Neurodegenerative disorders: Assessing the impact of natural vs drug‐induced treatment options

Abstract

Neurodegenerative illnesses refer to the gradual, cumulative loss of neural activity. Neurological conditions are considered to be the second leading cause of mortality in the modern world and the two most prevalent ones are Parkinson's disease and Alzheimer's disease. The negative side effects of pharmaceutical use are a major global concern, despite the availability of many different treatments for therapy. We concentrated on different types of neurological problems and their influence on targets, in vitro, in vivo, and in silico methods toward neurological disorders, as well as the molecular approaches influencing the same, in the first half of the review. The bulk of the second half of the review focuses on the many categories of treatment possibilities, including natural and artificial. Nevertheless, herbal treatment solutions are piquing scholarly attention due to their anti‐oxidative properties and accessibility. However, more quality investigations and innovations are undoubtedly needed to back up these conclusions.

Age, Epigenetics, Beta Amyloid, Genetic Mutations, Environmental Causes, Viruses, Herbicides, and Smoking are the well‐known factors that contribute to damage to the brain. These degenerative neurons are responsible for neurodegenerative diseases, ranging from commonly occurring Alzheimer's, Parkinson's, Amyotrophic Lateral Sclerosis and Spinal Muscular Dystrophy to even rare forms such as Friedreich ataxia. However, these degenerative disorders can be treated using both drugs as well as herbal‐based treatment methods. Drugs as medicines do offer relief from the symptoms but also contribute to a wide range of side effects which include dizziness, hormonal imbalance, and in serious cases, it may result in cancer. Herbal treatment on the other hand has currently not reported any side effects.

1. INTRODUCTION

In the modern world, neurological disorders are regarded as the second greatest cause of death. “Neuro‐,” which refers to nerve cells and “degeneration,” in the context to tissues or organs, denotes losing structure or function. Thus, neurodegeneration can be explained as a gradual loss in the functionality as well as the structure of neurons, ultimately resulting in death. ¹

There are significant medical and health care costs associated with degenerative disorders of the neurological system for people all over the world. Three of the main neurodegenerative illnesses include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Given that the frequency and incidence of these diseases grow sharply with aging, reported cases are anticipated to climb soon as life expectancies continue to rise in many nations. ²

For the therapeutic treatment of neurodegenerative disorders, there are many medications in the form of drugs like apomorphine, baclofen, donepezil, entacapone, etc. However, these medications offer very little benefit from the illness and are frequently accompanied by a wide range of side/harmful effects to the patient.

Due to their accessibility, minimum of side effects compared to pharmaceuticals, and antioxidant qualities, natural products may present chances in the prevention and control of neurological illness symptoms. For instance, P. ginseng has been shown to have positive benefits on neuronal degeneration illnesses because of its antioxidative and antiproliferative properties. Mechanism of action investigations showed they also regulate mitochondrial activity, cell surveillance or gene death, and intrinsic neuronal signaling as well as metabolism. ³

The objective of this review paper is to compare natural (herbal) and drug‐based treatments for neurological illnesses as well as to highlight the differences the benefits that the former holds.

1.1. Statistics of neurodegenerative disorders

People across the globe are affected by neurodegenerative disorders. The two most prevalent neurological illnesses are AD and PD. According to an estimate from the Alzheimer's Disease Association, 6.2 million people in the United States might suffer from AD in 2022. According to the Parkinson's Foundation, about a million Americans suffer from PD. ⁴

The number of people dying from neurological illnesses rose by 36.7% between 1990 and 2015; the majority of these increases were caused by stroke and infectious neurological diseases.

The most common neurological conditions were:

Headache due to stress, migraine, and headache due to excessive use of medication for AD and dementia.

The medium and maximum levels of SDI had the greatest and lowest incidence of stroke, respectively. Years of life lost (YLL) changed more than Disability‐Adjusted Life‐Years (DALY) rates of neurological illnesses with development. ⁵

To the total illness burden in India, non‐communicable and concussion‐related neurological diseases contributed more than twice as much over the course of 29 years, from 4%in 1990 to 8% in 2019.

In India, the neurological disorders that contributed the most DALYs overall in 2019 were:

Stroke, headache, epilepsy, cerebral palsy, and encephalitis.

Poor birth weight, shortened pregnancy, and poor air quality were the recognized risk factors for communicable illnesses with moderate impacts to DALYs(Table 1). ⁶

TABLE 1.

Types of neurodegenerative disorders and their effects on various targets

Neuro‐degenerative disorders	Factors	Effects	Targets	References
Parkinson's disease	Age	The faster rate of motor progression, cognition impairment, and dementia	Neuronal cells	Levy G (2007) 7
	Paraquat; known herbicide	Damages the bilateral dopaminergic system	Dopamine neurons	McCormack et al. (2002) 8
	Parkinson's due to the use of drugs	Dopamine activity is inhibited 9 , 10	Dopamine neurons	parkinsons.org UK and NHS. UK
	Cerebro‐vascular disorders	Macro and microscopic infarcts and arteriolosclerosis may contribute to mild signs. Small vessel accounts for both infarcts, the causes of symptoms may not only include infarcts, but also structure or function alterations in the neural cells. 11	Neurons either functional or structural aspect	Buchman et al, (2011)
	α‐synuclein	Protofibrils; the soluble oligomeric conformation of α‐synuclein disrupts cellular homeostasis and neuronal death 12	Neurons	Stefanis (2012)
	Oxidative stress	Degeneration of structure and function of neuronal cells 13	Neuronal cells	Jang et al (2016)
	Calcium dynamics	Overload of calcium due to accumulation of mitochondrial damage causes a loss of mitochondrial bio‐energetic function 14	Neurons and mitochondrial function	Reeve et al (2014)
Alzheimer's disease	Beta‐amyloid (Aβ)	Loss in memory or cognition is mainly due to misfolding of the Aβ protein that accumulates mainly in SP 15 , 16	Amyloid precursor protein; is proteolyzed by β‐ and γ‐secretases	Chen et al (2017), O'Brien et al (2011)
	Epileptic activity	Temporal lobe of the brain 17	Epileptic activity was associated with increased tau NFTs and seizures can hasten cognitive decline	Vossel et al (2017)
	Epigenetics	Genomic DNA 18	Addition of methyl group C residues of DNA decreases with age in tissues contributing to changes in the epigenome	Qazi et al (2018)
	Aluminium additives	Iron dependent cells 19	Al accumulates in Fe dependent cells dysregulating iron homeostasis and depletion of microtubules resulting changes in disconnection of efferent and afferent neurons, loss of functional and regional atrophy	Walton J. R. (2014)
	Type 2 diabetes	Hypothalamus 20	Disruption to pro‐inflammatory signaling due to AβOs, key synaptotoxins in AD, lead to attenuated insulin signaling and decreased cellular responsiveness	De Felice et al (2014)
FRDA	Mutation	Frataxin gene to target the production of frataxin protein 21	GAA trinucleotide repeat on chr9q13 causes transcriptional defect of the frataxin gene, leading to FRDA	Koeppen A. H. (2011)
	Fe	Frataxin deficiency imbalances normal equilibrium of Fe 22	Involvement of Fe in pathology of FRDA is not known; maybe due to accumulation or deficiency of Fe	Alsina et al (2018)
Spinal muscular atrophy	Genetics: FBXO38	Impairment in the activity of FBX038 gene causes gradual late‐onset of SMA with a weakness of muscles 23	Motor neurons	Sumner et al (2013)
	SMN1	Decline in the activity of motor neurons leads to weakness and thinning of muscle mass and movement 24 , 25	Motor neurons and skeletal muscles	Jangi et al (2017), Medlineplus
	DYNC1H1	Mutations in DYN (DYNC1H1) cause loss of spinal muscle mass 26	Disrupts DYN functioning	Harms et al (2015)
	BICD2	Mutations cause gradual weakness and decline of muscle mass of proximal and distal muscle of the leg 27	Motor neurons	Neveling et al (2013)
ALS	Environment causes 1. Smoking	Pooled analysis and meta‐analysis support this at least in women. Unclear whether the association between ALS and smoking is caused by nicotine, oxidative stress, or other toxic substances in tobacco smoke. 28 , 29	UMN and LMN	Oskarsson et al (2015), Martin et al (2017)
	Chemicals	Unclear regarding the participation of chemicals, such as heavy metals, aromatic hydrocarbons and pesticides 29	UMN and LMN	Martin et al (2017)
	Physical activity	Unclear whether higher levels of physical activity raise the occurrences of ALS 29	UMN and LMN	Martin et al (2017)
	Trauma	Not known whether Traumatic brain injury, might be a factor toward ALS 30	UMN and LMN	Franz et al (2019)
	Viruses	Person infected with the HIV‐1 or HTLV‐1, develop ALS‐like syndromes. HIV‐infected patients develop symptoms that overlaps with the symptoms of ALS. Enteroviruses in ALS, has not yet been established. 31 , 32	Targets motor neurons	Alfahad et al (2013), Xue et al (2018)
	Gender	In occasional ALS, men have greater chances of onset in the spinal regions, whereas women tend to have onset in the bulbar region due to different concentrations of toxins, repairability of damage and differences in nervous systems. 33	UMN and LMN	McCombe et al (2010)
	Age	Chances of ALS increases with age 28	UMN and LMN	Oskarsson et al (2015)

Abbreviations: ALS, amyotrophic lateral sclerosis; FRDA, Friedreich ataxia; LMN, lower motor neuron; NFT, intraneuronal neurofibrillary tangle; NHS, National Health System; SMA, spinal muscular atrophy; UMN, upper motor neuron.

1.2. Market overview of neurodegenerative diseases

The business for neurodegenerative diseases is predicted to grow at a compound annual growth rate (CAGR) of 6.93% from 2022 to 2027, from an average of US $45,441.30 million in 2021 to US $67,525.41 million in 2027.

In terms of the market for neurodegenerative diseases, North America dominates.

Increased awareness, an increase in the incidence of neurological disorders, and a robust treatment option for neurodegenerative diseases are the main drivers of market expansion. According to data from the National Institute of Environmental Health Sciences updated in June 2022, an estimated 6.2 million Americans may have AD.

The number of individuals above and/or 65 years of age with AD dementia is assumed to increase to 12.7 million by 2050, according to the Alzheimer's Association's 2021 Alzheimer's Disease Facts and Figures. The growing prevalence of AD increases the need for cutting‐edge treatments to combat the status of the illness.

The influence of the pandemic on the industry was considerable because it affected clinical trial procedures, research and development (R&D) operations, and mainline products. As a result, development even during this time was rather moderate despite a strong late‐stage product pipeline. ³⁴

2. MECHANISTIC APPROACHES OF NEURODEGENERATION

2.1. Role of reactive oxygen species, tau, and beta‐amyloid in neurodegeneration

A 140‐amino acid protein called α‐synuclein is hypothesized to control release of neurotransmitter dopamine, alterations that take place at synapses, the connectors between neurons that enable communication, and differentiation of cell. ³⁵

Although its biological form (non‐toxic) does not stimulate reactive oxygen species (ROS) generation in neurons and glia, it can cross plasma and intracellular membranes and elicit the release of ROS. In fact, the monomeric form agglomerates to a framework that develops insolvable harmful oligomeric intermediates. ³⁶

Overproduction of ROS within cells damages lipids, nucleic acids, amino acids, and membranes, which may trigger programmed cell death. ³⁷

ROS encourages poly (ADP‐ribose) polymerase (PARP) activity, which alters the energy homeostasis by lowering the NAD+ content, in PD‐related Fbxo7‐deprived cells. Oligomerized and transformed α‐synuclein induces PARP‐1 to create PAR, which in turn mediates cell death by continuing the synthesis of pathologic α‐synuclein. ³⁶

Both neurons and non‐neuronal cells like oligodendrocytes and astrocytes produce tau protein sparingly. It is a protein that binds to microtubules and maintains their structure, which is necessary for neural growth. Post‐translational modification (PTM), conformational alterations, and tau's misfolded conformation are involved in tau alteration, which causes tau to abnormally accumulate into neurofibrillary tangles (NFTs) and cause neurodegeneration. The complexity of AD and PD, relates to the amount of NFTs as well as tau alterations. ³⁸

Tau changes are actively promoted by ROS. Insoluble tau aggregation integrates into the membrane, thereby altering electrical currents and cell membrane voltage, and triggering voltage‐gated calcium (Ca2+) channels (VGCC). This results in an intracellular calcium influx that stimulates NADPH oxidase to produce ROS. Acute toxicity is likely to result from the interaction of each of these effects. ³⁹

Slight suppression of mitochondrial complex I cause the F1Fo ATPase to convert to backward mode in order to maintain the potential gradient of membrane of mitochondria. In cells with complex I inactivation, this form of mitochondrial potential maintenance could result in mitochondrial hyperpolarization, which increases the development of ROS (Figure 1). ³⁶

FIGURE 1.

Explains the role of tau and beta‐amyloid protein in ROS production. Tau not only causes a rapid increase in the generation of Ca2+ ions, which raises levels of reactive oxygen species, but it also oligomerizes to produce pores on the surfaces of astrocytes and lowers the activity of complex 1 located on the mitochondrial cell structure. The beta‐amyloid build‐up causes pores to develop, which also speeds up the generation of Ca2+ ions, however, it exercises its effect in three ways by firstly reducing the levels of GSH, secondly increasing the levels of PARP and thirdly on NAD(+) by decreasing its levels. Adapted from: Abramov et al. (2020). Created with BioRender.com.

The amyloid precursor protein is broken down into 39–43 amino acid peptides called Aβ peptides by the enzymes β‐ and γ‐secretases (APPs). In grown neuronal cells, β‐amyloid most efficiently binds to astrocyte membranes and can trigger ASK1 primarily through the release of ROS but not by inducing endoplasmic reticulum (ER) stress. ⁴⁰

The processes that astrocytes and neurons use to regulate internal levels of cholesterol and its transportation within the brain are very distinct, despite the fact that both types of cells generate cholesterol from start, albeit in varying quantities. Similar to the peripheral circulation, lipoproteins, which are made by astrocytes rather than neurons, interact with cholesterol in the brain. In contrast to neurons, which is solely triggered by lipoproteins, astrocytes are driven to release cholesterol through both lipid‐free apolipoproteins and lipoproteins. ⁴¹

Therefore, astrocytes have elevated levels of cholesterol than neurons, which then creates porous structure in their membranes that can induce a calcium signal. Such pores also induce GSH to drop significantly, the DNA‐repairing enzyme poly(ADP‐ribose) polymerase to be activated, mitochondria to depolarize, and the death of neurons in astrocytes. ³⁶

In parallel to Aβ‐peptides producing ROS in the presence of metallic ions, mitochondrial dysfunction is also involved in the development of AD through the formation of ROS by the mitochondria. ⁴²

Accordingly, ER stress, nitric oxide (NO), and ROS have been linked to Aβ‐induced neurotoxicity (Figure 1). ⁴⁰

2.2. Oxidation of mitochondrial and lipid involved in neurodegeneration

Oxidation of phospholipid bilayer, also known as lipid peroxidation, is a quasi‐mechanism that can be aided via COX, CYP, and LOX as well as variables of ROS. ⁴³

Oxidative deterioration of DNA, peptides, or phospholipid bilayer may result from excessive ROS generation. The tissue's makeup and the intrinsic antioxidant system's capacity to return ROS generation to baseline levels determine the degree of tissue oxidation degradation. As it contains a significant amount of oxidation‐prone polyunsaturated fatty acids (PUFAs). ⁴⁴

With greater contents of palmitate, omega‐6 PUFA arachidonic acid, and DHA but small amounts of EPA, the brain has a distinctive fatty acid profile that suggests the brain regulates concentrations through nutritional absorption. Because DHA serves as the most significant omega‐3 PUFA in terms of quantity in the brain, deficiencies in DHA and even EPA levels have been observed in neurological conditions. A growing body of research backs up the positive effects of increasing PUFA intake in a number of neurodegenerative disorders due to their preventative capabilities. ⁴⁵

Numerous neurogenic illnesses, such as AD, PD, Huntington's disease, ALS, and Spinocerebellar ataxia, and the preponderance of neurodegenerative disorders have also been demonstrated to include abnormalities in mitochondrial redox equilibrium and excessive generation of ROS. ⁴⁶

During enzymatic processes, GSH efficiently neutralizes free radicals as well as ROS and RNS. Its function as a co‐substrate for GPX has been acknowledged as the most significant pathway for the reductions of hydrogen peroxide and lipid hydroperoxides. It also serves as an antioxidant in the purification of byproducts resulting from ROS‐induced oxidation of lipids. Lack of GSH leads to oxidative stress, which is linked to the pathophysiology of illnesses, notably malignancy and dementia. ⁴⁷

By using GSH as a coenzyme to decrease lipid peroxides to the appropriate R‐OH or R‐CHO, glutathione peroxidase (GPx) uses the results of lipid oxidation to produce hydroxyl acids catalytically (Figure 2). ⁴³

FIGURE 2.

Explains the role of lipid peroxidation as a mechanism toward neurodegeneration. Lipid peroxidation can occur either due to excessive production of reactive oxygen species (ROS), by the increased action of cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes or by the involvement of transition metals. Once activated, lipid peroxidation induces the activation of phospholipases (each phospholipase carries out a different function). These phospholipases play a crucial role in neuronal inflammation. Using GSH as a coenzyme lipid peroxide can be reduced to the appropriate R‐OH or R‐CHO, GPx uses the results of lipid oxidation to produce hydroxyl acids catalytically. Adapted from Angelova et al. (2015). Created with BioRender.com.

Researchers have discovered that antioxidant nutraceuticals neutralize ROS or are necessary as coenzymes for antioxidative enzymes when consumed daily. Nutraceuticals are essential for proper aging and play important roles in the treatment of a range of age‐related illnesses such as neurodegenerative illnesses. ⁴⁸

Nutraceuticals are those foods that help with illness treatment as well as prevention. These are distinct from nutritional supplements, unlike the latter, which should just serve to enhance the diet, the former is involved in the treatment of the disorder. Examples of such substances include vitamin E, soy, vitamin D, green tea, etc. ⁴⁹

The endocrine mechanisms mediated by curcumin may directly decrease the synthesis of Aβ peptides. Tannic acid, a polyphenolic substance originating from plants, has been shown to have neuroprotective, anti‐inflammatory and antioxidant properties because it reduces toxic Aβ fibril accumulation. In addition to these, melatonin, berberine, and genistein displayed a notable mitigative impact. ⁵⁰

2.3. Neurodegeneration due to epigenetic changes

2.3.1. DNA damage contributing to neurodegeneration

When specific DNA lesions, such as base modification, mutation double or single stranded break occur, transcription and replication are disrupted, which causes cell death, senescence, and aging. DNA damage causes chromosomal abnormalities that can result in either cell malfunction or development of cancer. ⁵¹

Cerebellar neurons especially are affected by the predominance of neurodegenerative illnesses brought on by abnormalities in DNA repair genes, as opposed to motor neurons. ⁵²

The exact causes of defects in DNA repair in neurological system as a whole and the cerebellum in specifically are yet unclear. As a result of these flaws, reactive DNA deterioration gradually increases, which is a primary lead to cellular malfunction. This results in the loss of appropriate neurotransmission, which may then lead to the activation of defense pathways responsible for preserving genomic integrity thereby stimulating apoptosis and the death of neurons. ⁵³

In base excision repair and single stranded break repair, DNA production related to repair is mediated by the polymerase Polβ. Directed deletion of polβ results in new‐born mortality and extensive neuronal death in the growing central nervous system (CNS) and peripheral nervous system (PNS). ⁵¹

Etiologies as xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD), each of which has neurologic elements, are caused by mutations in nucleotide excision repair components. ⁵¹

Mice with downregulation of Ercc1 exhibit age‐dependent motor neuron deterioration and increase in the number of astrocytes as a consequence of neuron destruction from CNS all of which is comparable to ALS, this suggests that motor neurons might also be impacted by deficits in DNA repair. It is yet unknown if damage to DNA results from other pathogenic mechanisms or whether it directly causes motor neuron atrophy in ALS (Figure 3). ⁵²

FIGURE 3.

Explains the role of DNA damage in neurodegeneration pathway. DNA damage can occur either during failed/ error in replicative process or as a consequence of oxidative or de‐aminating agents. Base mutation, base modification, double stranded break repair, or single stranded base repair all of it contributes to degeneration of motor neurons. Adapted from Kok et al. (2021). Created with BioRender.com.

2.3.2. Role of misfolded proteins in neurodegeneration

The pathogenic hallmark of the majority of neurodegenerative disorders is a build‐up of protein aggregates, which may be a factor in synaptic atrophy and neuronal injury. Evidence suggests that overly produced ROS and reactive nitrogen species (RNS)‐dependent PTM, such as S‐nitrosylation and tyrosine nitration, cause this improper protein folding to aggregate in the brain. ⁵⁴

As they are important enablers of protein folding, molecular chaperones and the co‐chaperones are crucial in both health and sickness. Chains of HSP70 molecular chaperones have been linked to neurological disease brought on by misfolded protein. Congenital cardiac and neurological illnesses have been linked to abnormalities in multiple HSP70 co‐chaperones, directly connecting the HSP70 chaperone pathway to disease pathogenesis. ⁵⁵

The core of the cell connection of signaling molecules is made up of Hsp70 proteins. Through the interaction of their substrate binding domain with small non‐polar peptide sequences inside the substrate proteins, they support a wide range of protein folding activities in the cell. Because ATP drives the cellular cycle of binding and liberation of substrate, ATP binding and breakdown are crucial for their activity. ⁵⁶

The translational apparatus is connected directly to chaperones linked to protein synthesis (CLIPs). The proteome is guarded against environmental stressors like temperature, oxidative and hypoxic stresses by the second group of chaperones, known as heat shock proteins (HSPs). ⁵⁷

It has been discovered that a subgroup of chaperones, particularly CLIPs, are suppressed as the human brain ages and are triggered by simulating stress; these variations are especially prominent in the brains of patients with AD, Huntington's disease, or PD. These signs of physiological stress are thought to be a factor of neurodegeneration because they frequently appear in the progression of the disease (Tables 2, 3, 4, Figure 4). ⁵⁷

TABLE 2.

In vitro approach on neurodegeneration

In vitro approach
Compound	Target	Cell line	Inhibitory effect	Activation effect	Reference
Thymo‐quinone (TQ)	α‐synuclein aggregated	SH‐SY5Y (human neuroblastoma cells)	TQ reduced cell damage brought on by pre‐formed fibrils and decreased α‐ synuclein accumulation. TQ also inhibited the production of α‐synuclein‐fibrils and the toxicity. 58	N/A	Ardah et al (2019)
Novel chelators (M30, HLA20, and M32)	Lipid peroxidation and monoamine oxidase	Rat PC12 cells	Reduced the amount of 6‐hydroxydopamine and serum deprivation‐induced death of cells, it showed protective power equal to rasagiline, medication used in treatment of Parkinson's disease 59	N/A	Zheng et al (2005)
Trimethyltin (TMT), a neurotoxic organotin compound	Geijigadaehwang‐tang (GDT)	Microglial BV‐2 cells	IBA1, GFAP, NLRP3, and the phosphorylated (NF)‐B/total‐NF‐B ratio were all suppressed by GDT. Hindered the expression of TNF‐α, iNOS, ASC, caspase‐1, IL‐1 β, Nrf2, and HO‐1 mRNA as well. 60	N/A	Lee et al (2022)
Minocycline; semisynthetic tetracycline	Dopamine	Primary cultures of mesencephalic and CGN and/ or glia	iNOS generation caused by MPP and NO‐induced neurotoxicity were both reduced by minocycline. 61	N/A	Du et al (2001)
Statins	Neurons	HepG2, SK‐N‐MC and U87MG human cell lines	Greater potential for BBB permeability and decreasing effect on neurons' levels of cholesterol, derivatives of Monacolin J may be the greatest choices for preventing neurodegenerative diseases. Simvastatin offered the highest qualities for avoiding neurological diseases among the nine statins. 62	N/A	Sierra et al (2011)

Abbreviations: BBB, blood brain barrier; N/A, not applicable.

TABLE 3.

In vivo approach on neurodegeneration

In vivo approach
Compound	Target	Model used	Inhibitory effect	Activation effect	Reference
Melatonin	Prolonged melatonin therapy increased the activity of p‐PI3K, Ser 473, and Ser 9 in the Ab1‐42 treated mice, which reduced the hyper‐phosphorylation of tau protein through PI3K/Akt/GSK3b signaling.	Male wild‐type C57BL/6 N mice	N/A	Caspases are activated by Ab1‐42. Caspase‐3 that is stimulated splits PARP‐1, causing programmed cell death and degeneration on of neurons. 63	Ali et al (2015)
α ‐synuclein	MHC II Complex	C57BL/6 and MHCII KO mice	N/A	Complete human α‐syn production induces MHCII activity by microglia, whereas MHCII knockouts protect against α‐syn‐induced microglial stimulation, IgG accumulation, and dopaminergic neuronal degradation. 64	Harms et al (2013)
Homocysteine; neurotoxic amino acid	Memantine, MPEP, and LY367385 were used as NMDA, mGlu5, and mGlu1 antagonists	Male Sprague Dawley	N/A	Involvement of NMDA and group 1 mGluRs in Hcy‐induced degeneration and neurotoxic activity in the hippocampal region. 65	Yeganeh et al (2013)
Trimethyltin (TMT), a neurotoxic organotin compound	Geijigadaehwang‐tang (GDT)	C57BL6 mice	Depending upon the concentration of dosage given, neuroprotective effects of GDT were observed. 60	N/A	Lee S et al (2022)
N/A	Ca2+ homeostasis on Dopaminergic (DA) neurons	Drosophila melanogaster	In models of neuro‐degenerative diseases, mito‐Ca2+ equilibrium is disturbed. 66	N/A	Lee KS. et al (2018)
Quinolinic Acid	In mature mice that generated enlarged polyglutamine repeat version of the N‐terminal htt segment under the influence of a human promoter	Mice	N/A	Huntington disorders' excitation mediated toxic mechanisms triggers neuro‐degeneration 67	Slow et al (2005)
Ethanol	Neuronal cells	Seven‐day‐old C57BL/6 mice	N/A	During synapse formation, ethanol caused programmed cell death mediated degeneration of neurons in the brain. 68	Olney et al (2002)

Abbreviation: N/A, not applicable.

TABLE 4.

In silico approach on neurodegeneration

In silico approach
Compound	Approach	Target	Inhibitory effect	Activating effect	Reference
Melatonin and celecoxib	3‐D structures were constructed and docking analysis performed	IL1β, TNFα, TLR4, COX2, Nrf2, HO‐1 and iNOS	N/A	By reducing inflammation and apoptotic indicators, melatonin plus celecoxib may safeguard the brain. 69	AI Kury et al (2019)
N/A	Modeled in silico the receptor by using a multiple template approach	GPR17	GPR17 as a therapeutic option to thwart/avoid neuro‐degenerative diseases. 70	N/A	Eberini, et al (2011)
Artoflavano‐coumarin, natural product	Detailed‐atomistic molecular modeling	β‐secretase (BACE‐1)	Effective as a BACE‐1 inhibitor is Artoflavano‐coumarin. The outcome underlined the significance of flavonoids in the search for drugs to treat neuro‐degenerative disorders. 71	N/A	Razzaghi‐Asl et al (2018)
W. somnifera phytochemicals	Molecular docking and In silico evaluation	NMDA receptor	To avoid or treat neuro‐degenerative diseases, allosteric suppression of the NMDARs harboring GluN2B suppressed NMDA receptor‐mediated excitotoxicity. 72	N/A	Kumar et al (2016)
Tea polyphenols	Molecular docking	Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE)	By extending the time, tea polyphenols improve cholinergic neuro‐transmission by acting as AChE and BChE antagonists and have potential to manage AD. 73	N/A	Ali et al (2016)

Abbreviations: AD, Alzheimer's disease; N/A, not applicable.

FIGURE 4.

Explains the implication of protein misfolding in neurodegenerative disorders. In circumstances where misfolded proteins are present, these are removed by the activation of proteosome activators, which mediates their clearance by proteasomal destruction. Newly produced proteins are stabilized by the action of endogenous chaperons. PTM inhibitors, protein cleavage inhibitors, and extrinsic chaperones are, however, implicated in regulating the removal of these misfolded proteins in neurological disorders, either through autophagy or by endogenous clearance. Adapted from Sweeney et al. (2017). Created with BioRender.com.

3. NEURODEGENERATION TREATMENT OPTIONS

3.1. Herbal treatment and neurodegeneration

Curcumin (CUR) was created as a nanodrug form coupled with cholesteryl‐hyaluronic acid (CHA), which improved cell penetration and antitumor efficacy. Enhanced circulatory characteristics of CHA‐CUR at oral, i.p., and intravenous delivery ways were found by pharmacokinetic/pharmacodynamic (PK/PD) tests of the drug. CHA‐CUR has demonstrated tumor sites deposition and efficient tumor growth suppression in animal studies of severe orthotropic murine mammary carcinoma 4T1 and human pancreatic adenocarcinoma MiaPaCa‐2. CHA‐CUR therapy was very well accepted; hence, it could be used to cure and reduce the risk of cancer. ⁷⁴

To increase blood brain barrier (BBB) permeability, TSI nanoemulsion (TSI‐NE) was created and enhanced with a brain targeted agonist, lactoferrin (Lf). To make the approach more effective, pseudo‐ternary phase diagrams were used. Findings indicate that the Lf‐modified sustained optimum formation of the O/W nanoemulsion had been created and enhanced satisfactorily. Fluorescence intensity rose throughout the subsequent intervals in the sequence. The findings revealed that Coumarin‐6‐Lf‐BBB NE's permeability was superior to that of Coumarin‐6‐NE and Coumarin‐6 solution. Future research may improve TSI brain delivery using Lf tailored nanoemulsion. ⁷⁵

In order to create products that could heal injuries, aloe vera extract was sonochemically microemulsified with tragacanth gum. The notable benefit of the newly created injury healing product includes its relatively high antimicrobial properties, which result in microbial reductions of 84, 91, and 80% against E. coli, S. aureus, and C. albicans, a cell viability of 98% against human fibroblast cells, and a decent wound healing action with a considerable pace of fibroblast cell migration. ⁷⁶

To increase brain absorption, curcumin was enclosed in solid lipid nanoparticles (SLNs) and nanostructured lipid carrier (NLC). Curcumin has indeed been spread as an unstructured substance in the nanocarriers, according to the findings of various scanning calorimetry and X‐ray diffraction experiments. A study using the free radical scavenger 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) showed that the synthesis of curcumin had no discernible impact on its antioxidant properties. The utilization of curcumin‐loaded NLCs in the management of CNS illnesses both showed encouraging results. ⁷⁷

Appropriate chitosan coated nanostructured lipid carrier (CS‐NLC) formulation that can enter the brain following intranasal administration. When the nanoparticles were treated with erythrocytes, neither hemagglutination nor hemolysis events were seen, nor did any toxic signs manifested in the mouse nasal mucosa after CS‐NLC delivery. Last but not least, the bioavailability analysis of CS‐NLC‐DiR showed that the particles were effectively delivered to the brain following intranasal administration. In conclusion, CS‐NLC can be regarded as a secure and reliable nanocarrier for N to B drug delivery. ⁷⁸

3.2. Drug‐induced treatment and neurodegeneration

In order to enable nanoparticle receptor mediated transcytosis (RMT) across the BBB, 80‐nm gold nanoparticles with transferrin (Tf) and an acid‐cleavable connection between the Tf and the nanoparticle core were used. These findings are in line with prior findings of BBB endothelium. The acid‐cleavable linkage prevents substantial endothelium retention by losing surface Tf during their transcytosis. ⁷⁹

The heterobifunctional polyethylenglycol (PEG) linker NHS‐PEG‐MAL was used to connect lactoferrin (Lf) to β‐cyclodextrin (β‐CD), resulting in Lf conjugated ‐β cyclodextrin (Lf‐CD). According to the findings of tissue dispersion experiments, Lf‐CD/IR therapy significantly increased BBB efficiency levels. Additionally, a greater area under the curve (AUC) in brain tissue was a beneficial outcome of the inclusion of the Lf‐CD drug‐delivery system. These findings demonstrate the possibility of Lf‐CD nanoparticles as a hydrophobic drug delivery method that might reach the brain. ⁸⁰

Role of glial cells and cAMP as progenitors of neural tissue in EIN was investigated. Under conditions of maximum vital activity, it was discovered that the cAMP/PKA signaling induced the NSC to proliferate and hindered the NCP's mitotic activity. EIN causes the cAMP/PKA pathway, which controls NSC activities, to be inverted. The cAMP‐pathway has a variety of effects on how glial cells secrete NTF. Astrocytes and microglial cells in the EIN are stimulated to produce neurotrophins and to realize the growth prospects of NSC and NCP. These results demonstrate the potential of AC antagonists as novel, very successful medications for the treatment of alcoholic encephalopathy. ⁸¹

Synthetic chaperone made of mixed‐shell polymeric micelles (MSPMs) with adjustable structural characteristics was developed to prevent AD. These MSPM‐based chaperones might retain Aβ homeostasis by a conjunction of Aβ fibrillation inhibition and Aβ aggregate removal as well as simultaneous reduction of Aβ ‐promoted neurotoxicity. Researchers capitalized on biocompatibility, specificity against anomalous proteins, and blood circulation. To enhance the clinical efficacy of MSPMs, the hydrophilic/hydrophobic moieties on their interface must be balanced. ⁸²

O‐GlcNAc was shown to trigger specific small heat shock proteins' (sHSPs') anti‐amyloid action using synthetic protein chemistry. Whereas O‐GlcNAc levels are generally decreased in the brains of patients with AD, the alteration of pertinent sHSPs is either retained or enhanced, suggesting a pathway to retain possible protective O‐GlcNAc alteration. O‐GlcNAc boosts the capacity of sHSPs to suppress the amyloid creation of both α‐synuclein and Aβ(1–42). The findings had significant outcome for neurodegenerative conditions linked to amyloid production. ⁸³

One study concentrated on creating new lysosome/ER‐targeted compounds of 4‐phenylbutyric acid (4‐PBA). They prevented the neurodegenerative activity of the fly retina to varying degrees of effectiveness. Compound 9, an ER‐targeted peptide analogue, was the most effective chemical chaperons. The lysosome was the focus of yet another active compound 4. Novel chemical chaperons may provide a new category of therapeutic options for the treatment of ALS and other misfolded protein associated conditions as they were found to behave more efficiently than 4‐PBA. ⁸⁴

To prevent the production of Aβ‐(1–42) fibrils, biocompatible nanogels called cholesterol‐bearing pullulan (CHP) were created. These nanogels have a polysaccharide pullulan framework and hydrophobic cholesterol moiety. A shift from a random coil to a configuration rich in helixes or sheets as a result of the CHP‐nanogels. Additionally, the introduction of methyl‐cyclodextrin led the nanogels to dissociate, releasing monomeric Aβ molecules. During normal settings, amino‐group‐modified CHP (CHPNH2) nanogels had stronger suppressive activities than CHP‐nanogels, indicating the significance of electrostatic interactions between CHPNH2 and Aβ for preventing fibril development. ⁸⁵

A neutral counterpart of MKT‐077 called YM‐08 was created and manufactured. It bound to Hsp70 in vitro and decreased the levels of phosphorylated tau in cultivated brain slices. YM‐08 passed the BBB, according to pharmacokinetic analysis in CD1 mice. All these results pointed to YM‐08 as an exciting framework for the creation of Hsp70 inhibitors safe for usage in the CNS. ⁸⁶

However, drug‐based treatment does also lead to variety of side effects ranging from insomnia, dizziness, and hormonal imbalance. Some such as promazine, haloperidol, chlorpromazine, and pimozide may result in drug‐induced parkinsonian disorder.

4. CONCLUSION

The prevalence of neurodegenerative diseases has increased, which has caused widespread worry. It is now of the utmost importance to find the right treatment for these illnesses. The strength of this review is to provide a comprehensive distinction between the herbal and drug‐based treatment options. Although wide variety of drug‐based options are available for the treatment of neurodegenerative disorders but the negative effects that these prescriptions hold cannot be neglected. These medications only provide temporary relief from the symptoms but cannot stop their progression. Therefore, finding an alternative treatment option that might not only keep the symptoms from becoming worse but also guarantee fewer side effects becomes crucial. Many herbal compounds such as curcumin, aloe vera, epigallocatechin gallate, etc., due to their antioxidative qualities and accessibility, are now piquing the interest of academics. Despite wide range of benefits provided by herbal compounds, it is their low rate of absorption which imposes a restriction to their use in medicinal applications. To support these findings, however, additional high‐quality research and innovation are unquestionably required in order to understand the efficacy of these natural compounds.

AUTHOR CONTRIBUTIONS

Equal involvement and contribution from authors and have given acceptance to final manuscript.

FUNDING INFORMATION

This review received no specfic grant from any funding agency.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Mathur S, Gawas C, Ahmad IZ, Wani M, Tabassum H. Neurodegenerative disorders: Assessing the impact of natural vs drug‐induced treatment options. Aging Med. 2023;6:82‐97. doi: 10.1002/agm2.12243