Neurodegenerative disorders are probably the most prevalent form of condition nowadays. Neurodegenerative disorders are distinguished by gradual neuronal malfunction and the dying of neurons in a specific area of the cerebral cortex and spinal cord, which eventually spreads to other organs. It is distinguished by entropy such as Parkinson's disease (PD), Lou Gehrig's Disease, Alzheimer's syndrome, and Multiple cerebral sclerosis. The most common among these is Alzheimer's disease (AD), and Parkinson's disease (PD), it is mostly affecting people 65 years of age and above (Bisht et al., 2020). The main cause of this disorder is still not known, but these illnesses are thought to be caused mostly by genetic predisposition and environmental influences (Dinda et al., 2019). (See Fig. 1.) (See Table 1, Table 2.)

In 1817, James Parkinson released the first study report about Parkinson's illness and Shaking Palsy condition was known as Parkinson. Parkinson's disease is currently the world's second most prevalent neurological disease, impacting over six million individuals globally (Robert et al., 2019). Loss of Dopamine along with low norepinephrine causes the manifestation of movements that are (trembling in the hands, arms, legs, jaw, and head), bradykinesia (slow motion), inflexibility (stiffness of the limbs, making facial expressions and trunk) and postural instability are all Parkinson's disease symptoms. These signs rise when there is a shortage of 60–80% of cells that produce dopamine in the brain's substantia nigra (Verma et al., 2017). According to research the nonmotor symptoms may have a deleterious influence on the quality of life of Parkinson's disease patients. Stress is one of the possible factors that contribute to the progression of chronic neurodegenerative diseases, including Alzheimer's and Parkinson's disease (Peña-Bautista et al., 2020). Chronic psychological stress causes increased neuroinflammation, which may simply result in nigral cell death in Parkinson's disease. Trace elements including selenium, zinc and manganese, have also been shown to help with neurodegeneration. Their faulty metabolism can result in pathological situations like as depression and Parkinson's disease (Dallé and Mabandla, 2018).

The pervasiveness of Parkinson's disease differs from country to country. Parkinson's disease has a more common occurrence in countries like Europe and North America than in West Africa and Asia. The community-based studies from the western hemisphere reported ranging from 130 to 200 per 100,000. Because of the ageing population, the prevalence of Parkinson's disease is quickly increasing and reported to be as high as 2000/100,000 in persons above the age of 80. The prevalence report from Asia appears to be 51 to 177 per 100,000, In the western hemisphere the prevalence reported in younger generation 5–7% whereas in Japan is 10–14%. Probability is more likely to occur in young adults and children because they have a prolonged duration of disease when they reach the age of 60 as they endure more physical, economic, and psychological consequences (Mehanna and Jankovic, 2019). The population of 15 million people in England and Wales from which around 22 people died from this condition out of the 65 million population 5000 to 10,000 people in the United Kingdom experience Parkinson's disease. According to epidemic study, neurological illnesses are now the leading cause of impairment and one of the key causes is Parkinson's disease. Between 1990 and 2015, the overall number of patients with Parkinson's disease rose by 118%, from 6.2 million. Between 1990 and 2016, the condition of Parkinson's was worse in every part of the world, with a global prevalence rate of 22% (Dorsey et al., 2018). Parkinson was distributed in 204 nations and territories in 2019. In the period 1990–2019, massive percentage increases were observed in United Arab Emirates (854.71%) and Qatar (796.51%) however there was a reduction in percentage turnout in Niue (−6.81%) and Tokelau (−8.34%). There was a massive growth, when differentiated between female and male patients, patient aged over 65 showed a high pervasive number and the 80 years above patients showed a broad rise in the percentage (Ou et al., 2021). Based on the worldwide burden of Disease (GBD), China witnessed the greatest rise in generation-altered Parkinson's disease (Parkinson's disease) incidence between 1990 and 2016. The occurrence of Parkinson's disease cases was 99,235 in 1990, the Parkinson's disease cases increased by 2.04 times reaching 301,527 cases in 2019. From 1990 to 2019, people aged 20 to 24 years had a decreasing tendency in Parkinson's disease cases, whereas all other aged groups showed immense growth in Parkinson's disease cases. In China, the age-standardized incidence rate (ASIR) for Parkinson's disease rise from 13.24 per 100,000 people to 15.27 per 100,000 people in 2019. As age increases Parkinson's disease cases increased, vary from 0.15 per 100,000 populations for age 20–24 years to 214.2 per 100,000 populations for ages over 95 years in 2019 (Zheng et al., 2023).

The overall incidence of Parkinson's disease in India is the lowest in any nation. (70 per 100,000 in the general population). The Parsi tribe in Mumbai (India) has the greatest percentage of Parkinson's disease cases in the entire globe (328 per 100,000 population). The data were obtained from the neurosurgery outpatient department between September 2011 and August 2015, and it was discovered that the majority of the patients were from the North Indian states of Uttar Pradesh, Madhya Pradesh, Bihar, and Jharkhand. In India the disease's chronicity in patients was estimated 67.71 per 100,000, with a total of 260 cases of Parkinson's disease, 76.69% of them were male the male-to-female ratio was 2.66 (Verma et al., 2017). The frequency of Parkinson's disease in the Indian community varies by state and ethnicity. The number of Parkinson's disease cases has been estimated to be 14.1, 27 and 16.1 per 105 inhabitants in rural Kashmir in North India, rural Bengal in Eastern India and Bangalore in South India. According to Indian cultural background, the Muslim community has the lowest prevalence of Parkinson's disease (14/105) while the Parsi community has the greatest prevalence (328/105) (Surathi et al., 2016). The population in North India reported a prevalence of Parkinson's disease cases, 67.71/105 and it could be attributable to differences in race, place of residence or lifestyle. Males are more prone to get Parkinson's disease. Much research has been conducted, and the ratio of men to women for Parkinson's disease has been calculated to be 0.88–2.06.17. It was discovered that for age intervals of 40–49 years (3.11) and 50–59 years (3.12) to (3.29). It falls for the age groups 60–69 years (2.03) and 70–72 years (2.04) to (2.30) (Srivastav et al., 2017). According to the current study, 45.38% and 54.62% of cases were from rural and urban areas (Verma et al., 2017).

In Parkinson's disease pathophysiology involves genetic and environmental factors, mitochondrial malfunction, neural inflammation, oxidative stress, apoptosis, autophagy, and the lysosomal pathway (Chen et al., 2023). The growing degradation of the dopaminergic neurons in the substantia nigra in the brain of Parkinson's disease affected patients is not common. Many research studies have been investigated and thought to be a result of formation of Lewy bodies in the brain that consists of protein aggregates called lethal oligomeric form of α-syncline. This mutant type of α-syncline looks like fibrillary amyloid protein and is in charge for disrupting normal neuronal balance and other biological activities, ultimately leading to neuron necrosis. α-syncline not only damages the neurons in which it is present, but it is also harmful to adjacent neurons, and its presence ultimately causes excessive oxidative stress in the brain (Khan et al., 2021). Our bodies move in such a precise and coordinated manner because GABAergic neurons provide a control-coordinated movement by spiny projection neurons or medium spiny neurons which make up a major fraction of the striatal neuron. One of the most significant roles of dopamine is to raise transmission between the striatum, the thalamus, and the cortex. The proper balance of these two neurotransmitters, dopamine and acetylcholine, is critical for maintaining the balance coordination. Dopamine binding to the D1 receptor increases acetylcholine release, and both of these pathways function in tandem to provide high-performance coordinated movement. The decline of dopamine neurotransmitters in Parkinson's disease causes an imbalance in their action, eventually leading to the loss of coordinated movement (Liu, 2020).

Both genetic and environmental variables impact Parkinson's disease development through oxidative stress, alpha-syncline aggregation, abnormal protein clearance or mitochondrial malfunction. Mutations in the PARKIN and PINK1 genes are responsible for Parkinson's disease. PARKIN and PINK1 have been linked to a cellular process involving the lysosomal destruction of faulty mitochondria and autophagic-lysosomal degradation. Autophagy processes include macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy, each of which involves a distinct mode of substrate transport to lysosome (Cerri and Blandini, 2020). Macroautophagy, is a procedure called as “mitophagy.” Mitophagy is impaired when these genes are inactivated, resulting in an accretion of defective mitochondria. PARKIN indirectly affects PGC-1alpha levels, which in turn influence the expression of genes involved in mitochondrial biogenesis and numerous antioxidant defenses. DJ-1 gene causes autosomal-recessive early-onset Parkinson's disease and has antioxidant effects via several processes include the regulation of NRF2, a transcription factor that increases antioxidant defenses by increasing glutathione synthesis. Another common genetic factor that leads to Parkinson's disease is GBA gene mutations. GBA mutations induce a decrease in the activity of the lysosomal enzyme glucocerebrosidase (GCase), medicines that boost GCase activity, and a substance that targets substrate reduction in Parkinson's disease. (Simon et al., 2020).

Epidemiological and genetic research both supports the significance of neuroinflammation in the aetiology of Parkinson's disease. In the substantia nigra, activated microglial cells and invading lymphocytes occur. Where research showing and measuring T lymphocyte infiltration of CD4 and CD8 but not B lymphocyte infiltration in regions of the Parkinson's disease brain. Subsequent research has also proven that neuroinflammation is connected with the degenerative process of Parkinson's disease, with elevated amounts of proinflammatory cytokines in blood and cerebrospinal fluid (CSF). Cellular immunity in the blood is also altered, with modifications in blood monocytes and T cells, including changes in Treg/Teff ratios and the formation of memory T cells with responsiveness to specific α-synuclein determinant (Hirsch and Standaert, 2021).

Chronic stress and unregulated stress response have been linked to the aetiology of neurological conditions such as Parkinson's disease (Song et al., 2020). Motor disability is accompanied by mental stress, and people with Parkinson's disease have a reduced ability to do daily duties. Non-motor symptoms reduced the quality of life in individuals who were more subject to stress. Parkinson's disease is commonly accompanied by psychological stress and changes in hypothalamus pituitary adrenal axis function, which may be determined by cortisol and adrenocorticotropic hormone levels in the blood. Post-traumatic stress has been shown to be a significant risk factor for developing Parkinson's disease. Furthermore, stress triggers emotional stimuli which may lead to the worsening of motor symptoms in Parkinson's disease (Blakemore et al., 2018). The RTP801 protein is required for the mechanisms that regulate the stress impact on Parkinson's disease pathogenesis. Stress was shown to increase the quantity of RTP801 on the substantia nigra of dopaminergic neurons, preventing autophagy and encouraging α-synuclein gathering (Zhang et al., 2018).

Stress has been linked to the development of depression, and persons who suffer from depression are more likely to acquire Parkinson's disease later in life. Depression can be alleviated by stimulating areas near the substantia nigra and administering dopamine agonists. The dopaminergic pathways involved in emotions and cognitive functions in the mesocortical and mesolimbic regions of the brain may also have a role in Parkinson's disease-related depression. A recent research investigation in (animal model of Parkinson's disease) demonstrated that persistent psychological distress generated motor symptoms comparable to those seen in Parkinson's disease and contributed to the development of neurodegenerative diseases. Stress reduced mitochondrial respiration and glycolysis by up to 50%, as well as mitochondrial content, BDNF, and antioxidant proteins. The researchers discovered a rise in blood levels of interleukin1, interleukin6, and tumor necrosis factor, as well as an activation of NLRP3 expression and caspase 1 in the substantia nigra, which was followed by dopaminergic neuron destruction; As a result, early stress was shown to enhance microglia activation and dopaminergic neuron damage likely by speeding up the inflammatory response and activating the NLRP3 inflammasome (Khaspekov, 2021).

Dopamine is typically generated in these neurons from the necessary amino acid tyrosine. These are rate-limiting enzyme, aids in the conversion of tyrosine to levodopa. Dopa-decarboxylase is an enzyme that converts levodopa to dopamine. Just over 1 % of levodopa given is transformed into dopamine in the nervous system due to peripheral dopa-decarboxylase, an adequate quantity of levodopa penetrates the central nervous system by incorporating a dopa-decarboxylase inhibitor (DCI) that does not cross the blood-brain barrier, which includes benserazide or carbidopa. Carbidopa/levodopa, like Sinemet, Parcopa, and Atamet, is still the most effective and least expensive treatment, combo medicine is often administered with immediate-release and controlled-release compositions, and in oral form dissolving version (Parcopa) for those who have trouble the swallowing process (Halli-Tierney et al., 2020).

The second most successful class of medications is dopamine agonists, which involve ropinirole (Requip), bromocriptine (Parlodel) and pramipexole (Mirapex) (Paul and Yadav, 2020). Dopamine agonists activate the striatal postsynaptic dopamine D1–3 receptors without requiring increased dopaminergic neuron metabolism. Dopamine agonists are not as effective as levodopa addressing motor symptoms but they have been related to a lower risk of dyskinesia. Ropinirole and pramipexole are consumed in oral form and are available in extended-release forms, Rotigotine is administered once daily, Apomorphine, can be given via subcutaneous injection. Each can be used as a stand-alone treatment for mild to moderate Parkinson's disease or as an adjunctive treatment for moderate to severe disease. They have a longer half-life than levodopa and can be taken once daily (Cerri and Blandini, 2020).

Prior to 1969, only anticholinergic medicines were available to treat Parkinson's disease. Two examples (out of Cogentin) are trihexyphenidyl (Artane, Trihexane) and benztropine. Drugs like these are beneficial for treating tremors but not for treating stiffness, bradykinesia and balance problems but not for treating stiffness. Anticholinergics should only be explored for young individuals with severe tremors that are not responding favorably to standard Parkinson's medicines (Jankovic and Tan, 2020).

MAO-B Inhibitors have beneficial effects due to their capacity to inhibit the breakdown of dopamine and hence extend and intensify dopaminergic activation (Cereda et al., 2017). MAO-B inhibitors rasagiline (Azilect) and selegiline (Eldepryl, Zelapar) can be used as a stand-alone treatment for Parkinson's disease but are not as efficacious as levodopa. Rasagiline and selegiline are irreversible inhibitors of the enzyme and are used in early or mild Parkinson's disease because they provide minor symptomatic relief with lesser side effects than levodopa (Jost, 2022). Safinamide, a reverse MAO-B antagonist with additional features such as inhibiting voltage-dependent sodium channels, modulating calcium channels, and lowering glutamate discharge, is a new treatment option for people with Parkinson's disease in the middle and late stages (Schapira et al., 2017).

COMT enzymes execute levodopa metabolism in with the aid of a decarboxylase inhibitor: preventing these protein is employed in the management of Parkinson's disease as an adjuvant to levodopa for the improvement of locomotor changes, since it elevates levodopa half-life. Tolcapone (which has been associated with catastrophic acute hepatic failure and should be taken with caution), opicapone, and entacapone (It was just discovered and authorized in Europe) are currently available COMT inhibitors (Sivanandy et al., 2021).

Amantadine is a not competing N-methyl-D-aspartic acid (NMDA) receptor antagonist which has been clinically proven to diminish dyskinesias in Parkinson's disease patients, amantadine as an addition to levodopa resulted in a 52% reduction in dyskinesia intensity and amantadine-treated individuals had lower locomotor oscillations (Zhu et al., 2023).

Levodopa: The biggest concern with levodopa is that after 4 to 6 years of medication, 40% of individuals develop motor irregularities and dyskinesias. These effects tend to appear if treatment is started too soon or at an overly high dose. Motor variations can appear in several ways, including progressive weariness, sudden decline in efficiency, and random periodically efficiency. Furthermore, L-dopa has little effect on nonmotor parkinsonian symptoms such as hallucinations, orthostatic hypotension, or cognitive impairment and may even worsen them (Pringsheim et al., 2021).

Dopamine agonists: Hallucinations, nausea, vomiting, somnolence, confusion or sleep episodes, impulse control, edema and low blood pressure difficulties are all symptoms of bipolar illness. Pergolide, a fourth medication, is no longer accessible due to valvular heart problems. Drugs are associated with a number of undesirable side effects for the individual taking them. Ergot derivatives can cause psychological difficulties as well as cardiac problems, which can lead to myocardial infarctions and fatality. These medicines produce orthostatic dyskinesias, constipation, disorientation, hypotension, and sleeplessness in patients even at modest dosages (Ceravolo et al., 2016).

Anticholinergic drugs: According to recent evidence it does not substantially corroborate the concept that anticholinergics may have a greater impact on tremors than when compared with other drugs. Common adverse effects include confusion, sleepiness, agitation, and delusions. Memory impairments and greater dementia sensitivity have also been demonstrated (Pirker et al., 2023).

Monoamine oxidase B inhibitors: Early treatment with an MAO-B inhibitor appeared to postpone motor decline and eliminate the need for additional dopaminergic therapy in clinical trials; thus, various neuroprotective mechanisms are at work (avoidance of reactive oxygen species production, increase in neurotrophic and anti-apoptotic factors) (Robakis and Fahn, 2015).

Individuals with pre-existing cardiovascular disorders have few options because all medications have serious side effects. Orthostatic hypotension, for example, increases the risk of bone fractures (Houghton et al., 2024).

It causes anxiety, sadness, disorientation, and hallucinations in the central nervous system. These side effects are unbearable because Parkinson's disease primarily affects the elderly (Trevor et al., 2010).

Nicotine: The findings indicate that nicotine can help prevent neurodegenerative disease like Parkinson's disease patients. The drug nicotine, a nicotinic receptor catalyst, promotes the emission of dopamine from the neostratium and thereby protects nigrostriatal neurons against degradation (Hurst et al., 2013). Nicotine's capacity to increase dopamine release in mesolimbic cortical neurons leads to the activation of dependent motion (perhaps striatal). Moreover, nicotine is being demonstrated to be an antioxidant and free radical scavenger, avoiding the peroxidation of lipids and subsequent neurons decline, resulting in a substantial enhancement in the individual's psychological concentration, control of the body in moving around, hand use, and decreased anxiety soon after starting treatment (Thiriez et al., 2011).

Selenium: This metal was recently found owing to its function in the antioxidant enzyme glutathione peroxidase (GSH) activity, which prevents dopaminergic degeneration in the substantia nigra, and the crucial part that this enzyme plays in converting toxic hydrogen peroxide (H2O2) to water, which inhibits the formation of glutathione disulfide (GSSG). H2O2 can be broken down into the deadly hydroxyl free radical in the presence of iron, which has the potential to spread through lipid peroxidation and induce the destruction of cytoplasmic components and neurons, culminating in deterioration (Salaramoli et al., 2022).

Anti-inflammatory agents: In Parkinson's disease, levels of cyclo‑oxygenase (COX) as well as inflammatory mediators such as nitric oxide are raised (Zhang et al., 2005). Both aspirin, a non-selective COX inhibitor, and meloxicam, have been found to protect mice from MPTP-induced DA depletion. This link was discovered to be positive between aspirin use and the development of MPTP-induced Parkinson's disease. Other COX-activity inhibitors, including indomethacin, paracetamol, diclofenac, and the steroidal COX expression antagonist dexamethasone, have been shown to be unsuccessful in shielding neurons against the neurotoxicity of MPTP (Moore et al., 2010).

Ropinirole: Ropinirole is a non-ergot derivative with excellent choice for D2 receptors that is classified as a DA agonist. Ropinirole is recommended for Parkinson's disease patients (Klewe et al., 2008). Ropinirole formulation with a longer duration of effect can be found as RequipXL® extended-release tablets, allowing for only one administration of Ropinirole and thereby enhancing adherence. The associated side effects, similar to other DA agonists now in use, include somnolence, ataxia, tiredness, and hypotension. Complications related to behavioral responses, on the other hand, are to fewer extents. To overcome the limits of standard ropinirole formulations and boost medication uptake in the brain, the emphasis has switched to nanotechnology, notably nanoparticle-based delivery methods (Malewar et al., 2013).

Pramiprexole: Pramipexole, also known as Pramipexole dihydrochloride monohydrate and commercialized under the trademarked name Mirapex®, is a non-ergot derivative. It possesses intrinsic DA receptor action, specifically with the D2 subfamily, with a greater preference for D3 than other subtypes such as D2 or D4 receptors (Paul and Yadav, 2020). In addition to Parkinson's disease, Mirapex® pills are used to treat from moderate to a severe acute syndrome of restless legs. Niosomes and Liposomes have been studied as targeted medication delivery methods to improve the antiparkinsonian effect and brain penetration of pramipexole in the use of Parkinson's disease. Liposomes and niosomes encapsulated in polyethylene glycolylated (PEG). BBB penetration of pramipexole dihydrochloride monohydrate via liposomes and niosomes was studied after characterization and release studies (Gunay et al., 2017). All articulation of pramipexole-encapsulated liposomes and niosomes were shown to be BBB permeability and demonstrated potential medicinal properties at the time evaluated on a Parkinson's disease-associated animal model due to their tiny sizes and the presence of non-ionic surfactant characteristics (Paul and Yadav, 2020).

Antioxidants such as vitamins A, C, and E are well-known that work as free radical scavengers to keep lipids from peroxiding. The large open-access a study revealed that excessive quantities of both vitamin A and vitamin C delayed the use of levodopa or DA agonists by 2.5 years. Several research analyzing their function in neuronal degeneration prevention and studying the linkages between their absence and the occurrence of Parkinson's disease have generated promising results (Percário et al., 2020).

Rotigotine: Rotigotine, the other non-ergoline DA agonist used to treat Parkinson's disease and the non-prescription therapy of Willis-Ekbom Disease (also known as Stiff Leg Disease), has skeptic action on DA receptors with a preference for the D3 receptor among others. This class of medicines has no known mechanism of action; however it is thought to provoke DA in the caudate-putamen, especially the D2 receptor (LeWitt et al., 2007). To enable continuous Rotigotine administration for more than 24 h, a patch-based transdermal delivery device has been created. Neupro® is the brand name for this transdermal patch (Boroojerdi et al., 2010). Dermal medication delivery to the CNS may reduce drug solubility due to sluggish and faulty absorption of drugs from the applied area, as well as a hindrance from the arachnoid gland, retinal plexus, and BBB. As a result, researchers have done a number of nanocarrier-based drug transport studies on rotigotine to increase rotigotine distribution to the CNS, including an intranasal method with micro emulsion-based gel, lactoferrin-modified nanoparticles particles, tiny spheres, and nanoemulsion (Nirale et al., 2020).

Bromocriptine: Bromocriptine mesylate, an ergot derivative of DA agonist, is offered under the brand name Parlodel®. For oral use, they are available in tablet (SnapTabs®) and capsule dosage forms. Patients with Parkinson's disease who have reached end-of-dose failure or developed tolerance to LD medication may benefit from the addition of Parlodel remedy. Considering the severity and frequency of adverse effects caused by long-term LD therapy such as dyskinesia and on-off development of actions, administration of Parlodel medication (Paul and Yadav, 2020).