Introduction

The components of the nervous system that ordinarily transmit or send pain impulses are affected by abnormalities or diseases, leading to the development of chronic pain syndromes known as neuropathic pain illnesses. These are complex illnesses that are not caused by a single factor or particular condition ¹.  Neuropathic pain is frequent in clinical practise and severely reduces patients’ quality of lives.

The majority of patients fall into one of four broad categories include Central nervous system (CNS) lesions (such as Multiple Sclerosis, infarct, and spine injury), peripheral generalised polyneuropathies (toxic, metabolic, hereditary, or inflammatory), and focal and multi-focal neuropathic lesions in the periphery (distressing, ischemic, or inflammatory) (complex regional pain syndromes [CRPSs].

CRPSs (previously called as reflex sympathetic dystrophies, Subdeck’s atrophy, or causalgia) are painful illnesses that primarily affect the limbs and can arise as a disproportionate result of trauma ².  CRPS type I frequently occurs after a harmful damage to an extremity that does not result in a visible nerve lesion (e.g., bone fracture, surgery). After a trauma that is coupled with a significant nerve damage, CRPS type II occurs. However, CRPSs, unlike different types of neuropathic pain disabilities, include additional symptoms such as irregular perspiration and blood circulation as well as active and passive motor syndrome, indicating that they are systemic CNS illnesses.

One of the most common causes of early mortality in the world is neurodegenerative diseases. Peripheral alterations include, but are not limited to, oedema of the dermis and underlying tissues, systemic modifications, signs of inflammation, and a pain component supported by efferent sympathetic innervation. The continually growing life expectancy, the disease-related socioeconomic burden is predicted to rise ³.   Current scenario on numerous etiological pathways that lead to neurodegeneration. Neurodegeneration is a subsequent consequence of a main CVS cause, with artery or vein disease affecting the important homeostatic connections in between cerebral and the vascular, leading to cerebrovascular events, Alzheimer’s disease, and cognitive deficits like stroke and second, that systemic metabolic problems combined with the presence of senescent cells in brain circuits may promote neurodegeneration ⁴. The purpose of this literature review and overview is to explain the significance of polyphenols with radical-scavenging activity and the etiological role of oxidative stress or free radicals in neuropathy.   

Table 1: Types of Neuropathies:

Distal symmetric sensory polyneuropathy, which is commonly accompanied with autonomic neuropathy, is the most prevalent kind of neuropathy related with diabetes mellitus ⁹. Acute functional abnormalities in nerve fibres, followed by more chronic nerve fibre atrophy, damage, and complex loss due to microvascular dysfunction and slower nerve fibre regeneration, are characteristics of diabetic neuropathy, according to a growing body of research. The metabolic consequences of hyperglycaemia and/or other impacts of insulin insufficiency on the widely diversified cell components of peripheral nerve tissue and its associated connective tissue and vascular components are responsible for all of these problems ¹⁰.   Phenolic acids are among the most frequent kinds of polyphenol. They’re plentiful in foods like berries ¹¹, nuts ¹², coffee, and tea ¹³ as well as entire grains ¹⁴.   Importantly, phenolic acid-rich meals have been found to reduce the incidence of depression in a recent meta-analysis ¹⁵.  Men from the Mediterranean region and “health-conscious” UK consumers are not included in the survey (most of whom are vegetarians). In all categories, phenolic acids made up the majority of the polyphenols (52.5–56.9% in the diets of men and women, respectively). In general, the primary sources of total dietary polyphenols were hydroxycinnamic acids (varying from 27 percent in women from the “health-conscious” group in the UK to 53 percent in males from non-Mediterranean nations).  cis-chlorogenic acid, (primarily 5-caffeoylquinic, 4-caffeoylquinic, and 3-caffeoylquinic acid) were the most widely distributed phenolic acids, followed by feruloylquinic, gallic, galloylquinic, 4-hydroxyphenylacetic, homovanillic, 3,4-dihydroxyphenylacetic, and dihydro-p-coumaric acids. Phenolic acids have the potential to be useful in the management of neurological illnesses in the future ¹⁶. 

Neuropathy burden worldwide and their complications:

Up to 50% of people with the condition get diabetic neuropathy, which is a serious side effect of the diabetes. Yet consistent blood sugar management and adopting a healthy lifestyle can usually prevent or slow the growth of diabetic neuropathy. Neuropathy can affect anybody with diabetes. However, the things increase your probability towards developing nerve damage are poor blood sugar control, longer diabetes has existed, the more probable it is that you will to develop diabetic neuropathy, especially if your blood sugar isn’t adequately controlled ¹⁷.   Kidney disease, (Body Mass Index) BMI of 25 or more increases your probability towards developing diabetic neuropathy, Smoking causes your arteries to constrict and stiffen, limiting blood flow to your legs and feet. This makes wound healing more challenging and affects peripheral nerves ¹⁸. 

Alzheimer’s disease:

The most prevalent neurodegenerative disease worldwide is Alzheimer’s Disease (AD). Although AD affects everyone differently, these abnormalities in memory, cognition, and behaviour are the most common symptoms ¹⁹. Sometimes early symptoms are mistaken for stress or advancing age. There is no denying that memory loss is common, and it causes problems remembering past events. Assessments of behaviour and cognition are frequently used to confirm a diagnosis. Confusion, impatience, violence, mood swings, and seclusion become more prevalent as the condition advances. Individuals with the condition are unable to participate in typical living activities, and long-term care and institutionalisation are frequently needed in the disease’s latter stages ²⁰. The fundamental features of Alzheimer’s diseases include loss of neurons of corticals and, to a lesser degree, neurons of subcortical area and synapses on a pathological level.  As a result, a portion of the frontal brain, the cingulate gyrus, and the temporal and parietal lobes shrink. ²¹.  The two types of different senile plaques are extracellular senile plaques and tangles in the brain lesions. Both are made up of aberrant amyloid-β (Aβ) aggregations ²².  These are the most prevalent histopathologic Alzheimer’s symptoms, although it might be not an adequate to cause the disease’s severe and profound neuronal loss ²³. AD is a frequent and well-known condition with a variety of prospective therapy alternatives, although only a few are now in clinical use. A few more indications include the release of aggregated A, the decrease in neuro-inflammatory activity, the regulation of redox responses and oxidative stress, the suppression of ROS formation, immune-based neuro-degeneration in cells, tissues, and/or organs, and/or the protection and modulation of predictable biochemical responses ²⁴. Each of these would be vastly improved if medications could be administered selectively to damaged brain regions. If plaques, tangles, and/or neuropathological activity could be detected early in the course of the illness, and direct applications could enhance diagnoses. Hence, there has been a large effort in recent years to explore the application of nano formulations for detecting and treating Alzheimer’s disease. The majority of the novel treatment methods target well-established pathogenic processes that are well-known to directly contribute to neurodegeneration ^{25, 197}. 

Parkinson’s Disease:

Parkinson’s disease was initially described in an 1817 medical text written by a London physician named James Parkinson. The symptoms unique to the affected brain subregion develop gradually. Balance problems, mobility problems, resting tremors, bradykinesia, and stiffness in the limbs and trunk are some of these indications and symptoms. Parkinson’s disease is pathologically identified by the death of dopamine secreting neurons in the substantia nigra because the striatal dopaminergic connections to the caudate and putamen are lost. compacted nigra pars ²⁶. Parkinson’s disease is caused by a variety of factors, including misfolded proteins, neuronal damage, glial immune activation, ROS and free radicals’ production, exposure to toxins, host genetics, and ageing ²⁷. Although autonomic anomalies and dysfunction may be signs of a disease, it is apparent that the illness process begins long before any symptoms arise ²⁸. The release of neurotoxic chemicals, which is started by immune activated glia, causes neuronal injury and the collapse of the BBB (Blood Brain Barrier), which is linked to motor and subsequently cognitive decline ²⁹. As the disease progresses, the blood-brain barrier becomes less intact, allowing leukocytes to enter the brain and feed the neuroinflammatory cascade ³⁰. The Parkinson’s disease treatments that are currently available concentrate on the effects of the condition. They are used to replace missing dopamine, as D receptor agonists, or as selective monoamine oxidase inhibitors. The benefits and advantages of the dopamine substitute are extended by the latter’s metabolism of dopamine. Tremors can be reduced with the aid of additional medications such amantadine or anticholinergic drugs ³¹. Using nanomedicine techniques for Parkinson’s disease, though, is focused on striking a balance between slowing the progression of the illness and improving the absorption of more traditional drugs used to treat symptoms. 

Drug used in neurodegenerative diseases

Table 2: Alzheimer’s Disease

Table 3: Parkinsonism Disease

Table 4: Huntington’s Disease

Multiple Sclerosis

Table 5: Multiple Sclerosis

Table. 6: Amyotrophic Lateral Sclerosis

Table 7: List of polyphenols which are already reported with neuroprotective effect   Click here to view figure

Role of ROS in Neuropathy/ Neurodegeneration

Denham Harman first recognized free radicals in 1956, and they are responsible for cellular destruction, mutation, cancer, and the degenerative process in biological ageing. ^[179] ROS and RNS are two different forms of free radicals. However, Super oxide (O–O-), triplet-state molecular oxygen (•O–O••), hydroxyl radical (•O–H••), and singlet oxygen (•O–O) are all examples ROS. NO radical (NO•), nitrosonium cation (NO+), nitroxyl anion (NO-), and peroxynitrate are examples of RNS (ONOO-) ^[180]. In cells, reactive species such as superoxide, hydrogen peroxide, and nitric oxide work as signaling pathways to trigger a plethora of intrinsic enzymes and proteins, such as the epidermal growth factor receptor, c-Src, and the p38 mitogen-activated protein kinase, Ras, ¹⁸¹. Akt/protein kinase B, and transcription factors like NF-κB/activator protein-1 (AP-1). The stimulation of numerous genes with vital functions in physiology and disease occurs when these signalling cascades and redox-sensitive transcription factors are triggered ^[182].  ROS concentrations in neurons subjected to 5 mM glutamate rises 5–10-fold in the first 10 hours and 200–400-fold later 10 hours ¹⁸².  The slightly earlier moderate rise in ROS is related to glutathione depletion in the cytosol, whereas the late explosive increase in ROS is attributed to glutathione reduction in both the ETC in the cytosol and mitochondria ¹⁸². Increased ROS are known to cause apoptosis in smooth muscle cells via a p53-dependent mechanism. Our findings show that an abrupt rise in ROS lowers cell viability by triggering the production of proapoptotic proteinss, whereas a moderate spike in ROS enhances cell survival by inducing MAPK and transcription factors. ¹⁸³ Many ROS are implicated in painful pathological circumstances, even though it is unknown if a particular ROS subtype is required for central sensitization in neuropathic pain ^[184]. Thus, radicals are the first species created during the creation of ROS and have the ability to control inflammatory pain. ¹⁸⁴ . When nitric oxide reacts with extremely high concentrations of SO, stable peroxynitrate molecules are created (NO). The SOD is prevented from conducting its catalytic action by these chemical nitrates. The hydroxyl radical is the most harmful ROS while being unstable ^185. Cyclooxygenase, peroxisomes, endoplasmic reticulum, mitochondria, and inflammatory cytokines are examples of endogenous generators of ROS. Moreover, some examples of external sources of ROS are ultraviolet radiation, air pollution, chemotherapy, cigarette smoke, and ionising sources. Oxidative stress is brought on by the ROS. As a result, activities like protein oxidation, lipid peroxidation, and DNA damage affect physiological performance. Impaired physiological performance is the main cause of random cellular damage and a specific signalling route that also accelerates ageing, causes neurological diseases, and causes cell death. 

Figure 1: Dietary polyphenols have neuroprotective and anti-aging effects. Abbreviations: P38 MAPK stands for protein 38 mitogen-activated protein kinase, JNK for Jun N-terminal kinase,   Click here to view figure

Antioxidants and oxidative stress in neurodegenerative disorders

It is widely recognised that oxidative stress has a role in neurological disorders and the ageing process. By suppressing free radicals and regulating the expression of genes that cause inflammation, ascorbic acid has neuroprotective qualities that reduce neuroinflammation and the accumulation of amyloid-beta peptides. A decrease in the makeup of low-density lipoproteins and an increase in plasma levels of high-density lipoprotein were also linked to ascorbic acid administration. By reducing the conversion of macrophages to foam cells, ascorbic acid treatment may hence reduce atherosclerosis and the related systemic inflammation. Consuming ascorbic acid reduced miR155 levels by 90%, showing that ascorbic acid can reduce inflammation through controlling the levels of miRNA. ¹⁸⁶  Curcuma’s anti-oxidative effects on synapse-associated proteins were found in an AD animal model (APPswe/PS1dE9 double transgenic mice). The transgenic mice showed reduced PSD95 and Shank1 activity in the CA1 region of the hippocampus. Through altering PSD95 and Shank1 proteins, curcumin consumption may enhance synaptic structure and function ¹⁸⁷.  In the CA1 region of the hippocampus, phosphatidylinositol-3 kinase, serine-threonine kinase, and their phosphorylated forms were expressed more, whereas the levels of insulin receptor and insulin receptor substrate-1 were reduced. ¹⁸⁷ However, in double transgenic animals, the insulin receptor and insulin receptor substrate 1 were downregulated. The expression of insulin-like growth factor 1, insulin receptor substrate 2, phosphatidylinositol-3 kinase, and their phosphorylated forms all increased.

Figure 2:. The causes of human ailments brought on by OS. ROS produced by exogenous/endogenous sources causes OS, which contributes to the pathogenesis of a variety of human diseases by impairing physiological functioning,   Click here to view figure

Relation between stress, tension, hectic lifestyle and neurodegenerative diseases:

Because of urbanisation, changing lifestyles, and ageing populations, stroke rates are rising globally. In their mid-forties, people who had healthy, low-risk lifestyles, such as stopping smoking, exercising frequently, consuming alcohol in moderation, and keeping a moderate weight, had a decreased incidence of neurodegenerative diseases. Hence, regular exposure to risk factors including stress, inactivity, poor nutrition, obesity, high plasma cholesterol, smoking, drinking, or arterial hypertension may be to blame for the comparatively high incidence of neurodegenerative diseases ¹⁸⁸. One of the main dietary factors associated with a higher risk of atherosclerosis and cerebrovascular disease has been identified as a high-fat, high-cholesterol diet ^189.   Poor eating habits, on the other hand, can aggravate metabolic diseases like high blood pressure, metabolic syndrome, cardiovascular disease, stroke, insulin resistance, and type 2 diabetes (T2DM), which are all brought on by systemic, persistent inflammation, also known as metabolic arthritis or meta-inflammation ¹⁹⁰. Along with cytokines and adipokines, sphingolipids and eicosanoids are hypothesised to contribute to this process by causing negative regulatory reactions in target cells like macrophages ¹⁹¹. A high income, a shortage of food, dietary preferences, and lifestyle choices are all influences on the energy imbalance that the hypothalamus controls and which can result in weight gain.  The hypothalamus functions at the molecular level. O-GlcNAc-transferase regulates body weight by catalysing the transfer of N-acetylglucosamine from uridine-diphosphate to the hydroxyl group of serine or threonine residues in nucleocytoplasmic proteins. O—N-acetylglucosamine transferase was inhibited, although obesity and insulin resistance were increased as a result of a high-fat diet. ¹⁹².   A high income, a shortage of food, and dietary and lifestyle choices all contribute to an energy imbalance that the hypothalamus controls and can result in weight gain. By catalysing the transfer of -N-acetylglucosamine from uridine-diphosphate—N-acetylglucosamine to the hydroxyl group of serine or threonine residues in nucleocytoplasmic proteins, the hypothalamus O-GlcNAc transferase regulates body weight at the molecular level. O—N-acetylglucosamine transferase was disabled, yet high-fat diets led to a rise in obesity and insulin resistance.¹⁹³ An association between the disease and education was discovered in a recent study that examined the effects of 24 modifiable factors on the prevalence of Alzheimer’s disease, demonstrating that genetically predicted greater levels of education were associated with fewer incidences of the illness. The following dietary and lifestyle factors, as well as cigarette, coca/coffee drinking, and 25(OH) vitamin D levels, were found to be strongly linked with AD. A decreased risk of AD has been associated with higher levels of 25(OH) vitamin D, coffee drinking, and cigarette smoking ¹⁹⁴ . An increased risk of dementia and stroke is associated with increased use of artificially sweetened beverages. The risk of dementia and stroke has also been linked to sugary beverages or soft drinks with added sugar ^195,196. 

Figure 3: Pro-neurodegenerative factors balanced by anti-aging and anti-neurogenerative factors 184.    Click here to view figure

Discussion and Conclusion

This paper reviews the major neurodegenerative diseases that affect humans, including psychiatric conditions brought on by ageing and neuro-inflammation, as well as Alzheimer’s Disease, Huntington’s disease and multiple sclerosis. Neurodegenerative disorders currently have no known cure, and the medications that are available either treat the symptoms or slow the progression of the condition. The World Health Organisation (WHO) predicts that in 20 years, diseases with a focus on motor functions would surpass cancer as the second-leading cause of mortality, behind cardiovascular diseases. This underscores how important it is to treat ND. The majority of the research on neurodegenerative diseases has been conducted on amyotrophic lateral sclerosis, multiple sclerosis, huntington’s disease, and Parkinson’s disease, which are the focus of this pharmacological review.  Polyphenols are micronutrients that occur naturally in plants. They can be found in a variety of foods, including fruits, vegetables, teas, spices, and a number of dietary supplements. There is now research being done on a number of the therapeutic biological effects that polyphenols have. They consist of cardiac protective, neuroprotective, anti-inflammatory, antioxidant, anti-carcinogenic, anti-diabetic, and anti-allergic properties. Reactive oxygen species are the main contributor to neurodegenerative diseases. The excessive creation of free radicals, or ROS, often known as “oxidative stress,” has been linked to numerous molecular pathways of neuron and neurovascular injury. Antioxidants are therefore regarded as successful neuroprotection strategies. Neuroprotection has been significantly hampered by the increase in antioxidants’ blood-brain barrier penetration. With a better understanding of oxidative pathways, the treatment’s efficacy might be increased. Innate factors like ageing, neuroinflammation, brain injury, and oxidative stress can affect neurodegenerative illnesses, as can lifestyle factors like high-sugar diets, alcohol and tobacco addiction, or high-fat diets. The good news is that calorie restriction, exercise, and a variety of nutrient-rich dietary components, including polyunsaturated fatty acids and antioxidants, can all work together to slow down the ageing process and the onset of neurodegenerative illnesses.  So now a days ROS or oxidative stress is major etiological factor for various neurodegenerative diseases for this we have phytochemicals like polyphenols which are already registered with radical scavenging activity so might be they are good alternative in prophylactic manner  to synthetic medications to overcome their side effects and ADR.

Acknowledgement

I thank my mentor Dr. Ghanshyam B. Jadhav for their assistance and I would like to thank Respected Principal Dr. D. V Derle, NDMVP Samaj’s College of Pharmacy, Nashik for their Support. I also like to thank Respected Principal Dr.S. J. Kshirsagar, MET’s Instiitute of Pharmacy, Adgaon, Nashik for their Support.

Conflict of Interest

The authors declares that they have no conflict of interest 

Funding Source

There is no funding or financial support for this research work.

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