locate the platform, ↓MDA, ↓TNF-α, ↓AChE, ↓Tau, ↓Pyknotic neurons | 55 | ||
| Curcumin lipid core NPs | Swiss mice | 10 mg/kg | Alternate days for 12 days | ↓Non-aversive memory impairment, ↓Inflammation, ↓COX-2 | 56 | |
| Curcumin loaded T807/RPCNP | Primary astrocytes, HT22 | 5 μg/mL | 12 hours | ↑p-PKB, ↓p-Tau, ↓Mitochondrial ROS, ↓Apoptosis, ↓GSK-3β, ↓Astrocytes activation | 57 | |
| OA treated mice | 2 mg/kg, every two days | 10 days | ↑Spatial learning & memory, ↓p-Tau, ↓Cognitive impairment, ↓Neuronal cell death, ↓Abnormal activation of microglia | 57 | ||
| Bisdemethoxycurcumin | SK-N-SH cells | 15 μM | 30 min | ↑Cell survival, ↑p-AMPK, ↑Anti-oxidative stress ability, ↑SIRT1, ↑SOD, ↑GSH | 58 | |
| C57BL/6, APP/PS | 5 μg/kg/day | 1 month | ↑Improvement in cognitive function, ↑Number of neurons, ↑SIRT1, ↓Oxidative stress, ↓Aβ deposition | 59 | ||
| PGC | N2a cells, BV2 | 1, 10, 25 μM | – | ↓Aβ aggregation, ↓Aβ-induced neurotoxicity, ↓β-secretase, ↓Aβ-induced ROS, ↓Aβ-induced inflammation | 60 | |
| aluminium-induced AD rats | 16.5 mg/kg | 4 weeks | ↑Hippocampal activity, ↓Abnormal cells with nuclear condensation, ↓Aβ deposition & aggregation, ↓Neurodegeneration | 60 | ||
| pHDL/Cur-siBACE1 | BV2, SH-SY5Y | – | – | ↑IκBα, ↓Aβ, ↓Inflammatory cytokine release, ↓TNF-α, ↓IL-6, ↓IL-1β | 61 | |
| APP/PS1 mice | 200 μL (curcumin, 5.6 mg/kg & siBACE1, 0.71mg/kg) | Every 4 days for 7 times | ↑Focused search strategies, ↓Aβ burden, ↓NF-κB, ↓Escape latency, ↓Memory deficits, ↓Neuronal inflammation | 61 | ||
| Solid-lipid curcumin NPs | 5xFAD mice | 100 mg/kg | 2 months | ↑Discrimination index, ↑Exploration index, ↑Synaptophysin, ↑PSD95, ↑CREB, ↑p-CREB, ↓Spatial memory deficits, ↓Pyknotic cells, ↓Neurodegeneration, ↓Aβ plaque load, ↓Loss in dendritic branching & sprouting, ↓Loss in dendritic spines | 62 | |
| THC | BV2 | 0.1, 5, 20 μM | 24 hours | ↑Gab2, ↑K-Ras, ↑Cell viability in presence of Aβ, ↓Aβ-induced G1/S arrest, ↓Aβ -induced apoptosis, ↓Caspase-3 | 63 | |
| APP/PS1 mice | 400 mg/kg/day | 5 months | ↑Gab2, ↑K-Ras, ↑Learning & memory, ↓Escape latency, ↓Aβ burden, ↓Aβ42/Aβ40, ↓TNF-α, ↓TGF-β1 | 63 | ||
| Amyotrophic lateral sclerosis (ALS) | ||||||
| ALS | Curcumin | THP-1 cells | 0.5, 1, 5, 10, 20, 30 μM | 6, 24, 72 hours | ↓SOD1 aggregates, ↓Cell death | 64 |
| Curcumin NP | THP-1 cells | 0.5, 1, 5, 10, 20, 30 μM | 6, 24, 72 hours | ↓SOD1 aggregates, ↓Cell death | 64 | |
| DMC | NSC-34 with TDP-43 mutation | 15 μM | 3 days | ↑Complex I activity, ↑MMPo, ↑UCP2, ↓Mitochondrial swelling, ↓Cristal dilation | 65 | |
| DMC | NSC-34 | 15 μM | 24 hours | ↓WT & Q331K TDP-43-induced abnormal inactivation of Nav current, ↓Abnormal APs | 66 | |
| Monocarbonyl dimethoxy curcumin C | NSC-34 | 10 μM | 24 hours | ↑HO-1, ↓Insoluble TDP-43 fragments, ↓TDP-25, ↓Size of TDP-25 aggregates, ↓LDH, ↓MDA | 67 | |
| Canine DM | Curcumin | Dogs (PWC breed) | 13 mg | 1 to 2 divided doses | ↑Survival, ↓Non-weight bearing of hind/ thoracic limb | 68 |
| Epilepsy and Seizures | ||||||
| Curcumin | Organotypic slice culture model of hippocampus & entorhinal cortex obtained from Sprague-Dawley rats | 10 μmol/L | Every day from day 2 culture | ↑HMOX1, ↓Average AP frequency, ↓Seizure-like events, ↓pS6, ↓p-pS6Ser240/244, ↓p-MAPK, ↓IL-6, ↓IL-1β, ↓TGF-β | 69 | |
| Swiss albino inbred mice | 50, 100, 200 mg/kg | 21 days | ↑Seizure threshold, ↑Locomotor activity, ↑Protection against post-ictal mortality | 70 | ||
| Wistar rats | 1500 ppm | 5 weeks | ↑Prevention of grade III seizures, ↑Na-K ATPase activity, ↓DPH anisotropy, ↑Ambulatory activity, ↑Normal cellular architecture, ↓Onset & progression of seizures, ↓Lipid peroxidation, ↓Protein oxidation, ↓PKC activity, ↓Defecation, ↓Epilepsy-related memory decline | 71 | ||
| Sprague-Dawley rats | 10, 30, 100, 300 mg/kg | Throughout the kindling days | ↑After discharge threshold, ↑Stimulation current intensity required to evoke after discharge, ↓Behavioural seizure development | 72 | ||
| Albino Wistar rats | 50, 100, 200 mg/kg | 30 mins before KA treatment | ↑Mean latency of convulsion, ↓Percentage of convulsions, ↓MDA, ↓fall in GSH | 73 | ||
| Wistar rats | 100, 200, 300 mg/kg | 30 mins prior to PTZ treatment | ↑Delay in kindling development, ↑Latency to myoclonic jerks, ↑Latency to GTCS, ↑GSH, ↑Latency to clonic seizures, ↓Seizure severity, ↓Number of myoclonic jerks, ↓Duration of GTCS, ↓Retention transfer latency, ↓MDA | 74 | ||
| Wistar rats | 300 mg/kg | Prior to PTZ or MES | ↑Latency to myoclonic jerks, ↑Protection against GTCS, ↑GSH, ↓Retention transfer latency, ↓MDA | 75 | ||
| Sprague-Dawley rats | 30, 100, 300 mg/kg/day | 5 days | ↑Delayed onset of seizures, ↑SOD, ↑GSH, ↓Occurrence of seizures, ↓LDH | 76 | ||
| Wistar albino rats | 80 mg/kg | 21 days | ↑GSH, ↑Na-K ATPase activity, ↓AChE, ↓MDA, ↓NO, ↓CAT | 77 | ||
| Swiss albino mice | 50, 100, 200 mg/kg/p.o. | – | ↑GSH, ↓Incidence & seizure score, ↓MDA | 78 | ||
| Sprague-Dawley rats | 50, 100, 200 mg/kg | 3 days prior to Li & Pc administration | ↑Latency to seizure & SE, ↑Time spent in target quadrant, ↑Cognitive performance, ↑GSH, ↓Percentage of seizure & SE, ↓Frequency of seizure, PCS & STM episodes, ↓TBARS, ↓Mortality | 79 | ||
| Swiss albino mice | 50, 100, 200 mg/kg | 15 days after the last dose of PTZ | ↑Step down latency, ↑Brain norepinephrine, ↑Brain serotonin, ↓Seizure severity score, ↓Immobility period, ↓Number of mistakes, ↓Nitrite, ↓AChE | 80 | ||
| Wistar rats | 100 mg/kg/day | 1 week prior to surgery | ↓Seizure score, ↓SE, ↓MDA, ↓Nitrite & nitrate, ↓Neurodegeneration, ↓MFS width & staining density | 81 | ||
| Wistar rats | 100 mg/kg/day | 40 days | ↑GSH, ↑Cell devoid of pyknosis, ↑Entering safe compartment, ↑Latency to enter dark compartment, ↑Long term memory, ↓ROS, ↓Mitochondrial swelling, ↓MDA, ↓Mitochondrial structural abnormality | 82 | ||
| Wistar rats | 100 mg/kg | 40 days | ↓GFAP, ↓Iba-1, ↓Astrocyte & microglia activation, ↓TNF-α, ↓IL-1β, ↓IL-6, ↓MCP-1, ↓Escape latency | 83 | ||
| Wistar rats | 50, 100, 200 mg/kg | 24 days | ↑Protection against seizures, ↓Mean frequency of interictal discharge, ↓Mean frequency of epileptiform discharge | 84 | ||
| Wistar rats | 100 mg/kg | 14 days | ↑Time spent in target quadrant, ↓TNF-α, ↓IL-1β, ↓GFAP positive cells, ↓Activation of astrocytes, ↓Neuronal loss, ↓Severity of MFS, ↓Frequency of abnormal spikes, ↓Degree of SRS, ↓Escape latency | 85 | ||
| Wistar rats | 100, 200, 300 mg/kg | 1 hour prior to PTZ injection | ↑Latency to myoclonic jerks, ↑Latency to clonic seizures, ↑Latency to tonic-clonic seizures, ↓Seizure severity, ↓Oxidative stress, ↓Neuronal injury | 86 | ||
| Sprague-Dawley rats | 200, 300 mg/kg | 2 weeks | ↑Surviving neurons, ↑Beclin-1, ↑LC3BII/I, ↑Autophagosomes, ↓RIP-1, ↓Apoptotic neurons, ↓MLKL | 87 | ||
| Mice | 150 mg/kg | 25 mins prior to PTZ injection | ↑Seizure latency, ↑Tonic-clonic latency, ↑HTR7, ↓Duration of tonic & tonic-clonic seizures, ↓Death & falling parameters | 88 | ||
| Wistar rats | 100 mg/kg | 5 months before induction of epilepsy & 1 after induction of epilepsy | ↓Epileptiform activity, ↓Nav1.1, ↓Nav1.6, ↓Development & occurrence of seizures, ↓Epilepsy-associated MUA | 89 | ||
| Sprague-Dawley rats | 40, 80 μM | 4 days prior to PTZ injection | ↑Number of stimulations required to reach Racine stage IV seizures, ↑Delay in onset of seizures | 90 | ||
| Wistar rats | 80 mg/kg | 4 days | ↑Latency to onset of spasms & isolated clonic seizures ↓Duration of seizures, ↓Damage to hippocampus, ↓Seizure severity, ↓Muscle contraction, ↓Apoptosis | 91 | ||
| Curcuminoids | Wistar rats | 100 mg/kg | 7 days | ↑IL10RB, ↑CXCL16, ↑CXCL17, ↑NCSTN, ↑CX3CL1, ↑CX3CR1, ↑C3AR1, ↑CTSA, ↑CTSD | 92 | |
| Curcumin + Diazepam | Wistar rats | 80 mg/kg + 5 mg/kg | 4 days prior to PTZ injection | ↑Latency to onset of spasms & isolated clonic seizures ↓Duration of seizures, ↓Damage to hippocampus, ↓Seizure severity, ↓Muscle contraction, ↓Apoptosis | 91 | |
| Curcumin + Piperine | Wistar rats (pregnant) | 60 mg/kg + 10 mg/kg | Day 0 of gestation until parturition | ↑Working memory, ↑Correct entries to goal box, ↓TLR4 in pups, ↓Hyperthermia, ↓TNF-α, ↓IL-10, ↓IL-1β, ↓MDA | 93 | |
| Curcumin Nanoparticles | Wistar rats | 50 mg/kg | 4 days prior to atropine & pilocarpine administration | ↑AChE activity, ↑GSH, ↑ NO, ↓Oxidative stress, ↓Hippocampal TNF-α, ↓Caspase-3 | 94 | |
| Liposomal curcumin | Swiss albino mice | 25, 50 mg/kg | – | ↑Seizure threshold, ↑Latency to myoclonic jerk, ↑Latency to clonic seizures, ↓Duration of clonic seizure | 95 | |
| Micronized curcumin | Zebra fish (adult & larvae) | 0.5 mg/kg & 1 μM | – | ↓Locomotion, ↓Seizure occurrence, ↓Occurrence of tonic-clonic seizures, ↓Occurrence of stage III seizures | 96 | |
| Huntington's disease | ||||||
| Curcumin | CAG140 mice | 555 ppm | 23 weeks | ↑DARPP-32, ↑D1 receptor, ↑Rearing, ↓D1, ↓CB1, ↓Huntingtin stained nuclei & aggregates, ↓Neuropil aggregates | 97 | |
| Drosophila | 3, 5, 10, 15, 20 μM | 1, 7, 14 days post-eclosion | ↑Improvement in crawling ability, ↓Photoreceptor neuron degeneration, ↓Internal eye morphological defects, ↓Eye roughness, ↓Loss of pigmentation in eye, ↓Progressive loss of locomotion, ↓AO- positive cells, ↓Apoptotic cell death in eye discs, ↓Poly-Q-induced cytotoxicity | 98 | ||
| Drosophila | 10 μM | 12 hours, 1, 7, 13 days after eclosion | ↑Per, ↑Tim, ↓Motor deficits | 99 | ||
| Drosophila | 10, 15, 20 μM | From larval stage to till day 15 post eclosion | ↑Improvement in motor activity, ↑Median survival, ↑dSREBP, ↓Abnormal body weight, ↓Abnormal dry weight, ↓Elevation in H2O content, ↓Trehalose levels, ↓Dysregulation in total lipid content, ↓Lipid droplet size, ↓ROS, ↓Free radicals | 100 | ||
| Curcumin, Bioperine | R6/2 line of transgenic mice | 25 mg/kg, 1 mg/ kg | Entire gestation period, 3 weeks after offspring birth | ↑DARPP-32, ↑p-Akt, ↑p-ERK, ↑Preserved normal levels of BDNF, ↑Normal intestinal function, ↑Intestinal emptying, ↑Intestinal contractility, ↑Claudin-2, ↑ZO-1, ↑Occludin, ↓Motor deficit ↓Hind clasping behavior, ↓Brain weight loss, ↓Number of EM48+mHtt aggregates, ↓Body weight loss, ↓Villi loss and atrophy, ↓PAS+ globet cells | 101 | |
| C-SLN | Wistar rats | 40 mg/kg/day | 7 days | ↑SDH, ↑MTT reduction rate, ↑NADH dehydrogenase, ↑Cytochrome c oxidase, ↑Mitochondrial F1F0 synthase activity, ↑Cytochrome a, b, c1 & c, ↑GSH, ↑SOD, ↑Cytosolic & nuclear Nrf2, ↑Locomotor activity, ↑Average velocity to traverse the beam, ↑Stride length, ↓Mitochondrial swelling, ↓MDA, ↓Protein carbonyl, ↓ROS, ↓Total time to traverse the beam, ↓Distance between the two paws, ↓Stride width, ↓Gait angle | 102 | |
| SLCPs | YAC128 transgenic mice | 100 mg/kg/day | Alternate days for 8 weeks | ↑Length of dendrites, ↑Dendritic spine density, ↓Learning memory deficits, ↓Latency to escape, ↓PSD-95 | 103 | |
| Migraine | ||||||
| Curcumin | HUVECs | 10, 20, 30, 40, 50 μM | 12 hours | ↑Cell viability after H2O2 treatment, ↑GSH, ↑SOD, ↑Bcl-2, ↓LDH, ↓ROS, ↓MDA, ↓p21, ↓Bax, ↓p53, ↓Caspase-3 | 104 | |
| Wistar-Bratislava albino rats | 100 mg/kg | 14 days | ↓MDA, ↓NO, ↓TOS, ↓Flinches, ↓Shakes | 105 | ||
| Wistar-Bratislava albino rats | 10, 20 mg/kg | 30 mins after NTG injection | ↑Total anti-oxidant capacity, ↑Thiols, ↓MDA, ↓TOS, ↓Flinches, ↓Shakes | 106 | ||
| Wistar rats | 10, 20 mg/kg | 60 mins before NTG administration | ↑Total anti-oxidant capacity, ↓Flinches, ↓Shakes, ↓Biphasic response to nociceptive receptors | 107 | ||
| Liposomal curcumin | Wistar-Bratislava albino rats | 10, 20 mg/kg | 30 mins after NTG injection | ↑Total anti-oxidant capacity, ↑Thiols, ↓MDA, ↓TOS, ↓Flinches, ↓Shakes | 106 | |
| Wistar rats | 10, 20 mg/kg | 60 mins before NTG administration | ↑Total anti-oxidant capacity, ↓Flinches, ↓Shakes, ↓Biphasic response to nociceptive receptors | 107 | ||
| Multiple sclerosis | ||||||
| Curcumin | T cells | 0.5-10 μg/mL | 48 hours | ↓IL-12, ↓p-JAK2, ↓p-TK2, ↓STAT3, ↓STAT4, ↓T cell proliferation | 108 | |
| CD4+ T cells | 5, 10, 20, 40, 60 μM | 24, 48, 72 hours | ↑Apoptosis, ↑Bax, ↓Cell proliferation, ↑Caspase-3, ↓Colony formation, ↓Bcl-2, ↓CD25, ↓CD44 | 109 | ||
| BV-2 cells | 1–500 μM | 24 hours | ↑IL-10, ↓NO, ↓IL-6, ↓TNF-α, ↓iNOS, ↓AXL, ↓p-JAK2, ↓p-STAT3 | 110 | ||
| C8-D1A cells | 10, 20, 50 μM | 20, 24, 72 hours | ↑Cell proliferation at low concentration, ↓IL-2, ↓IL-6, ↓TNF-α, ↓IL-17A, ↓IFNγ | 111 | ||
| SJL/J mice | 50, 100 μg | Every other day for 25 days | ↓Clinical severity & duration, ↓IFNγ, ↓Inflammation, ↓Demyelination, ↓IL-12 | 108 | ||
| Lewis rats | 100, 200 mg/kg | 14 days | ↓MMCS, ↓Disease severity, ↓Immune cell infiltration, ↓Th17 cell proliferation, ↓IL-17 | 112 | ||
| C57BL/6 mice | 100 μg/day | 14 days (alternate day) | ↑T-bet, ↑IL-4, ↑IL-10, ↓Mean clinical score, ↓IFNγ, ↓IL-17, ↓CD4+IFNγ+ & CD4+IL-17+ T cells, ↓IL-12, ↓IL-23 | 113 | ||
| C57BL/6 mice | 20 mg/kg | 21 days | ↑Forelimb strength, ↑TGF-β, ↑SOD, ↓Disease severity, ↓Disease onset scores, ↓Weight loss, ↓IL-6, ↓TNF-α, ↓IL-17A, ↓IFNγ, ↓Demyelination | 114 | ||
| C57BL/6 mice | 10 mg/kg/day | 15 days | ↑LC3II, ↑Beclin, ↑Atg5, ↓p-Akt, ↓p-mTOR, ↓Infiltrated immune cells, ↓Demyelination, ↓p62, ↓IL-17, ↓IFNγ | 115 | ||
| Wistar rats | 20, 40 μg/kg | 5 days | ↑Distance travelled, ↓TAC, ↓CAT, ↓Escape latency, ↓SOD, ↓MDA | 116 | ||
| Wistar rats | 100 mg/kg/day | From 12th day for 24 days | ↑MBP, ↑Reduction in weight loss, ↓iNOS, ↓Cumulative disease disability, ↓NOGO-A | 117 | ||
| C56BL/6 mice | 100 mg/kg | 2 days prior to immunization to 21 days post immunization | ↓Infiltrated immune cells, ↓Demyelination, ↑Arg-I, ↑IL-10, ↑TGF-β, ↓COX-2, ↓IL-1β, ↓iNOS, ↓Activation of microglia, ↓AXL, ↓TMEM119 | 110 | ||
| C56BL/6 mice | 100 mg/kg | 15 days | ↑Sniffing of the novel object, ↑GSH, ↑SOD, ↑MBP, ↓Neurological severity, ↓Paralysis with neurological score, ↓Infiltration of immune cells, ↓Demyelination in spinal cord, ↓LTCD3, ↓LTCD4, ↓Behavioral abnormality, ↓MDA | 111 | ||
| Curcumin-linoleic acid conjugate | Wistar rats | 20, 40 μg/kg | 5 days | ↑Distance travelled, ↑TAC, ↓CAT, ↓Escape latency, ↓SOD, ↓MDA | 116 | |
| Dendrosomal nanocurcumin | NSCs | 1, 5 μM | 24 hours | ↑NSCs proliferation, ↑MAP2+ cells, ↑MBP+ cells, ↑NeuN, ↑Olig2, ↑Remyelination, ↑Differentiation of NSCs into oligodendroglial cells, ↓Differentiation of NSCs into astrocytes | 118 | |
| C57BL/6 mice | 12.5 mg/kg | 3 weeks | ↑Remyelination, ↑MBP, ↑CC1+/Olig2+ cells | 118 | ||
| C57BL/6 mice | 12.5 mg/kg | 6 weeks | ↑Olig2+ cells, ↑LFB staining, ↑MBP, ↓Number of microglial cells, ↓GFAP+ cells, ↓Astrocyte activation | 119 | ||
| Curcumin loaded HDL mimicking peptide-phospholipid scaffold | C57BL/6 mice | 1.8 mg/kg | 4 alternate days from 8th day (i.e. 8th, 10th, 12th, and 14th day) | ↑Delay in disease progression, ↓Morbidity, ↓Immune cell infiltration, ↓CD45+ cells, ↓CD45+CD11b+Ly6C+CCR2+ monocytes infiltration, ↓CD11b+ cells, ↓CD3+ T cells, ↓Th1 cells, ↓Th17 cells, ↓DC maturation, ↓DIR-BOA+ monocytes | 120 | |
| Polymerized nanocurcumin | Lewis rats | 12.5 mg/kg/day | Day 12–29 post- immunization | ↑Myelination, ↑IL-4, ↑IL-10, ↑HO-1, ↑NGF, ↑MBP, ↑Nestin, ↑Olig2, ↑PDGFR-α, ↓Peak & cumulative EAE scores, ↓MCP-1, ↓IL-1, ↓Demyelination, ↓iNOS, ↓EAE score, ↓TNF-α receptor, ↓IL-17, ↓CD8 | 121 | |
| Neuroblastoma | ||||||
| Curcumin | SH-SY5Y | 2.5, 5, 10, 20, 40, 80 μM | 2–24 hours | ↑Nuclear translocation of TFEB, ↑HO-1, ↑LAMP-1, ↑LC3II, ↑Nrf2 translocation, ↑MCOLN1, ↓GSK-3β, ↓p62, ↓ROS, ↓Aggregation of APP | 122 | |
| SH-SY5Y | 1, 2.5, 5, 10, 15 μM | 24 hours | ↓p-JNK/JNK ratio, ↓p-ERK, ↓p-Tau, ↓LC3BII/I, ↓H2O2-induced oxidative stress, ↓UBC9, ↓SUMO-1ylation | 123 | ||
| Curcumin, Curcumin-Mn complexes | NG108–15 | 1–50 μg/mL | - | ↑Cell viability, ↓H2O2, ↓Oxidative stress | 124 | |
| Neurotoxicity | ||||||
| aluminium- induced toxicity | curcumin | wistar rats | 100 mg/kg/day | 60 days | ↑Mg2+, ↑CAT, ↑Na+-K+-ATPase activity, ↑Mg2+ATPase activity, ↑Improvement in hippocampal structure, ↓Ca2+ | 125 |
| Curcumin | Wistar albino rats | 100 mg/Kg | 60, 90 days | ↑Body weight, ↑Memory recognition, ↑SOD, ↑CAT, ↑Hippocampal cell viability, ↑Normal morphology of neuronal cells, ↓Memory deficit, ↓Absolute hippocampus weight, ↓Time spent in the dark room, ↓Hippocampal AChE, ↓MDA, ↓Oxidative stress, ↓IFNγ, ↓IL-4, ↓Karyopyknotic neuronal cells, ↓Neutrophil infiltration, ↓Neurofibrillary tangles, ↓Hippocampal cell apoptosis | 126 | |
| Parkinson disease | ||||||
| Curcumin | PC12 cells | 20, 40 μmol/L | 24 hours | ↑Bcl-2, ↓MPP+-induced cytotoxicity & apoptosis, ↓Loss of MMPo, ↑Attenuation of ROS increase, ↓iNOS | 127 | |
| SH-SY5Y cells | 5, 10, 50 μM | 24, 48 hours | ↑α-Synuclein solubility, ↓α-Synuclein aggregation | 128 | ||
| MES23.5 cells | 10, 15 μmol/L | – | ↑Restoration of MMPo, ↑SOD, ↓6-OHDA-induced cytotoxicity, ↓ROS, ↓6-OHDA-induced NF-κB translocation | 129 | ||
| Rat mesencephalic cells | 10 nM | 3, 6, 12, 24 hours | ↑LRRK2 | 130 | ||
| SH-SY5Y cells | 0.5, 1, 5, 10, 25, 50 μM | 18 hours | ↑Cell viability, ↓MPP+-induced cell death, ↓MPP+-induced nuclear condensation, ↓MPP+-induced cleaved caspase-3, p-JNK, MKK4 activation, & p-c-Jun | 131 | ||
| SH-SY5Y cells | 4 μM | 2-24 hours | ↓α-Synuclein-induced toxicity, ROS, caspase-3 activity, & apoptosis | 132 | ||
| SH-SY5Y cells | 5, 10, 20 μM | 30 mins prior to 6-OHDA treatment | ↑Cell viability, ↓6-OHDA-induced cytotoxicity, ↓6-OHDA-induced cell death, ↓6-OHDA-induced ROS, ↓Bax/Bcl-2 ratio, ↓p-p53 | 133 | ||
| PC12 cells | 500 nM | – | ↓α-Synuclein-induced toxicity, cell death, ROS, mitochondrial depolarization, cytochrome c release, caspase-3 activity, caspase-9 activity | 134 | ||
| Deutocerebrum primary cells | 5, 10, 15 μmol/L | 6 days | ↑Cell viability, ↑Cell adhesion, ↑Normal cell morphology, ↑SOD, ↑GSH-Px, ↑Wnt3a, ↑β-catenin, ↑c-MYC, ↑Cyclin D1, ↓MDA, ↓Apoptosis, ↓MMPo | 135 | ||
| SH-SY5Y PD cells | 1, 2.5, 5, 10, 20, 25 μmol/L | 24, 48 hours | ↑Cell proliferation, ↑MAP2 cells, ↑TH- positive cells, ↓Apoptosis | 136 | ||
| PC12 cells | 0.5, 1, 2, 5, 10 μM | 6 hours | ↑Beclin-1, ↓6-OHDA-induced apoptosis, ↓ROS, ↓MDA, ↓p-Akt, ↓p-mTOR | 137 | ||
| Sprague-Dawley rats | 50 mg/kg | Daily for 4 days prior to 6-OHDA injection | ↓Mean percentage of TH-positive cell loss, ↓Loss of DOPAC, ↓Loss of HVA | 138 | ||
| Swiss albino mice | 80 mg/kg | 7 days | ↑SOD, ↑CAT, ↑GSH, ↓Lipid peroxidation | 139 | ||
| C57BL/6 mice | 50 mg/kg/day | 7 days | ↑Locomotion frequencies, ↑Traction scores, ↑Rearing frequencies, ↓MPTP-induced impairment in dopamine nervous system, ↓Activated astrocytes, ↓p-JNK1/2, ↓c-Jun, ↓Cleaved caspase-3 | 131 | ||
| Wistar rats | 50 mg/kg/day | 10 days | ↑Locomotion, ↑Number of Nissl neurons, ↓Bax/Bcl-2 | 140 | ||
| Wistar rats | 50 mg/kg | 24 days | ↑DOPAC, ↑TH-positive cells, ↓Iron stained cells | 141 | ||
| ICR mice | 200 mg/kg | 7 days | ↑TH-positive cells, ↓Microglia activation, ↓Astrocyte activation | 142 | ||
| ICR mice | 200 mg/kg/day | 7 days | ↑TH-positive cells, ↓Loss of DA neurons, ↓Microglia activation, ↓GFAP | 143 | ||
| Sprague-Dawley rats | 5, 10, 20 mg/kg/day | 30 days | ↑SOD, ↑GSH-Px, ↑AChE, ↑Improvement in neuroethological condition, ↑DA, ↑ SN cell mass, ↑SN cell cytoarchitecture, ↑bFGF, ↑NGF, ↑TrkA, ↑Hsp70, ↓Aberrated alteration in behaviour, ↓MDA | 144 | ||
| Sprague-Dawley rats | 10 μmol/L | One each day for 3 consecutive days | ↑Motor latency, ↑SOD, ↑Residence time on rotarod, ↑GSH-Px, ↑TH-positive cells, ↑Wnt3a, ↑β-catenin, ↑c-MYC, ↑Cyclin D1, ↓Rotation numbers, ↓Dopaminergic neuron death, ↓GFAP astrocytes activation, ↓MDA | 135 | ||
| Swiss albino mice | 80 mg/kg/day | 12 days | ↑Time spent on wire, ↑NE level, ↑DA level, ↑GSH, ↑SOD, ↑ATP, ↑SDH, ↓CRP, ↓IL-6, ↓A2AR expression, ↓α-synuclein, ↓MDA, ↓Ang-II, ↓Caspase-3, ↓DNA fragmentation, ↓Neurodegeneration changes in cells | 145 | ||
| C57BL mice transplanted with hUC- MSCs-CUR | – | – | ↑Improvement in rearing, ↑TH-positive cells, ↑Bcl-2, ↑DA levels, ↑IL-10, ↑HGF, ↑NGF, ↑VEGF, ↑G-CSF, ↓NADPH-d, ↓Bax, ↓Caspase-3, ↓Drop frequency | 136 | ||
| 6-OHDA lesioned Parkinsonian rats | 200 mg/kg | 2 weeks pre- and post- surgery | ↑TH-positive cells, ↑Neuroprotective effect, ↑Neuronal count | 146 | ||
| 6-OHDA lesioned Parkinsonian rats | 50 mg/kg/day | 2 weeks | ↑Parkinsonian disability score, ↑Autophagy score, ↓α-Synuclein, ↓TH, ↓p62 | 137 | ||
| Curcumin, Curcumin-Mn complexes | ICR mice | 6.25, 25, 50 mg/kg | Three times at 1, 3, 7 hours post MPTP injection | ↑Cognitive functions, ↓Learning memory impairment, ↓MPTP-induced striatal dopamine depletion, ↓Oxidative stress, ↓Dopaminergic neuronal damage | 124 | |
| Curcumin, Rotenone | Swiss albino mice | 50, 100, 200 mg/kg, 1 mg/kg | 3 weeks | ↑Improvement in rotarod activity, ↑Recovery of retention time on rotarod, ↑Improvement in locomotor activity, ↑Improvement in rearing, ↑Immobility time, ↑Grooming behaviour, ↑SOD, ↑GSH, ↑CAT, ↑SDH, ↑MTT reduction activity, ↓MDA, ↓Nitrite, ↓AChE | 147 | |
| Curcumin, THC | Swiss albino mice | 20, 40, 80, 160 mg/kg, 60 mg/kg | 7 days | ↑DA, ↑DOPAC, ↓MAO-B activity | 148 | |
| Curcumin monoglucoside | N27 cells | 0.25, 0.5, 1, 2.5 5 μM | 24 hours | ↑Cell viability, ↑GSH, ↑NQO1, ↑Complex I & complex IV activities, ↓LDH release, ↓ROS, ↓Hydroperoxides, ↓MDA, ↓NOS2, ↓DNA damage, ↓p-JNK, ↓p-c-Jun, ↓Cleaved procaspase-3 | 149 | |
| D. melanogaster | 10, 100, 500, 1000 μM | 14 days | ↑Free radicals scavenging, ↑GSH, ↓Mortality, ↓Locomotor deficits, ↓Turnover of DA, ↓(DOPAC+HVA)/DA | 149 | ||
| Curcumin nano emulsions | Swiss mice | 25, 50 mg/kg/day | 30 days | ↑Total distance travelled, ↑Number of rearings, ↑CAT, ↑Exploratory activity, ↑Improvement in balance, ↑GR activity, ↓Number of slip steps, ↓Bradykinesia, ↓TBARS, ↓GSH-Px, ↓Complex I inhibition by ROT | 150 | |
| Curcumin loaded HSA NPs | C. elegans | 10, 30 μg/mL | 24, 72, 120 hours | ↑Delay in age-related deterioration of movement, ↑Alcohol avoidance, ↑DA, transportation, ↓Movement speed | 151 | |
| hEnSCs-EXOs-CUR | PC12 cells | – | – | ↑Cell viability | 152 | |
| C57BL/6 mice | 1 mg/mL | 10 times every other day for 28 days | ↑TH-positive cells, ↑Motor latency, ↑Bcl-2, ↓Rotational numbers, ↓α-Synuclein, ↓Bax, ↓Caspase-3 | 152 | ||
| PR-EXO/PP@CUR nanocarrier | C57BL/6 mice | 9, 12 μg/mL curcumin | 6 h | ↑Improvement in movement, ↑Improvement in coordination ability, ↑DA, ↑DOPAC, ↓α-Synuclein aggregates, ↓TNF-α, ↓IL-1β, ↓IL-6 | 153 | |
| Soluplus-curcumin formulation | C57BL/6 mice | 48 mg/kg | 8 weeks (from 2 weeks after the LPS injection until the end of the study) | ↓Parkin protein, ↓p-Rab-10, ↓PINK1 | 154 | |
| Traumatic brain injury | ||||||
| Curcumin | Microglia | 0.5, 1, 2, 5, 10 μM | – | ↑IκB-α, ↓Cleaved caspase-3, ↓Neuronal damage, ↓Microglia activation, ↓IL-6, ↓IL-1β, ↓p-IκB-α, ↓NF-κB, ↓RANTES | 155 | |
| Sprague-Dawley rats | 500 ppm | 4 weeks | ↑BDNF, ↑p-Synapsin I, ↑Swimming timing in the target zone, ↓Oxidized proteins, ↓Escape latency | 156 | ||
| Sprague-Dawley rats | 500 ppm | 4 weeks | ↑p-AMPK/AMPK, ↑uMtCK, ↑UCP2, ↑Sir2, ↑COX-2 | 157 | ||
| CD-1 mice | 75, 150, 300 mg/kg | 15 mins prior to TBI or 30 mins to 1hr prior to TBI | ↑Overall locomotion, ↑Time spent on exploring a novel object, ↓Brain water content, ↓Cerebral edema, ↓AQP4, ↓IL-1β, ↓GFAP, ↓p-NF-κB | 158 | ||
| Wistar rats | 50, 100 mg/kg | 5 days before TBI | ↑Motor performance, ↑Recovery of balance, ↓Lesion volume, ↓MDA | 159 | ||
| C57BL/6 mice | 50, 100, 200 mg/kg | 15 mins post TBI | ↑IκB-α, ↓TLR4, ↓Cerebral edema, ↓Brain water content, ↓MCP-1, ↓IL-1β, ↓IL-6, ↓TLR4+ microglia/macrophages, ↓TNF-α, ↓RANTES, ↓NF-κB, ↓p-IκB-α, ↓MyD88 | 155 | ||
| ICR mice | 50, 100 mg/kg | 30 mins post TBI | ↑Bcl-2, ↑GSH-Px, ↑SOD, ↑HO-1, ↑NQO-1, ↑Nuclear Nrf2, ↓NSS score, ↓Brain water content, ↓Cerebral edema, ↓Neuronal apoptosis, ↓Cleaved caspase-3 | 160 | ||
| C57BL/6 mice | 50 mg/kg | 15 mins post TBI | ↑Nuclear Nrf2, ↑HO-1, ↑NQO-1, ↑Bcl-2, ↓Cleaved caspase-3, ↓MPO+ cells, ↓TNF-α, ↓IL-1β, ↓IL-6, ↓MDA | 161 | ||
| Sprague-Dawley rats | 100 mg/kg/day | Every other day for 7 days | ↑Body weight, ↑Liver weight, ↑T3, ↑T4, ↑TSH, ↑SOD, ↑Tg, ↑FOXE1, ↑TSHR, ↑TSHβ, ↓Thyroid weight, ↓MDA, ↓TRHR, ↓TTR, ↓GSH-Px, ↓Infiltration of immune cells, ↓ROS, ↓NF-κB, ↓Follicular cavity size, ↓PAX8, ↓TTF1, ↓NIS, ↓TPO | 162 | ||
| CNB-001 | Sprague-Dawley rats | 500 ppm | 2 weeks | ↑BDNF, ↑Synapsin I, ↑CREB, ↑SOD, ↑Learning ability, ↓Foot faults, ↓Oxidized protein levels | 163 | |
| THC | Sprague-Dawley rats | 10, 25, 50 mg/kg | 30 mins post TBI | ↑Nrf2 nuclear translocation, ↑Bcl-2, ↑SOD, ↑GSH-Px, ↓Cerebral edema, ↓Brain water content, ↓Neuronal degeneration, ↓Bax, ↓Cleaved caspase-3, ↓MDA | 164 | |
| Sprague-Dawley rats | 25, 50 mg/kg | 30 mins post TBI | ↑LC3II, ↑Beclin, ↑p-Akt, ↓Neurological deficits, ↓Brain water content, ↓Number of damaged neurons, ↓Neuronal apoptosis, ↓Cleaved caspase-3, ↓p62 | 165 | ||
| CM-NPs | Wistar rats | 50 mg/kg | Post TBI for 10 days | ↓mNSS score, ↓Brain water content, ↓Cerebral edema, ↓Iba-1+ cells, ↓GFAP+ cells, ↓TLR4+ cells, ↓NF-κB+ cells | 166 | |
Abbreviations.
6-OHDA, 6‑hydroxy dopamine; A2AR, Adenosine 2A receptor; ABCA1, ATP-binding cassette subfamily A member 1; Aβ42, Amyloid beta 42; AChE, Acetylcholinesterase; ADAM10, ADAM metallopeptidase domain 10; AGE, Advanced glycation end products; ALS, Amyotrophic lateral sclerosis; AMP, Adenosine monophosphate; AMPK, AMP-activated protein kinase; Ang-II, Angiotensin II; AO, Acridine orange; ApoA1, Apolipoprotein A1; ApoE4, Apolipoprotein E4; APP, Amyloid beta precursor protein; Aps, Action potentials; AQP4, Aquaporin 4; Arg-I, Arginase 1; Atg5; Autophagy related gene 5; ATP, Adenosine triphosphate; Bax, Bcl-2 associated X-protein; Bcl-2, B cell lymphoma 2; BDNF, Brain-derived neurotrophic factor; bFGF, Basic fibroblast growth factor; bmm, brummer gene encodes for triglyceride lipase in Drosophila; C3A, Complement 3A; C3AR1, Complement 3A receptor 1; C5A, Complement 5A; CAT, Catalase; CCR2; C—C motif chemokine receptor 2; CD25, Cluster of differentiation 25; CD44, Cluster of differentiation 44; CD68, Cluster of differentiation 68; COX-2, Cyclooxygenase-2; CREB, Cyclic AMP response element binding protein; CTSA, Cathepsin A; CTSD, Cathepsin D; CX3CL1, Chemokine (C-X-C motif) ligand 1; CXCL16, Chemokine (C-X-C motif) ligand 16; CXCL17, Chemokine (C-X-C motif) ligand 17; CX3CR1, Chemokine (C-X3-C motif) receptor 1; D1, Dopaminergic receptor 1; DA, Dopamine; DAB, 1,2-Diacetylbenzene; DAP12, DNAX activation protein 12; DARPP-32, Dopamine- and cAMP-regulated phosphoprotein 32 kDa; DC, Dendritic cells; DCX, Doublecortin; DiR-BOA, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide bisoleate; DOPAC, Dihydroxyphenyl acetic acid; DPH, Diphenylhexatriene; EAE, Experimental autoimmune encephalomyelitis; eIF2, Eukaryotic translation initiation factor alpha; ER, Endoplasmic reticulum; ERK, Extracellular signal-regulated kinase; ERS, Endoplasmic reticulum stress; FOXE1, Forkhead box E1; FRAP, Ferric reducing antioxidant power; Gab2, Growth factor receptor bound protein 2-associated protein 2; GABA, Gamma amino-butyric acid; G-CSF, Granulocyte colony stimulating factor; GFAP, Glial fibrillary acidic protein; GPx, Glutathione peroxidase; GSH, Glutathione reduced; GSK-3β, Glycogen synthase kinase 3 beta; GST, Glutathione S transferase; GRP78, Glucose-regulated protein 78 kDa; GTCS, Generalized tonic-clonic seizure; H2O, Water; H2O2, Hydrogen peroxide; HDL, HGF, Hepatocyte growth factor; High density lipoprotein; HMGB1, High mobility group box 1; HMW, High molecular weight; HO-1/HMOX1, Heme oxygenase 1; HSP70, Heat shock protein 70; HSP90, Heat shock protein 90; HTR, Hydroxy tryptamine receptor; HVA, Homovanilic acid; Iba-1, Ionized calcium binding adapter molecule 1; IDE, Insulin degrading enzyme; IFNγ, Interferon gamma; IL-1; Interleukin 1; IL-1α, Interleukin 1 alpha; IL-1β, Interleukin 1 beta; IL-4, Interleukin 4; IL-6, Interleukin 6; IL-10, Interleukin 10; IL10RB, Interleukin 10 receptor beta; IL-12; Interleukin 12; IL-17, Interleukin 17; IL-23, Interleukin 23; iNOS, Inducible nitric oxide synthase; IRE1-α, Inositol requiring enzyme 1 alpha; JAK2, Janus kinase 2; JMJD3, Jumonji domain containing protein 3; JNK, c-Jun N-terminal kinase; KRAS, Kristen rat sarcoma virus; LAMP-1; Lysosomal associated protein 1; LC3B, Light chain 3B; LDH, Lactate dehydrogenase; LFB, Luxol fast blue; LTCD3; Lymphocyte cluster of differentiation 3; LTCD4; Lymphocyte cluster of differentiation 4; LXR-β, Liver X receptor beta; MAP2; Microtubule associated protein 2; MAPK, Mitogen-activated protein kinase; MAO-B, Monoamine oxidase B; MBP, Myelin basic protein; MCOLN1, Mucolipin 1; MCP-1, Monocyte chemoattractant protein 1; MDA, Malondialdehyde; Mfn2, Mitofusin 2; MFS, Mossy fiber sprouting; MKK4, Mitogen activated protein kinase 4; MLKL, Mixed lineage kinase domain-like; MMP, Matrix metalloprotease; MMPo, Mitochondrial membrane potential; MPO, Myeloperoxidase; MPP, 1-Methyl-4-phenylpyridinium ion; MPTP, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; mTOR, Mammalian target of rapamycin; MTT, 3-(4,5-dimethylthiozolyly-2)−2,5-diphenyltetrazolium bromide; MUA, Multiple-unit activity; MYD88, Myeloid differentiation primary response 88; NAD, Nicotinamide adenine dinucleotide; NAv current, Voltage-gated sodium current; NCSTN, Nicastrin; NF-κB, Nuclear factor kappa B; NGF, Nerve growth factor; NIS, Sodium iodide symporter; NLRP3, NACHT, LRR, and PYD domain containing protein 3; NO, Nitric oxide; NOS2, Nitric oxide synthase 2; NQO1, NADPH quinone dehydrogenase 1; NSC, Neural stem cells; Nrf2, Nuclear factor erythroid 2-related factor 2; NSS, Neurologic severity score; NTG, Nitroglycerin; Olig2; Oligodendrocyte transcription factor 2; PAS+, Periodic acid-Schiff positive; PAX8, Paired box 8; PCS, Peripheral cholinergic signs; PDGRF-α, Platelet-derived growth factor alpha; Per, Period; PERK, Pancreatic EIF-2 alpha kinase; PKB, Protein kinase B; PKC, Protein kinase C; PSD-95, Postsynaptic density protein 95; RAGE, Receptor for advanced glycation end products; RANTES, Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted; RIP-1, Receptor interaction protein kinase 1; ROS, Reactive oxygen species; RXR-α, Retinoid X receptor alpha; ROT, Rotenone; SDH, Succinate dehydrogenase; SE, Status epilepticus; SREBP, Steroid regulatory proteins; Sir2, Silent information regulator 2; SIRT1, Sirtuin 1; SIRT3, Sirtuin 3; SN, Substantia nigra; SOD, Superoxide dismutase; SRS, Spontaneous recurrent seizures; STAT3, Signal transducer and activator of transcription 3; STAT4, Signal transducer and activator of transcription 4; STM, Stereotyped movements; TAC, Total antioxidant capacity; TBARS, Thiobarbituric acid-relative substances; TC, Total cholesterol; TDP-25, TAR DNA binding protein 25; TDP-43, TAR DNA binding protein 43; TFEB, Translocation of transcription factor EB; Tg, Thyroglobulin; TG, Thapsigargin; TGF-β, Transforming growth factor beta; TH, Tyrosine hydroxylase; Th17 cells, T helper 17 cells; THC, Tetrahydrocurcumin; Thrb, Thyroid hormone receptor beta; Tim, Timeless; TK2; Tyrosine kinase 2; TLR4, Toll-like receptor 4; TMEM119, Transmembrane protein 119; TNF-α, Tumor necrosis factor alpha; TOS, Total oxidative status; TPO, Thyroid peroxides; TREM1, Triggering receptor expressed on myeloid cells 1; TRHR, Thyrotropin-releasing hormone receptor; TrkA, Tyrosine kinase A; TSH, Thyroid stimulating hormone; TSHβ, Thyroid stimulating hormone beta;TSHR, Thyroid stimulating hormone receptor; TTF1, Thyroid transcription factor 1; TTR, Transthyretin; UBC9, Ubiquitin conjugating enzyme 2-homologus to yeast UBC9; UCP2, Uncoupling protein 2; uMtCK, Ubiquitous mitochondrial creatinine kinase; VEGF, Vascular endothelial growth factor; WT, Wild type; ZO-1, Zonula occludens 1.
Table 2.
Effect of Curcumin on Various Neurological Diseases in Humans.
| Disease | Curcumin & its formulation | Dose | Duration | Effects | Refs. |
|---|---|---|---|---|---|
| Alzheimer's disease | |||||
| C3 complex | 2 g/day, 4 g/day | 24 weeks | ↑Glucose, ↓Hematocrit | 167 | |
| Longvida | 40 g/day | 2 days | ↑Detection of amyloid spots (aided in diagnosis) | 168 | |
| Theracurmin | 180 mg/day | 18 months | ↑Improvement in memory, ↓Tau, ↓Amyloid | 169 | |
| ALS | |||||
| Curcumin | 600 mg/day | 6 months | Stable score of ALS-FRS-r, Stable FRAP values, ↓Lactate, ↓AOPPs | 170 | |
| Nanocurcumin | 80 mg/day | 12 months | ↑Survival | 171 | |
| Migraine | |||||
| Curcumin | 1000 mg/day | 8 weeks | ↓CGRP, ↓IL-6, ↓Severity, ↓Headache frequency, ↓Duration of headache | 172 | |
| Nanocurcumin | 80 mg/day | 2 months | ↓Frequency of headache attack | 173 | |
| 80 mg (1 capsule/day) | 2 months | ↓IL-6 mRNA, ↓IL-6, ↓hs-CRP | 174 | ||
| 80 mg (1 capsule/day) | 2 months | ↓COX-2, ↓Frequency of attack, ↓Severity of pain | 175 | ||
| 80 mg | 2 months | ↓Pentraxin-3 | 176 | ||
| 80 mg | 2 months | ↓IL-17 mRNA and serum levels | 177 | ||
| 80 mg/day | 8 weeks | ↓Headache frequency, severity, & duration | 178 | ||
| 80 mg/day | 2 months | ↓Headache frequency | 179 | ||
| 80 mg/day | 2 months | ↓MCP-1, ↓Headache attack frequency, ↓Headache severity & duration | 180 | ||
| Nanocurcumin + Coenzyme Q10 | 80 mg/day +300 mg/day | 8 weeks | ↓Headache frequency, severity, & duration | 178 | |
| Nanocurcumin + ω−3 FA | 80 mg/day + 2500 mg/day | 2 months | ↓Frequency of headache attack, ↓TNF-α | 173 | |
| 2 months | ↓ Frequency of headache attack, ↓Serum ICAM-1 levels | 181 | |||
| 80 mg (1 capsule /day) + 2500 mg (1 capsule/day) | 2 months | ↓IL-6 mRNA, ↓IL-6, ↓hs-CRP | 174 | ||
| 80 mg (1 capsule/day) + 1800 mg (2 capsules/day) | 2 months | ↓COX-2, ↓iNOS, ↓Frequency of attack, ↓Headache duration | 175 | ||
| 80 mg | 2 months | ↓VCAM | 182 | ||
| 80 mg/day | 2 months | ↓Headache frequency, ↓IL-1β | 179 | ||
| Multiple sclerosis | |||||
| Nanocurcumin | – | 6 months | ↑miR-145, ↑SOX2, ↑Sirtulin 1, ↑FOXP3, ↑PDCD1, ↑STAT5, ↓miR-132, ↓miR-16, ↓STAT1, ↓NF-κB, ↓AP-1, ↓IL-6, ↓TNF-α, ↓IL-1β, ↓IFNγ, ↓CCL2, ↓CCL5 | 183 | |
| 80 mg/day | 6 months | ↓Th17 cells, RORγt, IL-17 | 184 | ||
| – | 6 months | ↑Restoration of dysregulated miRNAs, ↓Demyelinating inflammation | 185 | ||
| 80 mg/day | 6 months | ↑Frequency of T-reg cells, ↑FoxP3, ↑TGF-β, ↑IL-10 | 186 | ||
| Parkinson's disease | |||||
| Curcumin | 80 mg/day | 9 months | ↓MDS-UPDRS part III score | 187 | |
| Spinal cord injury | |||||
| Curcumin | 110 mg/kg/day | 6 months | ↑BMD indicators of lumbar, femoral neck, & hip | 188 | |
| Curcumin + anti-inflammatory diet | 1200 mg/day | 12 weeks | ↑TRP/LNAA ratio, ↓IL-6, ↓IL-1β, ↓IFN-γ, ↓CRP, ↓Proinflammatory composite score | 189 | |
| Traumatic brain injury | |||||
| Curcuminoids (C3 complex) +piperine | 500 mg/day + 5 mg/day | 7 days | ↓Leptin | 190 | |
Abbreviations.
ALS, Amyotrophic lateral sclerosis; ALS-FRS-r, Revised ALS Functional rate scaling; AOPPs, Advanced oxidative protein products; AP-1, Activator protein 1; CCL2, C—C motif chemokine ligand 2; CCL5, C—C motif chemokine ligand 5; CGRP: Calcitonin gene related peptide; CRP, C-reactive protein; FOXP3: Forkhead box P3; FRAP, Ferric reducing antioxidant power; COX-2, Cyclooxygenase 2; hs-CRP, Heat-sensitive C-reactive protein; ICAM, Intracellular adhesion molecule; IFNγ, Interferon gamma; IL-1β, Interleukin 1 beta; IL-6, Interleukin 6; IL-10, Interleukin 10; IL-17, Interleukin 17; LNAA, Large neutral amino acids; MCP-1, Monocyte chemoattractant protein-1; MDS-UPDRS, Movement Disorder Society sponsored revision of the Unified Parkinson's Disease Rating Scale; mRNA, Messenger ribonucleic acid; NF-κB: Nuclear factor kappa B; PDCD1, Programmed cell death 1; RORγt, Retinoic-acid-receptor-related orphan nuclear receptor gamma; SOX2, SRY-box transcription factor 2; STAT1, Signal transducer and activator of transcription 1; STAT5, Signal transducer and activator of transcription 5; TGF-β, Transforming growth factor-beta; Th17 cells, T helper 17 cells; TNF-α, Tumor necrosis factor alpha; TRP, Tryptophan.
Curcumin has shown to be a potential candidate in treating various disorders including AD, ALS, MS, migraine, and HD, PD etc. (Fig. 2, Fig. 3). The efficacy of curcumin in treating these disease and associated inflammatory pathways have been discussed in detail.
Fig. 2.
Illustrates the curcumin activity against various NDs.
Fig. 3.
Neuropathological features associated with commonly occurring NDs and their outcomes.
3.1. Alzheimer's disease (AD)
AD is the most prevalent chronic neurodegenerative disorder characterized by dementia and cognitive impairment mainly due to the accumulation of amyloid β (Aβ) protein plaques. Even though the etiology of AD is largely unknown, however, both environmental and genetic factors have been shown to play a crucial role in the disease development.191, 192, 193 Growing lines of evidence suggest that environmental toxins including aluminium toxicity could act as causative factor by altering neuronal structure, blood brain barrier (BBB) and neurotransmission.193
Despite the various efforts since decades, there are no satisfactory preventive and curative medicines for AD. For instance, the drugs which are approved to treat AD such as acetyl choline esterase (AChE) inhibitors including donepezil and non-competitive N-methyl d-aspartate (NMDA) receptor antagonists, are unable to decelerate the AD progression. These drugs were also found to cause side effects such as nausea, diarrhea, and insomnia.193 Hence, it is imperative to develop novel efficacious medicines with least or no side effects for AD. Indeed, recent researches have shown that curcumin inhibits oxidative stress, inflammatory response and provides cytoprotective environment in AD in vitro and animal models. Curcumin treatment was found to inhibit the thapsigargin (TG)-induced cell toxicity and death in SH-SY5Y cells.38 TG is a guaianolide-type sesquiterpene lactone commonly found in Thapsia garganica plant.194,195 It is an inhibitor of endoplasmic reticulum (ER) Ca+-ATPase pump and is a known inducer of ER stress (ERS).195, 196, 197 ERS is one of the major contributor for AD development and progression.198 The experiments aim to uncover mechanistic insights revealed that curcumin reduced ROS by inhibiting TG-induced ERS and mitochondrial stress as evidenced by the downregulation of GRP78, pSer981-PERK, pSer51-eIF2α, and MFN2 in SH-SY5Y cells.38 Recently, another chemical 1,2-diacetylbenzene (DAB), a metabolite of 1,2-diethylbenzene, found in petrol and vehicle oils has gained the attention due to its harmful effects on CNS.199, 200, 201 This chemical has been shown to activate microglia, inflammation, oxidative stress, impede hippocampal neurogenesis, and cause the cognitive impairment similar to AD.200, 202, 203, 204 Interestingly, a recent research showed that curcumin treatment prevented DAB associated neuronal toxicity in vitro by promoting NRF2 and interleukin 10 (IL-10) expression and inhibiting triggering receptor expressed on myeloid receptor 1 (TREM1), DNAX activation protein 12 (DAP12), nuclear factor kappa B (NF-κB), cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), complement 3A (C3A), complement 5A (C5A), toll-like receptor 4 (TLR4), myeloid differentiation primary response protein 88 (MYD88), interleukin-6 (IL-6), nod-like receptor protein 3 (NLRP3), caspase-1, interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β), phospho-Tau, β-amyloid, glycogen synthase kinase-3 beta (GSK-3β), reactive ROS, and advanced glycation end-products (AGEs).39 In another study, curcumin rescued cell viability of amyloid beta 42 (Aβ42) treated primary hippocampal neurons isolated from mice by upregulating sirtuin 3 (SIRT3) deacetylation, nicotine adenine dinucleotide (NAD)+/NADH ratio, adenosine triphosphate (ATP), and thyroid hormone receptor beta (Thrb).37 This study also validated the changes in SIRT3, NAD/NADH ratio and Thrb in transgenic AD mice models.37 Similar study was also conducted by He et al., and found that curcumin effectively reduced the toxicity induced by Aβ 25–35 in microglial cells by downregulating high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), TLR4, IL-1β, and TNF-α levels.40 Further, curcumin treatment significantly reduced high molecular weight (HMW) Aβ42O-induced neurite damage and neuronal cell death and suppressed IL-1β and TNF-α release in rat microglial cells and neurons.41 Also, derivatives of curcumin has been shown to be effective in regulating HSP90, HSP70, Akt, caspase-3, glutathione (GSH), phospho Tau, ROS, nitrites and prevents aggregation of Aβ in to oligomers oxidative stress, and inflammation thereby providing the neuroprotection and rescuing neuronal cells from Aβ neurotoxicity and okadaic acid induced cytotoxicity in vitro and in vivo.48, 49, 205 Another study demonstrated that curcumin diethyl gamma amino butyrate (Cur-2GE) reduced nitric oxide (NO) production, TNF-α, and IL-6 levels to a greater extent than curcumin in lipopolysaccharide (LPS) stimulated BV-2 microglial cells.50 Further, bisdemethoxycurcumin treatment was found to ameliorate cell survival, phospho AMPK, anti-oxidative stress ability, SIRT1, SOD, and GSH levels in SK-N-SH neuronal cells treated with Aβ1–42 oligomers.58 Furthermore, tetrahydrocurcumin (THC) was reported to alleviate Aβ42/Aβ40 levels and Aβ-induced G1/S arrest and apoptosis in BV2 glial cells. This study also revealed that THC induced Gab2, K-Ras and inhibited caspase 3 levels leading to increased cell viability.63
The major feature of AD is the deposition of Aβ plaque results from the cleavage of amyloid precursor protein (APP), a transmembrane protein, or due to mutations in APP and presenilin genes (PSEN1 and PSEN2). Hence, the APP/PS1 transgenic mice with increased amount of Aβ plaque have been one among the best suitable model for studying pathophysiology of AD.42,206 In the APP/PS1 mouse models curcumin remarkably inhibited the formation of amyloid protein plaques and improved time spent in target quadrant, short term working memory, escape latency, spatial memory retention, platform crossing frequency, amyloid protein plaques, and swimming speed. Curcumin was also shown to augment the expression of ABCA1, ApoA1, RXR-α, LXR-β, BDNF, JMJD3, and high density lipoprotein (HDL) levels and downregulated glial fibrillary acidic protein (GFAP), COX-2, cluster of differentiation (CD68), HMGB1, TLR4, advanced glycation end product-specific receptor (RAGE), NF-κB, H3K27me3 BDNF and total cholesterol (TC) levels.42,43,44 Another study demonstrated that bisdemethoxycurcumin treatment for 1 month resulted in improved cognitive function, number of neurons, SIRT1, oxidative stress and markedly alleviated Aβ deposition.59 Besides, THC was found to ameliorate learning capabilities, memory, escape latency and inhibit Aβ burden, Aβ42/Aβ40 levels in APP/PS1 mice. THC was also shown to enhance the expression of Gab2 and K-Ras levels and suppress TNF-α and TGF-β1 levels in these mice models.63 In addition, curcumin magnetic nanoparticles (Cur-MNPs) have been shown to ameliorate memory, spatial learning, escape latency, finding the blind platform time, amyloid plaques, neuron generation, Aβ in brain, microglia activation, inflammation, BDNF levels, doublecortin (DCX) levels, NLRP3 inflammasome formation, IL-18 levels, and CD68 levels in APP/PS1 mice.53 Recently, Lin et al., synthesized novel poly(lactic-co-glycolic acid) (PLGA)-poly(ethylene glycol) (PEG) combined thermo-sensitive hydrogel loaded with curcumin (PGC) and reported that PGCs reduce β-secretase, Aβ aggregation, Aβ-induced neurotoxicity, and ROS levels in neuronal cell lines.60 HDL-inspired nano scavenger that contains curcumin, β-site APP cleavage enzyme 1 (BACE1) siRNA, and phosphatidic acid functionalized HDL (pHDL) (pHDL/Cur-siBACE1) treatment was shown to improve focused search strategies, Aβ burden, NF-κB, neuronal inflammation, escape latency, and memory deficits in APP/PS1 mice. Mechanistic studies have revealed that pHDL/Cur-siBACE1 nano scavengers eliminate Aβ plaque and suppress IκB-α, and inflammatory cytokines including TNF-α, IL-6 and IL-1β levels in vitro.61
Several studies have revealed that scopolamine, a nonselective and competitive inhibitor of muscarinic acetylcholine receptor, causes oxidative stress, neuronal inflammation, mitochondrial dysfunction, and apoptosis. The scopolamine lesioned animal models were shown to display the similarity with cholinergic hypothesis of aging and AD.45, 207, 208, 209 Treatment of scopolamine lesioned rat models with curcumin (200 mg/kg/day) for 7 days has been reported to remarkably reduce the length and time taken to reach the platform. Curcumin treatment was also shown to reduce the IL-6 levels significantly in these rats.45 A novel curcumin derivative, curcumin glucoside has been found to enhance GSH, FRAP and reduce protein carbonyls and memory impairments in scopolamine induced AD Wistar rats.47
Another chemical streptozotocin (STZ), a glucosamine derivative, is known to preferentially damage the pancreatic β cells and is often used to induce diabetes in animal models. Substantial amount of literature provide the evidence that STZ injected intracerebroventricularly at a sub diabetic level cause cognitive impairment, oxidative stress, Aβ deposition, neuronal inflammation, and memory deficits similar to manifestations in sporadic AD.55,210 The nanocurcumin administration was reported to alleviate the oxidative stress in STZ AD rat models by inducing GST, CAT, GSH-Px, SOD, insulin degrading enzymes (IDE), a disintegrin and metalloproteinase domain 10 (ADAM 10), and BDNF levels.54 The regimen was also found to enhance the Bcl-2 and suppress Aβ−42, AGEs, thiobarbituric acid reactive substances (TBARS), NO, TNF-α, IL-1β, AChE, Bax, phospho p38MAPK, phospho ERK, phospho MEK and phospho Tau levels in these models and thereby improving the normal architecture of pyramidal cells, memory deficits, swim time and distance and reducing the pyknotic pyramidal cells.54 Similarly, Noor et al. demonstrated that nanocurcumin supplementation resulted in increased GSH, Na+-K+- ATPases, restoration of NO, glutamine, glycine, GABA, and reduced latency to locate the platform, MDA, TNF-α, AChE, Tau, and pyknotic neurons in STZ lesioned AD rats.55
Apolipoprotein E (ApoE), a 34 kDa protein containing 299 amino acids play a crucial role in lipid transportation and lipoprotein metabolism.46 Among the three alleles i.e. ε2, ε3, and ε4 of ApoE, ε4 (ApoE4) has been shown to be involved in AD pathology. ApoE4 has been shown to be a risk factor for the development of various chronic diseases including atherosclerosis, diabetes, and AD.46, 211, 212, 213, 214 Curcumin has also been reported to be effective in ApoE4 transgenic AD mice models in which administration of 40 mg/kg/day curcumin for 3 weeks showed reduction in ApoE4, TNF-α, IL-1β, and nuclear translocation of NF-κB and improved time spent in the platform, number of times mice crossed the platform, spatial learning deficits, neuronal morphology, number of GRP78+ cells, number of IRE1-α+ cells and rescued neuronal cells from degenerative death.46
A novel highly bioavailable curcumin formulation called curcugreen treatment was found to restore spleen size, spleen and liver cytoarchitecture and inhibited bronchiolar degeneration, granulomatous inflammation, apoptotic death, amyloid deposits and phospho Tau levels in 3xTg, 5xFAD mice, AD mice models.51 In another study, treatment of oAβ25–35 induced acute C57B1/6 J AD mice and J20 transgenic mice with curcumin microemulsions (Cur ME) and curcumin conjugated to docosahexanoic acid (DHA) microemulsions (CurDHA ME) effectively restored spatial memory deficits, anxiety, depression, short-term memory and suppressed GFAP, phospho Tau, and phospho JNK2 levels.52 In addition, supplementation with lipid core co-encapsulated meloxicam and curcumin NPs showed reduced non-aversive memory impairment, inflammation, and COX-2 expression in Aβ peptide-induced AD Swiss mice.56 Recently, Gao et al., developed curcumin loaded red blood cell (RBC) membrane coated with PLGA bearing T807 (imaging agent) (curcumin loaded T807/RPCNP) biomimetic nanoparticles and tested their efficacy against AD both in vitro and in vivo.57 These nanoparticles showed to increase phospho protein kinase B (PKB), phospho Tau, mitochondrial ROS, GSK-3β and apoptosis in HT 22 neuronal cells. This study also showed Curcumin loaded T807/RPCNP reduces the activation of primary astrocytes in vitro.57 Additionally, supplementation of curcumin loaded T807/RPCNP (2 mg/kg, every 2 days) for 10 days showed enhanced spatial learning memory, and suppressed phospho Tau, cognitive impairment, neuronal cell death, and abnormal activation of microglia in okadaic acid lesioned AD mice.57 In Wistar rats curcumin was shown to mitigate aluminium induced neuronal cytotoxicity (symptoms similar to AD) as evidenced by increased Mg2+, CAT, SOD, Na+-K+ ATPase activity, Mg2+ATPase activity, improvement in hippocampal structure, normal morphology of neuronal cells, hippocampal cell viability body weight, memory recognition, and reduced Ca2+, hippocampal AChE, MDA, IFNγ, IL-4 levels, oxidative stress, memory deficit, absolute hippocampus weight, time spent in the dark room, karyopyknotic neuronal cells, neutrophil infiltration, neurofibrillary tangles, hippocampal cell apoptosis.125,126 Moreover, aluminium-induced AD rat models when treated with PGC improved hippocampal activity, and mitigated Aβ deposition and aggregation, nuclear condensation, and neurodegeneration.60 Another study explored the effect of solid-lipid curcumin nanoparticles on 5xFAD AD mice models and found that treatment with these nanoparticles significantly improved discrimination index, exploration index, synaptophysin, PSD95, CREB, phospho CREB, spatial memory deficits, pyknotic cells, neurodegeneration, Aβ plaque load, loss in dendritic branching and sprouting of dendritic cells and loss in dendritic spines.62
Taken together, these in vitro and in vivo evidences suggest that curcumin is effective in treating AD irrespective of the disease etiology and alleviated associated neuroinflammation. However, further investigation is reqiured to bring curcumin to bedside.167, 168, 169
3.2. Amyotrophic lateral sclerosis (ALS)
ALS is a rare devastating paralytic neurodegenerative disease principally affecting upper and lower motor neurons and frontotemporal system with a lifetime risk of 1 in 350 people.215,216 While cause of sporadic ALS is largely unknown, 10–20% of patients display familial ALS with a clear genetic etiology.215,216 Genetic makeup of ALS is extremely complex with greater than 40 associated genes have been identified till date which vary in mode of inheritance, frequency and penetrance.215 The most prevalent mutations being C9orf72 repeat expansions, missense mutation in SOD1 followed by mutations in TAR DNA binding protein (TARDBP) and fused in sarcoma (FUS) genes.215,217,218 Despite the extensive research, the current disease management of ALS is unsatisfactory. Increasing lines of evidence suggests that curcumin has the potential to treat ALS. For instance, monocytes (THP-1) cells treated with curcumin have shown reduced cell death upon treatment of SOD1 aggregates.64 Monocytes/macrophages, in general, produce higher amounts of SOD1, thus making them suitable model to study the ALS etiology.64,219 This study also showed that curcumin in solution inhibits DTT-induced aggregation of SOD1.64 Besides, curcumin treatment has been shown to improve the survival and non-weight bearing of hind/ thoracic limb in dogs of Pembroke Welsh Corgis (PWC) breed with canine degenerative myelopathy, a spontaneous ALS models.68 In addition, curcumin derivative dimethoxy curcumin (DMC) treatment was found to enhance complex I activity, MMPo, mitochondrial uncoupling protein 2 (UCP2), and alleviate mitochondrial swelling, cristal dilation, WT & Q331K TAR DNA binding protein 43 (TDP-43)-induced abnormal inactivation of voltage gated sodium channel current, abnormal action potentials in neuroblastoma spinal cord-34 (NSC-34) cells, that expresses several features of ALS motor neurons without inducing agents, in vitro.65,66 In another in vitro study, monocarbonyl DMC was shown to reduce insoluble TDP-43 fragments, TAR DNA binding protein 25 (TDP-25) and size of TDP-25 aggregates by upregulating hemeoxygenase-1 (HO-1) levels and was found to reduce oxidative stress by downregulating LDH and MDA levels in NSC-34 cells.67 Moreover, supplementation with 600 mg/day of curcumin for 6 months improved stable disease scores and ferric reducing antioxidant power (FRAP) values with reduced lactate and advanced oxidative protein products (AOPPs) values in ALS patients.170 In another clinical trial nanocurcumin treatment (80 mg/day) for an year showed to increase the survival rate in ALS patients.171 Hence, both preclinical and clinical studies support that curcumin treatment can significantly reduce oxidative stress and prevent neuronal degeneration in ALS.
3.3. Epilepsy and seizures
Epilepsy, one among the most prevalent CNS disorders affecting over 50 million individuals worldwide, poses enormous healthcare and socioeconomic burden.220, 221, 222 The spontaneous and abrupt onset of a seizure has become a serious medical emergency since it may result in additional difficulties.223 It is primarily identified by aberrant electrical activity in various brain areas. The sudden massive entry of Ca2+ into neurons is the principal neurotoxic process that results in cell death and progressively leads to neurodegeneration.222 The electric shocks due to seizure outbreak can affect either a portion of the body (partial) or the entire body (generalised). They are accompanied by a loss of consciousness and control over bowel movements.222 Due to the narrow therapeutic margin and hazardous side effects of prescribed pharmaceutical medications to treat epilepsy and the progressive development of treatment resistant refractory epilepsy, medicinal plants have gained increasing attention in recent years.220,222 Drion and colleagues have proved that curcumin enhanced HMOX1 levels and suppressed average action potential frequency, seizure-like events, pS6, phospho pS6Ser240/244, phospho MAPK, IL-6, IL-1β, and TGF-β levels in organotypic slice culture model of hippocampus & entorhinal cortex obtained from Sprague-Dawley rats.69 Curcumin administration was shown to attenuate electric shock induced seizures and provide protection against post-ictal mortality in Swiss albino inbred mice.70 In another study, curcumin was shown to protect against electro behavioral seizures as evidenced by increased prevention of grade III seizures, Na-K ATPase activity, ambulatory activity, normal cellular architecture, and reduced onset & progression of seizures, DPH anisotropy, lipid peroxidation, protein oxidation, PKC activity, defecation, and epilepsy-related memory decline in Wistar rats.71 Besides, curcumin administration throughout the kindling days were found to enhance after discharge threshold, stimulation of current intensity required to evoke after discharge and inhibit behavioural seizure development in Sprague-Dawley rats.72 Yet, another study showed that curcumin protects the Wistar rats against kainic acid (analogue of glutamic acid, produce convulsions by activating kainite excitatory neurons) induced seizures as observed by increased mean latency of convulsion, GSH levels, and time spent in target quadrant, and reduced percentage of convulsions, mossy fiber sprouting (MFS) intensity, activation of astrocytes and microglia, frequency of abnormal spikes, degree of spontaneous recurrent seizures (SRS), TNF-α, IL-1β, MDA, nitrite and nitrate levels.73, 81, 85 Curcumin was also shown to effectively attenuate seizures and cognitive impairment in pentylenetetrazole (PTZ) kindling models, widely accepted epileptogenic animal models. In these models curcumin was shown to enhance the delay in kindling development, latency to myoclonic jerks, latency to generalized tonic-clonic seizures (GTCS), latency to myoclonic jerks, latency to enter dark compartment, latency to onset of spasms, step down latency, brain norepinephrine, serotonin, 5-hydroxytryptamine receptor 7 (HTR7) and GSH levels and decreased number of myoclonic jerks, mean frequency of interictal discharge, mean frequency of epileptiform discharge, seizure severity scores, duration of GTCS, muscle contractions, retention transfer latency, mitochondrial swelling, mitochondrial structural abnormality, pyknotic cells, damage to hippocampus, nitrite, neuronal injury, oxidative stress, AChE, ROS and MDA levels.74, 75, 78, 80, 82, 84, 86, 88, 91 Kaur et al., deduced that curcumin administration alleviate inflammatory responses in PTZ induced epileptic rat models by suppressing GFAP, Iba-1, astrocyte and microglia activation, activation, TNF-α, IL-1β, IL-6 and MCP-1 levels.83 Studies have also recorded the beneficial effects of curcumin in treating pilocarpine (cholinergic agonist) induced epileptic rat models where curcumin administration was found to delay the onset of seizures, and augment SOD, Na-K ATPase activity and GSH levels and reduced occurrence of seizures, MDA, AChE, NO, and CAT levels.76,77 In another study curcumin was shown to protect the rat brain from lithium-pilocarpine induced status epilepticus (SE) by improving latency to seizure and SE, time spent in target quadrant, cognitive performance, beclin, LC3BII, receptor interaction protein kinase 1 (RIP-1), mixed lineage kinase domain-like (MLKL), and GSH levels, and reducing the percentage frequency of seizure and SE, peripheral cholinergic signs (PCS) and stereotyped movements (STM) episodes, TBARS, and mortality.79,87 In the iron induced epileptic rat models curcumin has been shown to inhibit epileptic activity, multiunit activity (MUA) and seizures.89 In another study, curcumin was found to increase number of stimulations required to reach Racine stage IV seizures and delayed in onset of seizures in Sprague-Dawley rats.90 Moreover, curcuminoids were shown to reduce inflammation in rat epileptic models. This study also reported that curcumin induced the expression of anti-inflammatory molecules including IL10RB, CXCL16, CXCL17, NCSTN, CX3CL1, CX3CR1, C3AR1, cathepsin A (CTSA), and cathepsin D (CTSD).92 Curcumin formulations such as curcumin plus piperine, curcumin plus diazepam, curcumin nanoparticles, liposomal curcumin and micronized curcumin have also been shown to be effective in treating epilepsy in animal models.91, 93, 94, 95, 96 These curcumin formulations have shown to improve latency to onset of spasms & isolated clonic seizures, duration of seizures, damage to hippocampus, seizure severity, occurrence of stage III seizures, muscle contraction, working memory, correct entries to goal box, GSH, and NO levels, and reduce TLR4 in pups, hyperthermia, TNF-α, IL-10, IL-1β, MDA, AChE activity, oxidative stress, and caspase-3 expression.91, 93, 94, 95, 96 Hence, curcumin and its derivatives can be used as potential candidates to treat epilepsy and associated diseases.
3.4. Huntington's disease (HD)
HD is a neurological disorder with autosomal dominant inheritance pattern and is characterized by massive neuronal degeneration, motor and cognitive impairments with psychiatric symptoms.224, 225, 226, 227 It arises from the mutation in Huntingtin gene as expansion of cytosine-adenosine-guanine repeats which results in elongation of polyglutamine (polyQ) segment in the Huntingtin protein.228,103 HD is generally a mid-life disease with certain exceptional cases of early onset in childhood (as early as 2 years) and late onset in mid-80 s.229 There is no approved-disease curing/modifying drugs at present for HD.227,230 Besides, the treatment modalities include anti-sense oligonucleotides, splicing modulators, and small molecule inhibitors generally provide marginal-relief to symptoms of HD and many of them possess severe adverse side effects.227,231,100 Interestingly, natural compounds are an alternative to these synthetic drugs with minimum or no side effects. Growing line of evidence indicate that curcumin and its formulation could be an effective therapy against HD.103,97, 98, 99, 100, 101, 102 Transgenic Drosophila models have established as a highly effective model system for studying HD since they mimic the majority of the characteristics of neurodegenerative diseases, including late onset, neurodegeneration, motor dysfunction, progressive accumulation of aggregates in the cytoplasm and neurites and shortened lifespan.98,232, 233, 234, 235 Treatment of transgenic Drosophila adult and larvae with various concentration of curcumin has been shown to be beneficial in reversing HD symptoms. Chontham and Agrawal treated transgenic HD models of Drosophila larvae with 3, 5, 10, 15, and 20 μM of curcumin for 1, 7, and 14 days post eclosion period and observed that curcumin effectively improved crawling ability and inhibited photoreceptor neuron degeneration, morphological defects in the internal part of the eye, eye roughness, loss of pigmentation in eye, acridine orange (AO)-positive cells, polyQ-induced cytotoxicity and apoptotic cell death in eye discs and progressive loss of locomotion in these flies.98 In another study, curcumin (10 μM) treatment for 1, 7, and 13 days after eclosion has been shown to reduce motor defects and increased mid-night levels of circadian genes Per and Tim miRNAs than mid-day levels.99 Moreover, curcumin (10, 15, and 20 μM) fed flies (from larvae to till 15 days after eclosion) exhibited improvement in motor activity and median survival rate, with induced mRNA expression of Drosophila sterol regulatory element binding protein (dSREBP) and brummer (bmm) that encodes triglyceride lipase.100 The treatment also reduced abnormal high body weight, abnormal high dry weight with elevation in H2O content, trehalose levels, dysregulation in total lipid content, lipid droplet size, ROS, free radicals, and mRNA expression of lipin.100 These studies also reported that curcumin of 10 μM shows the best effect against HD compared to higher and lower doses.100,98,99 Transgenic HD mice and rats also have been shown to recapitulates human HD pathology in vivo and are the suitable models for novel drug discovery.101,236, 237, 238 Curcumin treatment was also observed to be effective in these models. For example, dietary curcumin of 92 mg/kg for 23 weeks was shown to enhance striatal dopamine- and cAMP-regulated phosphoprotein 32 kDa (DARPP-32) and dopaminergic receptor 1 mRNAs and rearing and decrease cannabinoid receptor 1 (CB1) mRNAs neuropil aggregates, Huntingtin stained nuclei and aggregates in CAG140 mice (knock-in model of HD).97 Another study showed that dietary supplementation of curcumin (25 mg/kg) with Bioperine (1 mg/kg) in R6/2 line of transgenic mice for entire gestation period and 3 weeks after birth ameliorated HD severity by enhancing DARPP-32, phosphoAkt, phosphoERK, Claudin-2, ZO-1, occludin, and preserving normal levels of BDNF.101 The treatment also augmented normal intestinal functions including intestinal emptying and contractility.101 This study also showed that curcumin/Bioperine treatment remarkably inhibited motor deficits, hind clasping behaviour, brain and body weight loss, number of EM48+ mHtt aggregates, villi loss and atrophy and PAS+ globet cells.101 In another study, curcumin solid lipid particle formulation (SLCPs) in 100 mg/kg doses (alternate days for 8 weeks) increased the length of dendrites and density of dendritic spines and alleviated learning memory deficits, latency to escape and post-synaptic density protein-95 (PSD-95) levels in YAC128 transgenic mice.103 Another curcumin solid-lipid nanoparticle formulation (40 mg/kg for 7 days) when given orally to 3-nitropropionic acid induced HD models of wistar rats significantly upregulated SDH activity, NADH dehydrogenase activity, cytochrome c oxidase activity, mitochondrial F1F0 synthase activity, cytochrome a, b, c1 & c levels, GSH levels, SOD levels, cytosolic & nuclear Nrf2 levels and 3-(4,5-dimethylthiazolyl-2)−2,5-diphenyltetrazolium bromide (MTT) reduction rate.102 This treatment also resulted in improved locomotor activity, average velocity to traverse the beam, stride length, and reduced mitochondrial swelling, MDA levels, protein carbonyl levels, ROS, total time to traverse the beam, distance between the two paws, stride width and gait angle in these rat HD models.102 Collectively these studies indicated that curcumin reduces the HD symptoms severity via modulating multiple pathways including Akt pathway, ERK pathway, dopamine and cannabinoid receptor mediated pathway, ROS, mitochondrial respiratory chain and inflammatory pathways.
3.5. Migraine
Migraine is a neurovascular disorder, ranked second most prevalent disorder and sixth cause of disability in the world with typical symptom of recurrent headache.104, 106, 107, 239, 240, 241 Migraine associated pain disability reduces work capacity and productivity leading to considerable economic burden on society.104,242 Although there is an armamentarium of migraine-specific medications, the long-term usage of these drugs cause dependency, habituation, and addiction.243,244 The use of non-migraine specific drugs to relive migraine associated pain is also alarming and is a key risk factor for transformation into chronic migraine.243, 244, 245 Hence, there is an urgent need for scientists to develop adequate preventive and curative medicines for migraine. Various preclinical and clinical studies have been reported curcumin to be beneficial in treating migraine. For instance, Ouyang and colleagues demonstrated that curcumin (10, 20, 30, 40, and 50 μM) increases viability of endothelial cells treated with H2O2 by upregulating GSH, SOD, Bcl-2, and downregulating LDH, ROS, MDA, p21, Bax, p53, and caspase-3 levels.104 This study showed that curcumin mitigates H2O2-induced oxidative stress and cell death in vascular cells indicating the potential in treating migraine.104 Besides, several studies have shown that curcumin and/or liposomal curcumin formulations effectively reduced MDA, nitric oxide, total oxidative stress, flinches, shakes, and biphasic response to nociceptive receptors and enhance TAC and thiols levels in nitro-glycerine (a vasodilator) induced experimental rat migraine models.107,106,105 In addition, curcumin at 1 g/day dose for 8 weeks has been effectively shown to reduce headache attack frequency, duration and severity in migraine patients.172 This study also showed that curcumin remarkably reduced inflammatory marker IL-6 and calcitonin-gene related peptide (CGRP).172 Several randomized clinical trials have shown that nanocurcumin (80–160 mg/day) with or without omega-3 FA for 2 months alleviated frequency of headache attack, severity of pain, duration of headache with simultaneous downregulation of inflammatory molecules such as IL-6, IL-17, hs-CRP, COX-2, MCP-1, ICAM1, TNF-α, VCAM, and pentraxin 3.173, 174, 175, 176, 177, 178, 179, 180, 181, 182 In another study, administration of curcumin along with coenzyme Q10 was shown to diminish headache frequency, severity, and duration in migraine patients.178 Therefore, curcumin can effectively alleviate the symptoms by regulating inflammatory markers in migraine patients and can be a potential drug candidate to treat these patients.
3.6. Multiple sclerosis (MS)
MS is an autoimmune disease of CNS affected over 2 million people globally and is characterized by progressive demyelination, neuroinflammation, axonal damage, breakdown of BBB, oligodendrocyte loss, and neuronal death.109, 111, 246, 247, 248, 249, 250, 251 It primarily affects individuals between the 20 to 40 years old, with females being more at risk than males.252 Despite the fact that more than 10 disease-modifying medications are clinically available for MS treatment, the majority of MS patients continue to have varied degrees of impairment and ongoing clinical symptoms.115 Besides, the long term usage of these drugs have shown several adverse side effects.117,253 Hence, it is important to research and understand how natural substances affect the pathophysiology of disease. Fortunately, experimental autoimmune encephalomyelitis (EAE) has given researchers a great chance to explore substances in-depth for potential therapeutic applications for MS since EAE and MS are both auto-inflammatory diseases.250,117,254 Accumulating evidences suggest that curcumin prevents the onset and progression of MS and associated autoimmune encephalitis in vitro by increasing Bax, IL-10, caspase-3, and reducing T cell proliferation, IL-12, phosphoJAK2, phospho TK2, STAT3 STAT4, NO, IL-6, TNF-α, iNOS, Bcl-2, CD25, CD44, AXL, IL-2, IL-17A, and IFNγ levels.109,111,108,110 In the autoimmune MS mice models, treatment of curcumin significantly alleviated clinical severity and duration, inflammation, disease severity, behavioural abnormality demyelination, disease onset scores, weight loss, paralysis, IL-12, mean clinical score, IFNγ, IL-17, IL-6, TNF-α, phospho Akt, phospho mTOR, IFNγ , p62, CD4+IFNγ+ and CD4+IL-17+ T cells, infiltrated immune cells, iNOS, IL-1β, IL-12, IL-23, COX-2, TMEM119, AXL, MDA, LTCD3, and LTCD4, and improved sniffing of the novel object, TGF-β, SOD, LC3II, Beclin, Atg5, IL-10, Arg-I, GSH, SOD and MBP levels.111,115,108, 110, 113, 114 In addition, in autoimmune rat models curcumin was found to be effective in increasing distance travelled, TAC, and MBP levels and inhibited CAT, MMCS, disease severity, immune cell infiltration, Th17 cell proliferation, IL-17, latency, SOD, MDA, weight loss, iNOS, cumulative disease disability, and NOGO-A levels.117,112,116 In another study, treatment of curcumin-linoleic acid conjugate improved distance travelled, TAC, CAT, escape latency, SOD, and suppressed MDA in autoimmune Wistar rats.116 Moreover, dendrosomal curcumin treatment resulted in NSCs proliferation, increased MAP2+ cells, MBP+ cells, NeuN, Olig2, remyelination, differentiation of NSCs into oligodendroglial cells,CC1+/Olig2+ cells, Olig2+ cells, and LFB staining, and reduced GFAP+ cells, astrocyte activation, and differentiation of NSCs into astrocytes both in vitro and in vivo models.118,119 Further, curcumin loaded HDL mimicking peptide-phospholipid complex delay in disease progression, morbidity, immune cell infiltration, CD45+ cells, CD45+CD11b+Ly6C+CCR2+ monocytes infiltration, CD11b+ cells, CD3+ T cells, TH1 cells, TH17 cells, DC maturation, and DIR-BOA+ monocytes.120 Furthermore, bioavailable polymerized nanoparticle increased myelination, IL-4, IL-10, HO-1, NGF MBP, Nestin, Olig2, PDGRF-α, and reduced peak and cumulative EAE scores, MCP-1, IL-1, demyelination, iNOS, EAE score, TNF-α receptor, IL-17, CD8 in MS animal models.121
In the clinical settings nanocurcumin administration has been shown to improve disease condition and alleviate inflammation by upregulating miR-145, SOX2, sirtulin 1, FOXP3, PDCD1, STAT5, and downregulating miR-132, miR-16, STAT1, NF-κB, AP-1, IL-6, TNF-α, IL-1β, IFNγ, CCL2, CCL5 in MS patients.183 Besides, in a randomized clinical trial nanocurcumin supplementation inhibited Th17 cells, RORγt, IL-17 levels in MS patients.184 Nanocurcumin treatment was also found to increase the frequency of T-reg cells, FoxP3, TGF-β, and IL-10.186 Another study compared the miRNAs expressed in MS patients with normal healthy subjects and identified putative dysregulated miRNAs in MS patients. These dysregulated miRNAs were found to be restored after 6 months of nanocurcumin treatment in MS patients.185
These evidences suggest that curcumin ameliorate autoimmune encephalitis and MS in animal models.
3.7. Parkinson's disease (PD)
PD is the second most prevalent neurodegenerative disease with an estimated 10 million patients suffering worldwide in 2020.255 The disease predominantly results in the degeneration of dopamine-producing neurons in the substantia nigra of brain leading to defects in locomotor and cognitive functions. The pathophysiological mechanism underlying the disease development include increased aggregation and reduced degradation of α-synuclein and mitochondrial dysfunction affecting majorly complex I.255, 256, 257, 258 The currently available treatment modalities only provide symptomatic relief, for example, supplement with dopamine temporarily control motor deficits.256 Deep brain simulation is generally used in patients with drug resistance.255 Natural antioxidants such as curcumin remains a promising alternative therapy to prevent or inhibit oxidative stress and disease progression. Study conducted by Chen et al., used PD recapitulating 1-methyl-4-phenylpyridinium ions (MPP+) treated PC12 in vitro models to demonstrate positive effects of curcumin.127 MPP+ is an active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) which has shown to cause Parkinsonism in primates including humans by inducing oxidative stress, mitochondrial dysfunction, and neuronal cell death.127, 259, 260 Curcumin was demonstrated to protect PC12 cells from MPP+-induced damage by upregulating Bcl-2 and downregulating iNOS. It was also shown to prevent the loss of MMPo and attenuate increase in ROS upon MPP+ treatment in these cells.127 Curcumin was also shown to enhance SH-SY5Y cell viability, proliferation, tyrosine hydroxylase (TH) positive cells and microtubular-associated protein 2 (MAP2) positive cells upon MPP treatment and reduce MPP+-induced nuclear condensation and cell death by inhibiting cleaved caspase-3, phosphoJNK, phosphoJun and MKK4 activation.131,136 MPP+-induced Swiss albino mice Parkinson model showed reduced oxidative stress and lipid peroxidation when treated with curcumin as evidenced by upregulation of SOD, CAT and GSH.139 MPP+-induced dopamine neurotoxicity in C57BL/6 mice was also found to be reduced when curcumin was administered.131 This study also showed that curcumin increased locomotion frequencies, traction scores, and rearing frequencies and inhibited activation of astrocytes, phosphoJNK1/2, c-Jun, and cleaved caspase-3 in these models.131 Interestingly, another study demonstrated that MPTP-lesioned C57BL mice transplanted with curcumin activated mesenchymal stem cells (MSCs) derived from human umbilical cord exhibited improved rearing, dopamine levels, drop frequency and TH-positive cells. This study also showed that transplantation of curcumin activated MSCs modulated IL-10, HGF, NGF, VEGF, G-CSF, NADPH dehydrogenase, Bcl-2, Bax, and caspase-3 expression in these models.136 MPTP-induced neurodegeneration was also shown to be inhibited by curcumin and its derivative tetrahydro curcumin in Swiss albino mice models by inducing dopamine, DOPAC and inhibiting MAO-B activity.148 Curcumin and curcumin-manganese complexes improved cognitive functions, learning memory, dopaminergic neuronal damage and oxidative stress in MPTP-induced ICR mice Parkinson models.124 Another study revealed that treatment of novel curcumin nanocarrier formulation, PR-EXO/PP@CUR, markedly improved movement, coordination ability, dopamine levels, DOPAC and impeded α-synuclein aggregates, TNF-α, IL-1β, and IL-6 levels in MPTP-induced PD mice models.153
Similarly, 6-hydroxydopamine (6-OHDA) is another chemical used to induce PD symptoms in various models.129 Curcumin treatment was shown to inhibit 6-OHDA-induced cytotoxicity and NF-κB translocation in mesencephalon hybrid dopaminergic cell line MES23.5.129 It was also shown to inhibit 6-OHDA-induced cytotoxicity and cell death of SH-SY5Y cells by downregulating p53 and Bax/Bcl-2 ratio.133 Curcumin also restored MMPo and upregulated SOD levels and inhibited ROS production in these cells.129 Another study demonstrated that curcumin rescued 6-OHDA lesioned PC12 cell models by upregulating Beclin-1, and inhibiting phospho Akt, phospho mTOR, ROS, and MDA production.137 Moreover, curcumin inhibited α-synuclein aggregation and augmented α-synuclein solubility in A53T-mutant α-synuclein expressing SH-SY5Y cells.128 Additionally, curcumin also inhibited α-synuclein-induced toxicity, mitochondrial depolarization, ROS, caspase-3 activity, caspase-9 activity, and apoptosis in PC12 cells expressing inducible A53T-mutant α-synuclein.132,134 In another study, treatment of curcumin resulted in overexpression of leucine-rich repeat kinase 2 (LRRK2), mutation in which was reported in familial PD, in rat mesenchymal cells.130 In line with these, curcumin was also found to augment cell viability, adhesion, normal cell architecture of deutocerebrum primary cells compared to cells treated with 6-OHDA by upregulating SOD, GSH-Px, Wnt3a, β-catenin, c-MYC, and cyclin D1 and inhibiting MDA, apoptosis, and MMPo.135 Besides, curcumin administration enhanced TH-positive cells inhibited microglia and astrocytes activation seen as reduced GFAP in these cells, and prevented the degeneration of dopaminergic neurons in 6-OHDA lesioned ICR mice.142,143 Also, curcumin treatment induced SOD, GSH-Px, AChE, DA, FGF, NGF, TrkA, Hsp70, Wnt3a, β-catenin, c-MYC, cyclin D1, TH-positive cells, substantia nigra (SN) cells mass, SN cell cytoarchitecture, and reduced mean percentage of TH-positive cell loss, loss of dihydroxyphenyl acetic acid (DOPAC), loss of homovanilic acid (HVA), aberrated alteration in behaviour, rotation numbers, dopaminergic neuron death, GFAP astrocytes activation, and MDA levels in 6-OHDA-induced PD Sprague-Dawley rat models and thereby improved motor latency and neuroethological conditions.135,138,144 In the 6-OHDA lesioned Wistar rats curcumin increased DOPAC, TH-positive cells and decreased iron-stained cells.141 Further, curcumin supplementation also prevented TH-positive cell loss as evidenced by enhanced TH expression and neuronal count via upregulating autophagy score and reduced p62 and α-synuclein expression in 6-OHDA-induced Parkinsonian rats.137,146 Curcumin-loaded human endometrial stem cell derived exosomes (hEnSCs-EXOs-CUR) was found to effectively increased the 6-OHDA treated PC12 cell viability in vitro.152 This study also found that hEnSCs-EXOs-CUR treatment enhanced TH-positive cells, motor latency, rotational numbers and Bcl-2 expression and suppressed α-synuclein, Bax and caspase-3 in 6-OHDA lesioned mice.152 Another chemical rotenone (ROT), a pesticide and fish poison, has shown to be neurotoxic and several studies have used this chemical to generate animal models of PD.147, 261, 262 Curcumin was also shown to be effective in treating ROT-induced PD in Swiss albino mice models. In these models, curcumin treatment enhanced time spent on wire, locomotor activity, rearing, rotarod activity, retention time on rotarod, grooming behaviour, norepinephrine level, dopamine level, GSH, SOD, ATP, SDH, CAT, and MTT reduction activity and impeded CRP, IL-6, adenosine A2AR expression, α-synuclein, MDA, nitrite, AChE, angiotensin-II, caspase-3, DNA fragmentation, and neurodegeneration changes.147,145 A novel curcumin formulation, curcumin monoglucoside was also found to mitigate ROT-lesioned Parkinsonism by increasing cell viability, GSH, NQO1, complex I and complex IV activities, LDH release, and diminished ROS, hydroperoxides, MDA, NOS2, phospho JNK, phospho c-Jun, cleaved procaspase-3 and DNA damage, in N27 dopaminergic neuronal cells in vitro.149 This study also showed that curcumin monoglucoside supplementation ameliorated free radicals scavenging, GSH, and reduced mortality, locomotor deficits, dopamine turnover, and (DOPAC+HVA)/DA ratio in ROT-induced Parkinson's Drosophila flies.149 In another study, administration of curcumin nanoparticles was found to augment total body balance, distance travelled, number of rearings, CAT, and reduced number of slip steps, bradykinesia, TBARS, GSH-Px, GSH reductase activity, complex I inhibition in ROT-induced Parkinson's Swiss mice.150 Furthermore, supplementation with Soluplus (a polycarrier)-curcumin formulation significantly reduced Parkin protein, phospho Rab-10, and PINK1 in LPS model of Parkinson's C57BL/6 mice.154 Another study showed that curcumin is also beneficial in treating homocysteine Wistar rat model of Parkinson where it improved locomotory functions, neurons with Nissl bodies and Bax/Bcl-2 ratio.140 Also, curcumin loaded human serum albumin nanoparticles have been found to alleviate symptoms in PD in vivo. In this study, curcumin induced delay in age-related deterioration of movement, increased alcohol avoidance and dopamine transportation and reduced movement speed.151 Clinical trials aimed to understand the effect of curcumin on PD are scarce which is mainly due to the difficulty in obtaining desired number of patients samples. Recently, Ghodsi et al., showed that administration of curcumin (80 mg/day) reduced disease progression score i.e. Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III score in PD patients (n = 60) compared to those who received gelatin capsule as placebo.187 However, the post hoc analysis did not show significant difference between two groups.187 Although, several studies suggest that curcumin remarkably inhibit PD symptoms and alleviate inflammation in vivo, further clinical trials are imperative to establish its potential in treating PD.
3.8. Brain tumors
The prevalence of primary CNS cancers is drastically increasing with a current incidence rate of 27.86 per 100,000 individuals. Glioblastoma (GBM) is a most frequently occurring tumor among malignant primary CNS tumors, with an annual incidence of 3.19 per 100,000. GBM accounts for nearly 15.4% of all primary brain tumours and 45.6% of all primary malignant brain tumours.263, 264, 265 At present, surgical resection followed by the adjuvant chemo and radiation therapy is the standard care regimen for GBM and this practice is in use for more than ten years with no progress.266, 267, 268 The median overall survival of GBM patients is increased by this rigorous multimodal therapy to 15 months.266, 267, 268 Due to the poor prognosis and side effects of existing therapeutics, it is imperative to develop the novel therapeutics to enhance the survival rate and QoL of patients.265 Contemporary medications and plant chemicals have been widely explored as anti-brain cancer agents due to their minimal toxicity profiles. Curcumin treatment has been shown to augment cell viability, nuclear translocation of TFEB, HO-1, LAMP-1, LC3II, Nrf2 translocation, MCOLN1, and modulate GSK-3β, p62, ROS, phosphoJNK/JNK ratio, phospho ERK, phospho Tau, LC3BII/I, H2O2-induced oxidative stress, UBC9, and SUMO-ylation in SH-SY5Y neuroblastoma cells.124,122,123
3.9. Traumatic brain injury (TBI)
Traumatic brain injury (TBI) is a serious CNS damage often known as a sudden insult brought on by falls, sports, auto accidents and neuronal inflammation.32,269,270 TBI affects more than 10 million young and old people annually worldwide.269,271 Localized brain damage results from primary TBI, whereas secondary TBI commences with inflammatory activity and progresses to disruption of the BBB, CNS edema, enhanced peripheral immune cell infiltration and the release of a myriad of immune mediators, such as chemokines and interleukins. TBI changes neuronal cell architecture, integrity, molecular signalling and functioning.272 TBI generally disrupts brain physiology, impairs cognition, decision-making capability, memory, attention, and speaking abilities in addition to tissue damage like axonal damage, hemorrhage and contusions.272 Due to the underlying complex pathophysiological mechanism, effective pharmaceutical treatment for TBI is still elusive.32 Several studies indicate that curcumin attenuates cerebral edema, promote energy homeostasis and inhibit oxidative stress followed by TBI. For example, curcumin was found to reduce inflammatory markers including TLR4, MCP-1, IL-1β, IL-6, TNF-α, regulated upon activation, normal T-cell expressed and presumably secreted (RANTES), NF-κB, phospho IκB-α, myeloid differentiation primary response gene 88 (MYD88), and infiltration of TLR4+ microglia/macrophages followed by cerebral edema, and brain water content in craniotomy-induced TBI mice. This study also reported that curcumin enhanced IκB-α levels in these mice TBI models.155 The experiments aimed to identify molecular mechanisms also have shown that curcumin treatment effectively increase IκB-α levels and inhibit cleaved caspase-3, neuronal damage, microglia activation, IL-6, IL-1β, phospho IκB-a, NF-κB, and RANTES in LPS treated microglia cells in vitro.155 In another study curcumin was reported to improve overall locomotion, time spent on exploring a novel object, and suppress IL-1β, GFAP, and phospho NF-κB levels.158 Curcumin treatment was shown to profoundly reduce brain water content and cerebral edema via downregulating aquaporin 4 (AQP4) levels.158 Administration of curcumin was also shown to improve motor performance, recovery balance, lesion healing and inhibit MDA levels in surgically-induced TBI rat models.159 Besides, dietary supplement of curcumin promoted BDNF, phospho synapsin I, swimming timing in the target zone, and suppressed oxidized proteins, escape latency in Sprague-Dawley rats with post fluid percussion injury (FPI) induced TBI.156 Similar study conducted on Sprague-Dawley rats with FPI-induced TBI showed that curcumin treatment efficiently upregulated phospho AMPK/AMPK ratio, ubiquitous mitochondrial creatinine kinase (uMtCK), UCP2, silent information regulator 2 (Sir2) and COX-2 levels.157 In addition, in the surgery-induced TBI ICR-mice models curcumin supplementation was shown to reduce neurological severity scoring (NSS) score, brain water content, cerebral edema, and neuronal apoptosis.160 Studies have also proven that at the molecular level curcumin upregulated Bcl-2, GSH-Px, SOD, HO-1, NQO-1, and nuclear translocation of Nrf2, and downregulated cleaved caspase-3, MPO+ cells, TNF-α, IL-1β, IL-6, and MDA levels in TBI mice models.160,161 Recently, Dong et al., demonstrated that administration of curcumin resulted in alleviation of thyroid and liver injuries in gas explosion (GE) induced TBI Sprague-Dawley rats. This study showed that curcumin treatment effectively increased body weight, liver weight, triiodothyronine (T3), tetraiodothyronine (T4), thyroid stimulating hormone (TSH), SOD, thyroglobulin, FOXE1, thyroid stimulating hormone receptor (TSHR), and thyroid stimulating hormone beta (TSHβ) levels, and reduced thyroid weight, immune cells infiltration, thyroid follicular cavity size, MDA thyrotropin-releasing hormone receptor (TRHR), transthyretin (TTR), GSH-Px, ROS, NF-κB, paired box 8 (PAX8), thyroid transcription factor 1 (TTF1), NIS, and thyroid peroxidase (TPO) levels in these GE-induced TBI rat models.162 In another study, a curcumin derivative CNB-001 administration was reported to promote BDNF, synapsin I, CREB, SOD and learning ability and reduce foot faults and oxidized protein levels in FPI-induced TBI Sprague-Dawley rats.163 Moreover, THC was found to significantly inhibit brain water accumulation and edema, neuronal damage and apoptosis by upregulating Nrf2 nuclear translocation, Bcl-2, SOD, GSH-Px, LC3II, beclin, and phospho Akt, and downregulating cleaved caspase-3, Bax, p62 and MDA levels in TBI rat models.164,165 Further, curcumin niosomal NPs have been shown to suppress NSS score, brain water content, cerebral edema, Iba-1+ cells, GFAP+ cells, TLR4+ cells, NF-κB+ cells in TBI Wistar rats.166
Althouth clinical trials have shown that curcumin administration reduces inflammation in patients with spinal cord injury and TBI, well-planned large-scale trials are necessary to prove it's therapeutic potential. 188, 189, 190 Collectively, these studies suggest that curcumin and its derivatives attenuate cerebral edema and TBI by inhibiting associated inflammatory pathways.
4. Conclusions
Several etiological factors including inflammation, oxidative stress, and neuronal cell degeneration contribute to the onset and progression of NDs. Neuroinflammation followed by neuronal damage due to surge in inflammatory molecules is believed to be the major cause of NDs. Symptoms and damage related to these diseases can be treated using various approaches. FDA and European medicine agency (EMA) have been approved several drugs to treat NDs till date. However, these medications are either focused to provide temporary symptom relief or on improving patient QoL instead of disease cure and are also found to be associated with severe adverse side effects and habituation. Compelling evidences suggest that curcumin, its derivatives and formulations prevent the onset and progression of various NDs. In particular, in vitro, in vivo, and clinical studies focusing at the effects of curcumin on NDs revealed that curcumin modulates important signalling pathways and molecules that regulate neuroinflammation. For example, curcumin and its derivatives have been found to regulate Akt/mTOR pathway, NF-κB pathway, β-catenin pathway, NLRP3 inflammasome pathway, BDNF/TrkB pathway, Nrf2, IL-6/STAT3 inflammatory pathways and DNA repair pathways. For decades, the low bioavailability of oral curcumin was restricted its use in NDs. However, recent development in conjugation, nanocurcumin and liposomal formulation have successfully addressed these issues and pharmacokinetics and pharmacodynamic studies have shown that these formulations facilitate the better absorption and cellular availability and can be used as effective and safer agents to treat NDs in animal models and clinical settings. Additionally, curcumin and their formulations have been found to downregulate inflammatory cytokines including IL-6, IL-1, TNF-α, IL-13, IL-17, IL-23 and upregulate anti-inflammatory molecules such as TGF and IL-10. Recent studies have also shown that curcumin and its formulations reduced cognitive impairment, memory impairment, oxidative stress, and neurodegeneration, and improved spatial learning memory, and motor activities. However, clinical trials are scarce on NDs and the current trials with low sample size have concluded the effect of curcumin. Nevertheless, it is necessary to design clinical trials for curcumin and its formulations with higher sample size to characterize the appropriate dosage, bioavailability, and safety in patients who are at risk and diagnosed with NDs.
CRediT authorship contribution statement
Prachi Garodia: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. Mangala Hegde: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. Ajaikumar B. Kunnumakkara: Conceptualization, Methodology, Funding acquisition, Writing – original draft, Writing – review & editing. Bharat B. Aggarwal: Supervision, Conceptualization, Project administration, Writing – review & editing.
Acknowledgments
Acknowledgment
Mangala Hegde acknowledges Science and Engineering Research Board (SERB)-National Post-Doctoral Fellowship (NPDF) (PDF/2021/004053). All the figures are created using Biorender.com.
Conflicts of interests
The authors declare that they have no conflict of interest.
Funding
This project was supported by BT/556/NE/U-Excel/2016 grant awarded to ABK by Department of Biotechnology (DBT), Government of India.
Ethical statement
Not applicable.
Data availability
Data sharing is not applicable to this manuscript as no new data were created or analysed in this study.
Footnotes
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.imr.2023.100968.
Contributor Information
Prachi Garodia, Email: prachigarodia@hotmail.com.
Bharat B. Aggarwal, Email: bbaggarwal@gmail.com.
Appendix. Supplementary materials
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