Review. Published Time: 2022-04-20.
Parkinson’s disease (PD) refers to one of the eminently grievous, preponderant, tortuous nerve-cell-devastating ailments that markedly impacts the dopaminergic (DArgic) nerve cells of the midbrain region, namely the substantia nigra pars compacta (SN-PC). Even though the exact etiopathology of the ailment is yet indefinite, the existing corroborations have suggested that aging, genetic predisposition, and environmental toxins tremendously influence the PD advancement. Additionally, pathophysiological mechanisms entailed in PD advancement encompass the clumping of α-synuclein inside the lewy bodies (LBs) and lewy neurites, oxidative stress, apoptosis, neuronal-inflammation, and abnormalities in the operation of mitochondria, autophagy lysosomal pathway (ALP), and ubiquitin–proteasome system (UPS). The ongoing therapeutic approaches can merely mitigate the PD-associated manifestations, but until now, no therapeutic candidate has been depicted to fully arrest the disease advancement. Neuropeptides (NPs) are little, protein-comprehending additional messenger substances that are typically produced and liberated by nerve cells within the entire nervous system. Numerous NPs, for instance, substance P (SP), ghrelin, neuropeptide Y (NPY), neurotensin, pituitary adenylate cyclase-activating polypeptide (PACAP), nesfatin-1, and somatostatin, have been displayed to exhibit consequential neuroprotection in both in vivo and in vitro PD models via suppressing apoptosis, cytotoxicity, oxidative stress, inflammation, autophagy, neuronal toxicity, microglia stimulation, attenuating disease-associated manifestations, and stimulating chondriosomal bioenergetics. The current scrutiny is an effort to illuminate the neuroprotective action of NPs in various PD-experiencing models. The authors carried out a methodical inspection of the published work procured through reputable online portals like PubMed, MEDLINE, EMBASE, and Frontier, by employing specific keywords in the subject of our article. Additionally, the manuscript concentrates on representing the pathways concerned in bringing neuroprotective action of NPs in PD. In sum, NPs exert substantial neuroprotection through regulating paramount pathways indulged in PD advancement, and consequently, might be a newfangled and eloquent perspective in PD therapy.
Parkinson’s disease (PD), a clinical state portrayed around 20.5 decades ago by an English surgeon named James Parkinson as paralysis agitans, is currently acknowledged as the second leading, mystifying, and incapacitating neurodegenerative disease in older individuals [1]. The condition is represented by a tetrad of cardinal manifestations, viz., rigor, tremor, postural deformities, and bradykinesia [2,3]. The aforenamed pivotal manifestations are ascribable to the deterioration of dopaminergic (DArgic) nerve cells in the substantia nigra pars compacta (SN-PC), a region pinpointed in the midbrain [4]. With a tremendous upsurge in the prevalence and incidence rates across the different regions of the nation, PD is emerging as a grievous age-associated and intricate malady [5,6]. Owing to the profound nerve cell protection exhibited by estrogen in females, the females display a de-escalated possibility of encountering PD comparably to males [7]. Although the exact etiopathogenesis of the malady remains perplexing, multifaceted, and vague, extensive data robustly propounds that aging, genetic predisposition, and subjection to environmental toxins unitedly partake in the progression of the malady [8,9,10,11,12,13,14]. The pathophysiological processes embroiled in PD comprehends the clumping of α-synuclein inside the lewy bodies (LBs) and lewy neurites, oxidative stress, apoptosis, neuronal-inflammation, and abnormalities in the operation of mitochondria, autophagy lysosomal pathway (ALP), and ubiquitin–proteasome system (UPS). However, the interrelationship among these processes is still inexplicit [8,15]. Up to the present time, the treatment with the assistance of dopamine (DA) precursor (levodopa), DA agonists, catechol-O-methyltransferase (COMT) inhibitors, and monoamine oxidase B (MAO-B) inhibitors principally focuses on the mitigation of PD-related manifestations, but hitherto no therapeutic candidate has been indicated to totally abolish the progression of the ailment [16,17,18].
Neuropeptides (NPs) are designated as tiny, protein-comprising additional messenger substances that are fundamentally generated and liberated by nerve cells inside the entire nervous system, comprehending the central nervous system (CNS) and the peripheral nervous system (PNS) [19,20]. NPs are synthesized in the cell body from their large protein precursors denominated as prepropeptides (which are synthesized on palade granules at the endoplasmic reticulum and processed by means of Golgi complex). The NPs are principally transcripted and translated from the prepropeptides genes. Further, the activation of prepropeptides carried by proteases/proteinases (peptide bonds hydrolyzing biocatalysts) culminates in the conversion of prepropeptides into propeptides, and at last, following the stimulation of converting biocatalysts, NPs are procured [21,22,23]. Proteolytic processing has been reported to significantly partake in the activation, partial inactivation, or inactivation of the modulatory peptides, for instance, NPs. Proteases, otherwise denominated as proteinases, carry out the breakdown, and as a consequence, might activate, inactivate, or liberate other proteins/peptides [24,25]. These modulatory proteases are fundamentally pinpointed on the surface of the cell or are liberated by the cells. Although the duo forms of proteases tend to perform identical operations, the existing literature has elucidated that cell-surface proteases possess significantly greater regulatory and specialized operations in comparison to those proteases which are liberated by the cells [25]. The cell-surface proteases exert their action by carrying out deterioration of the duo, i.e., the bioactive peptides, and the cellular operations. Apart from the proteolytic deterioration, and conjugation and oxidation reactions, the eradication via filtration/diffusion, is of paramount importance [25]. The majority of the cell-surface proteases have been originally marked as the clearing biocatalysts despite the fact that they possess the aptitude to break the peptides having not more than eighty residues. Currently, they are considered as the regulatory proteases (for instance, angiotensin-converting enzyme (ACE), endothelin-converting enzyme (ECE), neutral endopeptidase (NEP), and dipeptidyl peptidase IV (DPP IV)) that hold the enormous aptitude to modulate the activation/inactivation of NPs [23]. Following their synthesis, NPs are stored/packaged in the large and dense vesicles, and finally their liberation is facilitated by means of an expulsion process termed exocytosis (following depolarization of the cell) [21,22,23]. Thereafter, NPs undergo interaction with receptors, namely G-protein coupled receptors (GPCRs), in order to instigate their physiological actions and regulate nerve cell operation [19,26]. The NPs and their seven transmembrane domain (7TM) receptors/GPCRs are pinpointed ubiquitously in the body, and they usually exist in amalgamation with classic neurotransmitters [18,20,21,27,28]. NPs consequentially partake in the modulation of the immune system, biological equilibrium (for instance, biotransformation of blood sugar, blood pressure, equilibrium in the water content, feeding behavior, stress reaction, and pain), and neuronal protection [29]. Presently, numerous NPs have been elucidated to exhibit substantial neuronal protection in both in vivo and in vitro models of PD, for instance, substance P (SP) [30], ghrelin [31,32], neuropeptide Y (NPY) [33], neurotensin [34], pituitary adenylate cyclase-activating polypeptide (PACAP) [35], nesfatin-1 [36], and somatostatin (SST) [37] via suppressing apoptosis, cytotoxicity, oxidative stress, autophagy, inflammation, nerve cell toxicity, microglia stimulation, attenuating disease-associated manifestations, and stimulating chondriosomal bioenergetics.
In the current scrutiny, the authors attempt to enlighten the linkage between the aforenamed NPs and PD, and elucidate the pathways by means of which these NPs contribute to significant nerve cell protection in PD. A comprehensive examination has been carried out by means of existing literature, i.e., both review and research articles, which were searched through esteemed and well-renowned medical databases, for instance, PubMed, MEDLINE, EMBASE, Frontier, etc., by employing particular keywords in the theme of our paper. The outcome is an explanatory work that would be a tremendously valuable resource for upcoming papers in this respective discipline.
PD, a mystified, multifaceted, and debilitating malady, is depicted by the devastation of DArgic nerve cells inside the SN-PC (pinpointed in the midbrain region), which eventually contributes to DA scantiness in the striatal region. It has been elucidated that deposition of a protein termed α-synuclein within the LBs and lewy neurites is thought to be the characteristic neuropathogenic hallmark of PD [38]. Generally, PD is marked as a motor system ailment exhibiting a quadriad of imperative manifestations, comprehending rigor (stiffness), tremor (shaking in the hands, feets, and legs), postural deformities (abnormal balance and body posture), and bradykinesia (slowed/difficult movement). Nonmotor manifestations, such as urinary and sexual abnormalities, sleep disturbances, psychosis, dementia, anxiety, apathy, depression, constipation, and erectile dysfunction, are also encountered by individuals suffering from PD; however, they are somewhat less apparent in comparison to motor manifestations ([Figure 1](https://www.frankenthalerfoundation.org [39].
Analogous to other frequently emerging age-associated nerve cell deteriorating ailments, PD also commences owing to the amalgamation of the trio, namely aging, genetic predisposition, and subjection to environmental toxins, and is recklessly impacting the global economy [40,41]. According to a meta-analysis, the incidence of PD is expanding at an alarming rate in advanced and well-established parts of the nation, and it has been revealed to escalate abruptly with aging [42]. Another investigation has demonstrated that people falling under the age range of 30–40 years rarely experience PD, while it hits nearly 2% of people going above 60–70 years of age grade, and nearly 5% of people falling above the age range of 80–90 years nationwide ([Figure 1](https://www.frankenthalerfoundation.org [43]. Even the gender differences enormously impact the PD emergence, i.e., males are comparably more prone to PD than females because of the nerve cell safeguarding action of estrogen in females in the initial stages of the disease [44,45]. There are no further gender differences in PD following its progression to the disastrous or later/severe stages, although estrogen partakes in bringing considerable neuronal protection in PD, and it renders no safeguarding effects following the commencement of clinical manifestations [45].
Apart from aging, the duo, namely genetic profile and subjection to environmental toxins, are recognized as fundamental participants indulged in the commencement and advancement of different forms of PD, by triggering DArgic nerve cell demise, as illustrated in [Figure 2](https://www.frankenthalerfoundation.org Over the last few years, a profusion of exploration in the domain of PD has culminated in the elucidation that nearly 5–10% of the delayed commencement sorts of the PD are immensely related with genetic mutations [46]. To date, numerous genes have been reported to be implicated in the PD evolution, encompassing α-synuclein (SNCA) [46,47,48] Parkin RBR E3 ubiquitin–protein ligase (Parkin) [49], ubiquitin carboxy (C)-terminal hydrolase L1 (UCHL1) [50], PTEN-induced kinase 1 (PINK1) [51], protein deglycase (DJ-1) [52], leucine-rich repeat kinase 2 (LRRK2) [53], glucocerebrosidase (GBA) [54], vacuolar protein sorting 35 (VPS35) [55], neuronal P-type adenosine triphosphate (ATP)ase gene (ATP13A2) [56], high temperature requirement A2 (HTRA2) [57], and synaptojanin 1 (SYNJ1) [58]. In addition, a plethora of corroborations profoundly indicate that exposure to nerve cell toxic agents (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [38,51,52], and 6-hydroxy DA (6-OHDA) [38,51]), pesticides (paraquat) [46,59,60], rotenone [46,59,60], dieldrin [61], zineb [46,62], ziram [46,63] and thiram [64], fungicides (nabam [65], and maneb [65]), and solvents (methanol (CH 3 OH) [66], perchloroethylene (PERC) [66,67], trichloroethylene (TCE) [66,67], and carbon tetrachloride (CCl
