INTRODUCTION:

Affecting 3% of those over 65, Parkinson's disease (PD) is the second utmost prevalent neurological illness¹. It is projected that by 2040, there would be more than 12 million cases². We are still learning more about Parkinson's disease (PD), which was initially identified by James Parkinson in 1817 and later extensively defined by Jean-Martin Charcot³.

PD is an age-related neurodegenerative condition whose pathological characteristic is primarily linked to the substantia nigra (SN) progressive harm of dopaminergic innervation in the nigrostriatal region.

Clinical manifestations include rigidity, hypokinesia (loss of facial expression), bradykinesia (difficulties starting movement), rest tremor (forearm rolling), and non-motor characteristics such as depression, psychosis, autonomic dysfunction, and expressionless facial movements.^4,5Parkinson's disease (PD) brains have reduced levels of dopamine, a neurotransmitter involved in memory, movement, and other processes, as a consequence of dopaminergic cell death. Reduced dopamine levels in the PD brain have been linked to motor dysfunction and the cognitive deficit seen in some patients. Early diagnosis of PD can be challenging due to the long-time lag between the initial loss to dopaminergic cells and the start of clinical symptoms. The current diagnostic criteria require the presence of two of the following clinical characteristics: rigidity, bradykinesia, resting tremor, and/or postural instability. The diagnosis is made based on clinical symptoms. Clinical criteria alone, however, are only sufficient to diagnose probable PD. Histopathological evaluation and the detection of Lewy bodies (LBs) or Lewy neurites comprising α-synuclein are essential for a definitive diagnosis³. It usually takes the destruction of 70–80% of dopaminergic neurons before PD symptoms and indicators manifest^,6,7.

However, researchers have found that various factors like mitochondrial stress, elevated reactive oxygen species and inflammatory process have also a significant role in PD pathogenesis⁸.

MOLECULAR MECHANISMS OF PATHOGENESIS IN PD⁹

α-Synuclein aggregation^3,10

The 15 kDa protein Syn is made by the SNCA gene, which is situated on chromosome 4's long arm (Chr 4q22.1). This protein's 140 amino acids are dispersed among three fields, as seen in figure no. 1. The N-terminal, which is the first region, is made up of four regions with eleven "imperfect" replications and agreement sequence (KTKGEV) that has a lot of lysine. This region is crucial for alpha helix conformation because it allows the syn protein to bind to negatively stimulating lipids. But this domain is especially vulnerable to missense mutations (like A53T, A30P, and E46K) that have different symptoms and pathogenic pathways in PD. Next is the "non amyloidogenic component" (NAC), which is positioned in the middle and is recognized for being hydrophobic but can aggregate in some situations because of its reactivity to conformational varies in α-syn, from α-sheet structures in an oligomeric state to random coiled coils. The final section is called the carboxyl-terminal area, where there is presence of acidic residues that give α-syn an intrinsic construction that mediates interactions between proteins. This domain may encompass structural modifications like truncation, which entails the removal of acidic residues to promote the α-syn aggregation into fibrils. Accordingly, the C-terminal domain may experience post-translational modifications at serine 129 and 87 for phosphorylation, at E3 ubiquitin-ligases for ubiquitination, at tyrosine residues for Y39, Y125, Y133, and Y136 for nitration, and at threonine remains for T33, T34, T54, and T59 for O-GlcNAcylation.

Figure 1. Structure of α-synuclein

The abnormal aggregation of α-synuclein is a widely accepted theory explaining the death of nigrostriatal neurons in PD. α-synuclein is a putative chaperone that is involved in intracellular trafficking, mitochondrial activity, and synaptic vesicle dynamics. It has a cytosolic and nuclear localization. There is proof that the protein plays a role in the brain's lipid metabolism, which is connected to the onset of PD. Soluble α-synuclein monomers first form small protofibrils when they combine to form oligomers, which then grow into large, insoluble fibrils. By itself, α-synuclein may become neurotoxic as a result of this process.

A defective a-synuclein that is unable to fold correctly causes misfolded protein when the SNCA gene is mutated¹¹.

Mechanism of protein aggregation¹²

As we get older, Reactive Oxygen Species (ROS) oxidize biomolecules, producing quinones, epoxides, and ketones. Strong nucleophiles, these compounds can interact with amino and sulfhydryl groups, to produce cross-linked proteins, among other nucleophiles. As such, the construction of protein aggregates is a conjoint process of cellular aging. These proteins are normally eliminated by the proteasome as they mature creating equilibrium. Nevertheless, the breakdown of aberrant proteins by the proteasome requires ATP, which raises the energy requirement during oxidative stress. Neurons and other oxidatively stressed cells will reduce their mitochondria's respiration in an effort to reduce the production of free radicals. For the proteasome to degrade damaged proteins, additional ATP is required. These conflicts are resolved by the precipitation of damaged proteins to form plaques or tangles. However, an initiator is required for the protein precipitation process. We think that proteins like tau, PARKIN, β-amyloid peptide, and syncline could be such initiators. The most important of these proteins is α-synuclein, which is capable of causing protein aggregation when hydroxylases such as tyrosine hydroxylase, phenylalanine hydroxylase, and possibly tryptophan hydroxylase convert its C-terminal tyrosine residues to catechol’s.

Effect of Protein aggregates on cells¹³

For every cell, protein aggregates are an essential part of cellular metabolism. If, however, the cells were unable to eliminate protein clumps below the threshold, they would age more rapidly and experience several negative consequences. Numerous negative effects of protein aggregates on cells interact and promote the formation of complex networks among them. ROS, alter the conditions required for protein synthesis in addition to causing damage to DNA. This can set off a vicious cycle with more serious repercussions, such as errors in synthesis of and aggregate formation. Figure 2 illustrates the various impacts of protein aggregates. Stopping the intrusion of protein aggregates and ending the cycle of negative effects is the primary objective of treatment for protein aggregation build-up. Proteins lose function when they aggregate because their normal structures are upset. Numerous biological functions, including signal transduction, enzymatic reactions, and structural support, may be hampered as a result. In addition to interfering with the substantia nigra's Tlr4-dependent p38 and Akt-mTOR signaling to trigger microglial autophagy, the α-syn protein accumulates in autolysosomes to impede their ability to break down metabolic wastes¹⁴. Protein aggregates have two effects on lysosome function: first, they directly disrupt the structure and function of lysosomes, which leads to the build-up of metabolic waste in the cytoplasm and hydrolase leakage; second, they disrupt the expression of genes linked to lysosomes or lysosome fusion, which lowers the lysosomes' capacity for degradation. These two processes interact, upend the intracellular environment, and produce a more complex mechanism of damage. α-synuclein aggregates were found in the midbrain cultures of PD patients; these aggregates cause ER disintegration and impair ER protein folding ability, which causes protein misfiling and aggregation [4]. (Ivan Stojkovska, 2021). According to some studies, ROS might be the primary mediator separating protein aggregates from ER stress¹⁵.

One important indicator of cell aging is DNA damage¹⁶. In light of the DNA damage process, protein aggregates are harmful in three ways: (1) by directly breaking the structure of DNA through contact. (2) Accidental DNA deterioration caused by ROS and related substances. (3) Obstructing DNA repair mechanisms, which increases damage¹⁶. These modes are not engaged in separate combat; rather, they interact and support one another. Although DNA can be damaged by protein aggregates, the DNA damage repair system is responsible for safeguarding and mending genetic material that is easily damaged. However, this life-saving straw is also hampered by protein aggregates. Base excision repair (BER) deficits were discovered in the brains of AD patients by Lior Weissman et al.¹⁷ indicating a diminished ability to repair oxidative DNA damage. It is now widely acknowledged that the interaction between redox and Ca⁺⁺ signals is essential for physiological processes in the brain. Nevertheless, nitrosative and oxidative stressors promote an excessive release of Ca⁺⁺, which can result in detrimental reactions and the death of neurons¹⁸. Protein clumps change the calcium exchange balance, which further upsets biological metabolism. Some scientists revealed that certain forms of protein accretion can inset into plasma membrane constructions and function as non-selective ion channels^19,20. The development of pore transmembrane structures in the smooth ER is an indication that there is an imbalance in metabolism leading to a significant loss of calcium ions to the cytoplasm. By distributing the lipid head groups apart, protein aggregates can also deteriorate the bilayer and lower the permeability barrier, enabling calcium ions to pass through the membrane and is responsible for increase in conductance of membrane also responsible for penetration of charged species. To keep calcium homeostasis, the calcium pumps inadvertently deplete vital neuronal energy. However, the condition of calcium homeostasis is more alike to what occurs when the membrane system fails. It is noteworthy that the calcium channel does not allow protein aggregates to change the level of calcium homeostasis. This is so because Even with closed calcium channels, there is still a calcium imbalance. According to Gurvir S. Virdi et al., PD patients may have impaired mitochondrial calcium handling, elevated basal calcium, and impaired intracellular calcium signaling^21,22. Also Autophagy and the ubiquitin-proteasome systems may be overloaded by excessive or persistent protein aggregation, which results in the build-up of damaged proteins and additional cellular stress⁴. ROS produced by protein aggregates have the potential to oxidize any material inside a cell. Afterwards, protein aggregates reacted with transition element ions like Fe⁺⁺ and Cu⁺⁺ to produce hydroxyl radicals. The generation of hydroxyl radicals was, however, inhibited by catalase or metal cheaters. Prior research has discovered that patients with PD have lower action in Complex I of the breathing chain in their Substantia Nigra pars compacta (SNpc), which could lead to an overabundance of ROS production and subsequent apoptosis²³. There have also been reports of mitochondrial Complex I deficit in blood platelets, fibroblasts, and the frontal cortex in Parkinson's disease patients. Moreover, research indicates that the Complex I inhibitors, like 1-methyl-4-phenyl1,2,3,4-tetrahydropyridine (MPTP) and its metabolite, 1-methyl4-phenylpyridinium (MPP⁺), may cause nigral deterioration with cytoplasmic α-synuclein and have cytotoxic effects on DA neurons, producing a phenotype that is clinically parkinsonian²⁴. Even in the initial phases of PD, alterations in antioxidant molecules have been documented. For instance, although this finding is not unique to PD, the levels of GSH, which is significant antioxidant is also lowered in the SNpc of PD²⁵. Furthermore, higher iron levels were seen in the PD SNpc compared to controls, which could be the result of dysfunctional transportation of iron to the mitochondria in dopaminergic neurons of PD patients. It has also been described that quantity of iron was amplified in DA neurons in PD, ferrous iron come in contact with H₂O₂and increases the production of hydroxyl radicals (OH^-). And in this way increased iron in SNpc responsible for damage of dopaminergic neurons.²⁶

Figure 2. Schematic representation of effects of Protein Aggregates

Elimination of protein aggregates:¹³

Since aggregated proteins can cause a variety of diseases, including neurodegenerative situations like Alzheimer's and Parkinson's disease, getting rid of protein aggregates is a difficult task. Although the method for removing protein aggregates varies depending on the particular disease, researchers have looked into the following broad approaches and techniques:

The following points can be used to summarize the strategies used to resist protein aggregates:

a. Refolding incorrectly folded proteins and dissolving aggregates

b. Using the ubiquitin-proteasome pathway (UPP) to break down protein aggregates

c. Using the autophagy-lysosome pathway to break down protein aggregates (ALP).

d. Reduce asymmetric cell division (ACD) caused by proteins.

All of these are defending proteostasis stability.

a. Refolding misfolded proteins and depolymerizing aggregates.

Cells first decide to refold and depolymerize protein clumps in order to sustain the proteostasis balance in a usual condition and conserve valuable resources. Particularly important is an effective and economical way to recycle or rescue misfolded proteins. This role is well played by molecular chaperones²⁷. The Heat Shock Protein (HSP) family is the molecular chaperone that typically protects proteostasis. PD is primarily associated with HSPs 26, 40, 60, 70, 90, and 100. In PD, the levels of certain HSPs, which are found in synapses and axons, are downregulated. HSPs play a significant role in reducing toxicity by binding to aggregated SNCA, tau oligomers, or prefibrillar constructions and intrusive by becoming low molecular weight soluble oligomers or higher order insoluble structures. HSPs are also essential for the control and accurate operation of autophagy-lysosomal pathways and ubiquitin proteasomes. HSP70 co-expression inhibits DA cell death in drosophila and yeast models of PD by reducing SNCA toxicity, while HSP70 ATPase domain mutations (K71S) increase toxicity. In rat brain slices, over-expression of HSP70 reduces the neurotoxicity caused by MPTP or rotenone ⁴. It's interesting to note that ubiquitin, the protein that tags protein aggregates, may also be responsible for depolymerizing them²⁸. The interaction between HSP70 and the protein aggregations attracts HSP100. An active HSP100 is managed by HSP70. HSP100 proteins use their aromatic pore loops to thread individual polypeptides apart. This threading action can begin at the midway, C-terminus, or N-terminus of the polypeptide. Each stage of the polypeptide's movement through HSP100 necessitates the use of an ATP. Because Hsp70 interplay increases substrate release's susceptibility to cellular Hsp70 availability and guarantees that damaged proteins can effectively refold under ideal folding conditions, it has a substantial impact on protein homeostasis²⁹. After the polypeptide unfolds, heat shock proteins can assist in the refolding process, or it can occur on its own³⁰.

b. Degradation of protein aggregates with Ubiquitin-Proteasome Pathway (UPP):³

The UPP serves as the main mechanism in the cytoplasm, nucleus, and ER that enables the deprivation of soluble intracellular proteins. Unfolded polypeptides and soluble misfolded proteins are the main problems that UPP handles. UPP is unable to eliminate these protein aggregates once they have been gathered. Activated ubiquitin monomers are small, stable globular proteins that are first covalently attached, in an ATP-dependent process, to the lysine of the substrate protein. The successive action of ubiquitin ligases (E3), ubiquitin-activating enzymes (E1), and ubiquitin-conjugating enzymes (E2) starts and directs this process. The proteasome uses the ubiquitin chain as a signal to recognize it. Short peptide fragments produced by proteasomal degradation are subsequently broken down by peptidases, enabling the recycling of amino acids for the creation of new proteins.

c. Degrading protein aggregates via Autophagy-Lysosome Pathway (ALP):^4,10

Macrophage and chaperone-mediated autophagy are the two ALP processes connected to the α-syn degradation process. Autophagosomes are produced when macroautophagy breaks down α-syn. To create autolysosomes, they combine with lysosomes. α-syn aggregates weaken macroautophagy and decrease autophagosome authorization as PD worsens, which raises the death rate of dopaminergic neurons. It is true that conditional removal of the expression of the macroautophagy gene ATG-7 from dopaminergic neurons results in a decrease in striatal dopamine levels and cell loss. The second autophagy mechanism linked to PD is, Chaperone-Mediated Autophagy (CMA), is a highly selective catabolic process as opposed to vesicle generation. Substrates instead enter the lysosome lumen by directly passing through the lysosome membrane. The 70 kDa HSP8 (Hsc70) forms a chaperone complex that is exclusive to cytosolic proteins and recognizes the CMA-related targeting motif (KFERQ). Once this is realized, they proceed to the lysosome and come into contact with, the lysosome-associated membrane protein type 2A (LAMP2A), which sets off the hydrolytic collapse of the constituent parts by enzymes. Because aggregated a-synuclein causes fragmentation of ER and alters ER protein folding capacity, immature lysosome b-glucocerebrosidase misfolds and aggregates.

d. Asymmetric cell division (ACD) or exocytosis:¹³

ACD is a useful technique for reducing the formation of protein clumps in daughter cells, whether the cells are dividing or not. Protein aggregates may pose a threat to the cardiovascular and neurological systems. Because ACD cannot remove protein aggregates from G0 cells, such as matured neurons or cardiac cells. On the other hand, they can also exocytose and secrete clumps. Surprisingly, ACD functions as the main protective mechanism for daughter cells against protein aggregates during neuronal development. In embryonic Drosophila neuroblasts, protein aggregates were transported to the microtubule consolidating center (MTOC) by dynein, where they interrelated with the peri-centriolar material (PCM). The PCM was pulled to one side of the cell by the mother centrosome, or older centrosome, as it separated from the other centrosomes during mitosis. During this phase, there may also be an enrichment of protein aggregates on one side of the shaft body. The daughter centrosome would form the new PCM if there were less protein clumps. When a daughter cell receives protein aggregates, it may eventually go through apoptosis, which lets the other cell live longer and get better resources.

Mitochondrial dysfunction:

In addition to playing a critical role in energy production, mitochondria are also involved in neuronal function, including apoptosis and calcium homeostasis³¹. Mitochondria are crucial for cellular activity and homeostasis, especially for buffering cytosolic calcium, generating ATP, and serving as a significant source of ROS. There is evidence of mitochondrial dysfunction in PD, which results in reduced energy synthesis and elevated ROS production. This malfunction may additionally exacerbate the effects of oxidative stress and neuronal injury. ROS, such as superoxide radicals (O₂^-) and hydrogen peroxide (H₂O₂) are formed by oxidative phosphorylation. Moderate ROS levels induce physiological pathways that guarantee appropriate operation (e.g., intracellular signaling cascades targeted at preserving cell homeostasis). Increased ROS levels can in fact cause mutations that harm mitochondrial lipids, proteins, and mtDNA. These mutations impair oxidative phosphorylation, fragment mitochondria, and disrupt mitochondrial function. Apoptosis will ultimately result from mitochondrial damage, which will also cause ATP to be depleted, calcium to enter the cell, and the mitochondrial permeability pore to open^32,33. ROS and oxidative stress have been adequately proven to be key initiating factors in the etiology of PD^3,34,35.

Oxidative stress³⁶

Oxidative stress is a leading cause to damage cells by oxidation³⁷. An imbalance in the body's capability to use antioxidants to rid itself of the harmful effects of free radical production and elimination leads to oxidative stress.

ROS oxidize various types of biomolecules, finally leading to cellular lesions by damaging DNA or stimulating apoptosis for cell death³⁸.

The disturbance in the prooxidant and antioxidant balance responsible for potential damage producing oxidative stress. Numerous types of free radicals like hydrogen peroxide, the hydroxyl radical, nitric oxide (NO), and the superoxide radical can be formed within the body because of increased lipid peroxidation and vital antioxidants in the human body are glutathione, superoxide dismutase (SOD), catalase³⁹.

By-products of lipid peroxidation responsible for alteration of the structural organization and functions of the cell membrane which includes decrease in membrane fluidity, higher membrane permeability, inactivation of membrane-bound enzymes and loss of essential fatty acids⁴⁰. Superoxide radicals are changed into hydrogen peroxide by SOD, which is then converted into oxygen as well as water by glutathione peroxidase and catalase. Furthermore, nitrate is altered into nitrite by glutathione peroxidase, showing that NO is present. Xanthine oxidase changes uric acid during the rate-limiting stage of purine catabolism. Furthermore, 8-OHdG is a sign for DNA loss and malondialdehyde (MDA) is a noteworthy byproduct of lipid peroxidation. One explanation for the onset of PD is that all cell components, including proteins, lipids, and DNA, are harmed by the antioxidant defense system's incapacity to prevent the creation of free radicals, which ultimately leads to cell death^41,42,43. Some external sources free radicals are cigarette smoke, environmental pollution, radiation, drugs, pesticides, industrial chemicals and ozone.

Neuroinflammation:

The inflammatory response facilitates tissue repair and effectively removes the causative agent ⁴³. Inflammation is induced by primary inflammatory stimuli, which include microbially produced molecules and structures, combined or misfolded proteins, and the cytokines interleukin-1β (IL1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). The Toll-like receptors (TLRs), IL-1 receptor (IL-1R), IL-6 receptor (IL-6R), and TNF receptor (TNFR) interact to cause it to be activated. Intracellular signal transduction cascades, such as the Janus kinase indication transducer and activator of transcription (JAK-STAT) trail, nuclear factor kappa-B (NF-κB), and Mitogen-Activated Protein Kinase (MAPK) pathways, are triggered by the triggered receptors. Through a complex web of interactions, effector macrophages and lymphocytes release pro and anti-inflammatory cytokines that draw in additional leucocytes and control the inflammation itself, controlling the process's growth and intensity. ⁴³

Variation in level of oxdative parameters like reduced glutathione (GSH), Malondialdehyde (MDA), and inflammatory mediaters like Interleukins (ILs), Tumor necrosis factor (TNF-α) observed in Neuroinflammation ⁴⁴. The brain parenchyma's first line of defense is provided by microglia, but when they become overly activated, they can release chemicals that damage neurons directly, such as prostaglandin E2, nitric oxide, inflammatory cytokines (like IL-1, IL-6, and TNF-α), and various reactive oxygen and nitrogen species. Moreover, activated microglia has been shown to injure cell debris while phagocytizing adjacent cells. In response to neuronal injury, microglia produce extracellular superoxide, and proteases that modify the extracellular matrix (ECM) may be essential for this process to occur. Two functionally different phenotypes, M1 and M2, are produced by the complex reaction of microglial activation in response to infection or injury ⁴⁵. The general model, albeit significantly simplified, states that pro-inflammatory cytokines (IL-1β, IL-6, IL-12, and TNFα) secreted by M1 microglia cause neurodegeneration. These mediators may straight contribute to neuronal death and widen the immune reply. TNFα is acknowledged for its pro-apoptotic properties, which rely on the downregulation of c-Rel, an NF-κB homologue that prevents cell death and inspires the endurance of neurons. Overexpression of M1 cells enzymes produces ROS that have antibacterial attributes, which increases oxidative stress. Pro-inflammatory cells release chemicals such as IL-10 to prevent them from activating. M2 microglia associated with phagocytic receptors, which clears cell debris ⁴⁶. However, different studies have revealed that heterogeneity in microglia is so complicated, having different microglial phenotypes. The molecular mechanisms generating microglia heterogeneity are currently not well understood ^43,46,47. Astrocytes maintain the blood-brain barrier's integrity and permeability. Microglia and astrocytes both contribute to the neuroinflammation seen in PD. Astrocytes help neurons with their metabolic processes by dispersing lactate and transferring it to the Krebs cycle ⁴⁸. They can nullify antioxidants and neuronal waste products like combined α-Syn and spoiled mitochondria. The nervous system is remodeled by astrocytes filling in the gaps left by dying neurons, a process known as astroglial scarring ⁴³. The A1 astrocytic population creates pro-inflammatory proteins like TNFα, C1q, and IL-1α, that hurries the process of inflammation and neuronal death. On the other hand, the A2 population upholds the survival and neuroprotection of spoiled neurons ⁴⁹.

Ferroptosis:

Ferroptosis can result in a variety of diseases, ranging such as liver, renal, and cardiovascular problems as well as neurological disorders. The connection between ferroptosis and neurodegeneration was examined by Masaldan et al.^50,51. Aging causes iron to build up in the brain, which makes these processes more likely and worse. Both directly and as a cofactor necessary for the activity of enzymes mediating redox reactions and lipid peroxidation, iron promotes ferroptosis. The regulation of epigenetic modifications could alter a cell's susceptibility to ferroptosis iron content within cells, oxidative stress, and fat metabolism. All neural system cell types, including neurons, glial cells, and pericytes, are impacted by ferroptosis. The main cells in disease that accumulate iron are called microglia. Inducible Nitric Oxide Synthase (iNOS) is responsible for activation of microglia promos neuroinflammation and oxidative stress ⁵². ROS from various sources, most notably the accumulation of free intracellular divalent iron (Fe⁺⁺), damage membranes by peroxidizing polyunsaturated fatty acids (PUFAs), which leads to ferroptosis. Reduced intracellular availability of antioxidant enzymes, especially glutathione peroxidases (GPXs), is a primary cause of ferroptosis. Nerve tissue has a high rate of oxygen consumption and lipid content, making it especially susceptible to ferroptosis and oxidative damage⁵³.

Gut dysbiosis:

Multiple theories suggest that intestinal symbiosis either causes or facilitates PD. In mice that overexpress α-Syn, the GI micro biota worsens microglial activation, α -Syn disease, and motor deficits. In the absence of micro biota, the deficiencies diminish but do not totally disappear ⁵⁴. In 2016—Sampson et al. Oral rotenone administration over time has been validated to cause GI dysfunction and abdominal symbiosis preceding to the exhibition of motor dysfunction and CNS illness⁵⁵. PD is thought to be brought on by intestinal symbiosis through a number of different pathways, including oxidative stress and inflammation, increased blood-brain barrier and intestinal barrier permeability, decreased dopamine synthesis, and molecular mimicry ⁵⁶.

CONCLUSION:

Pathophysiology of PD is complex and it is combination of different environmental and genetic factors. Important contributors for PD may include α- synuclein aggregation, oxidative stress, mitochondrial dysfunction, ferroptosis, and gut dysbiosis—which are responsible for destruction of dopaminergic neurons. The PD mechanism has been extensively investigated, but the disease remains incurable as the disease involves multiple neurotransmitters like dopamine, acetylcholine, glutamate, serotonin and GABA and they are having different roles in their own way. The challenges facing medical professionals and researchers in the future will focus on identifying biomarkers for an early diagnosis of these diseases at the preclinical stage in the field of Parkinson's disease (PD) and related disorders. Also Additional research is mandatory to entirely comprehend the multifaceted mechanism that underlies how these mechanisms influence Parkinson's disease. This review will stimulate further investigation into a range of ligands that may enhance treatment outcomes for Parkinson's disease and/or reduce side effects.

ACKNOWLEDGEMENTS:

We are very grateful to our guide and mentor Dr. Prof. Suvarna Pramod Ingale for providing guidance time to time. Authors are also thankful to Marathwada Mitramandals College of Pharmacy, for assistance.

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Received on 22.01.2024 Modified on 09.05.2024

Research J. Pharm. and Tech 2024; 17(10):5167-5174.

DOI: 10.52711/0974-360X.2024.00791