Table 1.
Antioxidant and mitochondrially targeted neuroprotective drugs in different neuropathological models.
| Drug Class (Compound) | Mechanism of Action | Therapeutic Outcomes | References |
|---|---|---|---|
| a-Lipoic acid | Scavenges the toxic by-products of lipid peroxidation | Antioxidant properties in AD | [18,19] |
| Bacopa monnieri extract | Reduces oxidative stress | Ameliorates learning and memory impairments through synaptic protein, neurogranin, pro-and mature BDNF signaling, and HPA axis in PNS in the rat brain | [20] |
| Carotenoid (Lycopene) | Suppress oxidative damage | Antioxidant, anti-inflammatory, memory enhancing and neuroprotective activities in HD | [18,21] |
| Cholest-4-en-3-one | Scavenges the toxic by-products of lipid peroxidation | Effective in treating painful diabetic and chemotherapy-induced neuropathies | [18] |
| Cryptotanshinone (quinoid) | Reduces oxidative stress and inflammation | Anti-apoptotic properties in PD-hiNPCs, significantly reduced cellular apoptosis through mitochondrial restoration (reactive oxygen species and mitochondrial membrane potential). These effects are mediated via the nuclear factor erythroid 2-related factor 2 (NRF2) pathway in PD-hiNPCs. | [22] |
| Curcumin (volatile oil) (Curcuma longa) | Suppress tumor necrotic factor (TNF) activity, formation of Aβ plaques and protects brain cells from noxious agents | Antioxidant, anti-inflammatory and amyloid disaggregating properties in AD | [17,18,21,23,24] |
| Cystamine (CYS) | Reduces oxidative stress/apoptosis | Increased BDNF protein levels in mouse frontal cortex, prevention of chronic HAL treatment-induced reduction in BDNF, GSH, and Bcl-xl protein levels, prevention of reduction in neuronal cell viability, BDNF protein levels and apoptosis in ND. | [25,26] |
| DHA (fatty acid) | Reduces oxidative stress and modulates membrane fluidity | Increased membrane fluidity and non-amyloidogenic processing of APP in AD HEK293 cells, leading to enhanced secretion of sAPPα. This enhanced secretion of sAPPα was associated with substantial protection against apoptosis induced by ER Ca2+ store depletion | [27] |
| Dichloroacetate | Activates the pyruvate dehydrogenase complex and lower cerebral lactate amounts | Neuroprotective activity in HD | [18,28] |
| Disaccharide (Trehalose) | Inhibits amyloid formation, aggregation of β-amyloid and autophagic activities against aggregation proteins (huntingtin) | Neuroprotective properties in HD | [18,21] |
| Epigallocatechin-3-gallate (Camellia sinensis) | Stabilize mitochondrial functions like ATP levels | Antioxidant properties in AD | [18,21,23] |
| Ferulic acid (Smallanthus sonchifolius) | Neuroprotective effect against oxidative stress and cell death induced by Aβ42 oligomers | Antioxidant properties in AD | [18,21,23] |
| Flavones | Reduces oxidative stress | Neuroprotection was found to be mediated via activation of the anti-apoptotic cell survival proteins of the ERK1/2 and PI3K/Akt pathways in neuroblastoma cell lines. | [29] |
| Ginsenosides Rg1 and Rg3 (Ginseng) | Suppress Aβ induced neurotoxicity, Aβ associated generation of ROS and cell death | Neuroprotective effect in AD | [18,21,23] |
| JM-20 (anxiolytic) | Acts through mitochondrial metabolism | Strong antioxidant action and neuroprotective effects against Ca2+-induced impairment in rats brain, which are both elicited at the mitochondrial level | [30] |
| LMWSC (sulfated chitosan is the structural analog of heparin converted to low molecular weight polymer by γ-irradiation) | Lipids | Reduction of the intracellular ROS levels in PD, normalization of antioxidant enzymes, mitigation of rotenone induced mitochondrial dysfunction and apoptosis in neuroblastoma cell lines | [31] |
| Melatonin | Direct scavenger of many ROS species such as free radicals, peroxylnitrites, hydroxyls, peroxyls, and other nitrous oxides under normal conditions | Antioxidant properties in ND. Protective role against H-89-induced memory impairment in mice brain | [11,32] |
| Mitoquinone | Produces direct antioxidant action by scavenging peroxyl, peroxynitrite and superoxide ROS | Antioxidant properties in PD | [33] |
| N-acetylcysteine | Protects against cadmium-induced ROS toxicity marked by reduced mitochondrial membrane potential, high cytoplasmic cytochrome c release, reduced Bcl-2 expression, p53 expression and caspase pathways | Neuroprotective properties | [18,34] |
| N-acetyl-l-tryptophan (L-NAT) | Neuroprotective in primary motor neurons by inhibition of the secretion of Substance P and IL-1β and mitochondrial dysfunction by inhibiting the release of cytochrome c/Smac/AIF and activation of apoptotic pathways (caspase-1, -9, and -3), as well as proteasomal dysfunction through restoring chymotrypsin-like, trypsin-like, and caspase-like proteasome activity in ALS. | [35] | |
| Naringin, hesperidin and kaempferol (flavonoids) | Exerts protective action against peroxynitrite induced oxidative damage and inhibit nitric oxide synthase (involved in HD) | Anti-inflammatory, antioxidant and neuroprotection in HD | [18] |
| Nicotinamide | Reduces oxidative stress, acts through mitochondria | Inhibition of ketamine-induced neuro-apoptosis by downregulating Bax, inhibiting cytochrome c release from mitochondria into cytosol, and inhibiting the expression of activated caspase-3 | [36] |
| Olanzapine | An antipsychotic agent with affinity for D1 and D2 dopamine receptors as well as 5-HT2A serotonin receptors | Improved motor symptoms in HD | [18] |
| Olesoxime | Scavenges the toxic by-products of lipid peroxidation | Antioxidant and neuroprotective activities in NP | [37] |
| P7C3 (aminopropyl carbazole) | Acts through mitochondria | P7C3 stabilized mitochondrial membrane potential in PD (dopaminergic cell lines), reduced ROS production, and inhibited GSK3β activation, p53 activity, Bax upregulation and cytochrome c release exposed to MPP+, and prevented neuronal loss in the substantia nigra (mice brain) | [38], p. 3 |
| Celastrol (Celastrus regelii) | Inhibits nitric oxide synthase (involved in PD and HD) | Anti-inflammatory, antioxidant and neuroprotective activities in PD and HD | [18,21] |
| Peroxiredoxin | Reduces oxidative stress and apoptosis (via signal-regulating kinase (ASK1)-dependent activation of the c-Jun N-terminal kinase/c-Jun and p38 pro-death pathways) | In vitro and in vivo neuroprotection against 6-OHDA toxicity in DA neurons, and preserved motor functions involving the dopamine system in mouse (PD). PRX2 exhibited antioxidant and anti-apoptotic effects via suppression of apoptosis signal-regulating kinase (ASK1)-dependent activation of the c-Jun N-terminal kinase/c-Jun and p38 pro-death pathways | [39] |
| Quercetin (flavonoid) | Reduces oxidative stress and inflammatory parameters | Quercetin supplementation decreased the neuronal damage, scavenged the free radicals induced by PCBs and protects PCB-induced apoptosis and oxidative stress in the rat brain. | [40] |
| Retinoic acid | Acts through the proteasome | A treatment of cultured neuroblastoma cells sets up conditions under which proteasome inhibition, and the resultant accumulation of ubiquitinated proteins, loses its ability to kill the cells (PD) | [41] |
| Riluzole | Reduces ROS generation via induction of glutathione production | Antioxidant properties in ALS | [42] |
| Sesamol (Sesamum indicum) | Suppress inducible nitric oxide synthase (iNOS) expression and neuroinflammation in hippocampus neurons | Antioxidant and neuroprotective activities in HD | [18] |
| Sildenafil (phosphodiesterase type 5 inhibitor) | Acts through cyclic GMP phosphodiesterase | Inhibited nitrosative stress and augmented the levels of LC3, beclin-1, ATG5, p-CREB and BDNF and decreased mTOR levels, as well as augmented p-AMPK in mice spinal cord (MS). | [43] |
| Steroidal lactones (withaferin A, withanolide A, withanolide D-P) (Withania somnifera) | Improves cognitive functions and restores acetyl cholinesterase enzyme activity | Antioxidant and neuroprotective properties in HD | [18] |
| Terpene lactones (ginkgolides and bilobalides) and flavonoids (flavonols and flavone glycosides) (Ginkgo biloba) | Stabilize mitochondrial functions like ATP levels and interacts with mitochondrial electron transport chain | Antioxidant and neuroprotective properties in dementia, AD and PD | [18,21,23] |
| Triterpene saponin (glycyrrhizin) and phenol (isoliquiritigenin) (Glycyrrhiza) | Reduces oxidative stress and damage to brain cells | Antioxidant, anti-inflammatory and neuroprotective properties in dementia, AD and PD | [18,21,23] |
| Triterpenoid saponins (Bacosides A and B) (Herpestis monniera) | Scavenging of free radicals and improves memory | Antioxidant, anti-stress, antidepressant and useful in HD treatment | [18,21] |
| Triterpenoid saponins (asiaticoside, asiatic acid and madecassoside) (Centella asiatica) | Reduction in the activity of electron transport chain enzymes and decreased mitochondrial viability | Antioxidant and neuroprotective properties in HD | [18] |
| VDAC1-derived peptide | Forms the permeability transition pore that further promotes apoptosis (through mitochondria) | Aβ Entry into SH-SY5Y Cells (AD) Is Inhibited by the VDAC1 N-Ter Peptide | [44] |
| Vitamin C | Maintains the integrity of cellular membranes in mitochondria | Antioxidant and neuroprotective activities in NP | [18] |
| Vitamin E | Maintains the integrity of cellular membranes in mitochondria | Antioxidant properties in AD | [18,19] |
| Y27632/NAD+/ZVAD-FMK/resveratrol | Kinase/Caspase | Y27632 and NAD+ exert strong synapto-protective activities whereas zVAD-FMK and resveratrol fail to protect synapses (in primary neuronal cultures from mice brain) (neurodegeneration) | [45] |
6-OHDA, 6- hydroxide dopamine; AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; APP, β-amyloid precursor protein; BDNF, brain derived neurotrophic factor; DHA, omega-3 fatty; HAL, haloperidol; HD, Huntington’s disease; hiNPS, human induced neuroprogenitor stem cells; HPA, hypothalamic–pituitary–adrenal; GSK3β, glycogen synthase kinase-3 beta; L-NAT, N-acetyl-l-tryptophan; LMWSC, low molecular weight sulfated chitosan; MPP+, 1-methyl-4-phenylpyridinium; MS, multiple sclerosis; NAD+ nicotinamide adenine dinucleotide; ND, neurodegeneration; PD, Parkinson’s disease; PNS, prenatal stress; RD, retinal degeneration; RNCs, retinal cells; ROS, reactive oxygen species; TH, tyrosine hydroxylase; Y27632, Rho Kinase inhibitor.