Neuroinflammation is the body's immune reaction that occurs inside the central nervous system to keep brain cells balanced and healthy. Uncontrolled and chronic neuroinflammation can start damaging neuronal cells and lead to neurodegenerative diseases. Glial cells, especially microglia and astrocytes, play an important role in this process. Microglia act as immune guards of the brain, shifting between protective and harmful states depending on certain signals such as NADPH oxidase 2, histone deacetylases, and transforming growth factor. Astrocytes support neurons and maintain the blood-brain barrier. During injury or stress, they become overactive and release numerous chemicals that make inflammation worse. Further, neuroinflammation is controlled by several signalling pathways, including NF-κB, PI3K/Akt, and MAPK. When these systems lose their balance, they cause ongoing inflammation and oxidative stress, which eventually harm brain cells. During the progression of neurodegenerative disorders, especially Alzheimer's Disease (AD) and Parkinson's Disease (PD), overactive microglia and astrocytes release large amounts of cytokines, reactive oxygen species, and inflammasome components that speed up neuron loss. The constant interaction between NF-κB, NLRP3, and oxidative stress worsens this damage, linking faulty molecular signals with the progression of these disorders. Ferulic acid, a natural antioxidant found in grains, fruits, and vegetables, has shown remarkable protective effects on the brain. It is biologically synthesized from aromatic amino acids L-phenylalanine and L-tyrosine through the shikimate pathway. By clearing free radicals and stopping lipid damage, ferulic acid protects neurons from degeneration. Experimental studies have shown that ferulic acid offers significant antioxidant and anti-neuroinflammatory effects and prevents the accumulation of harmful proteins, such as Aβ and α-synuclein, in the brain. Furthermore, ferulic acid has a strong capacity to modulate several cellular and molecular signaling pathways, including Nrf2/HO-1, NF-κB, and MAPK, which are closely linked to the development and progression of neurodegenerative disorders such as AD and PD. Interestingly, ferulic acid inhibits the generation of pro-inflammatory mediators, ameliorates mitochondrial dysfunction, prevents apoptosis, and consequently protects cholinergic and dopaminergic neurons in the brain, thereby exhibiting remarkable neuroprotective effects. Thus, the current review addressed that ferulic acid is considered a promising natural compound that could be an alternative natural phytoconstituent for the prevention and management of neuroinflammationassociated neurodegenerative disorders like AD and PD.

Icariside II (ICS II), a PDE5 inhibitor, is a flavonoid glycoside and primary metabolite of icariin, derived from the herb Herba epimedii, and exhibits promising neuroprotective potential in various pre-clinical studies. The current review provides evidence that ICS II shows neuroprotective potential against various neurological disorders, mainly including Alzheimer's disease, Parkinson's disease and Cerebral ischemia through modulating neuroinflammation, oxidative stress, neural apoptosis, neurogenesis, mitochondrial and cognitive dysfunction. It regulates multiple signalling pathways including PI3K/Akt, Keap1/Nrf2, TLR4/MyD88/NF-κB, cGMP/PKG/CREB, TGFB1/Smad, Wnt/β-catenin signaling and BDNF/TrkB/CREB. The pre-clinical evidence suggests that ICS II attenuates oxidative stress through increasing antioxidant enzymes SOD, GSH, catalase, and HO-1, with decreasing MDA and lipid peroxidation. Neuroinflammation is suppressed by inhibition of pro-inflammatory cytokines and down-regulation of IL-1β, IL-6, TNF-α, COX-2, iNOS levels and up-regulation of tight-junction proteins like occludin, claudin-5, ZO-1. Apoptosis is regulated via altering PARP, Bcl-2, Bax/Bcl-2 ratio and reducing caspase-3 activation. Mitochondrial dysfunction is ameliorated by restoring Complex I activity and increasing mitofusin-1/2 expression and reducing mitochondrial fission factors. Collectively, these molecular mechanisms show promise for ICS II as a potential candidate in different in vivo and in vitro studies of neurological disorders.

It has come to our notice that in the published version of this article [1], the reference [96] was cited erroneously. The author has now corrected the reference sequence, and it is now cited as [95]. The revised section is provided below. The original article can be found online at https://www.eurekaselect.com/article/145138.

Parkinson's disease (PD) is an idiopathic and age-related neurodegenerative disorder, marked by the selective loss of dopaminergic neurons in the SNpc and the formation of α-synuclein aggregates. Consequently, this leads to motor and non-motor complications in PD-like patients. Research on plant-based secondary metabolites, such as polyphenols, confirmed that they may slow the development and progression of PD. Flavonoids generated the peak of interest due to their medicinal properties, including mitigation of the risk of PD. Quercetin, a subclass of flavonol type of flavonoids, attracted attention as a potential neuroprotective agent. Quercetin has been demonstrated to have anti-oxidant, anti-inflammatory, anti-apoptotic, and neuroprotective properties, along with obstruction of α-synuclein accumulation and mitochondrial protection. Moreover, studies also revealed that quercetin ameliorates the striatal dopamine content and distinctly modulates the various signalling pathways, including PI3K/AKT, Nrf2, MAPK and NF-kB that are involved in the disruption of disease. Further, quercetin modulates oxidative stress through upregulation of anti-oxidant enzymes, inhibits neuroinflammation via suppression of pro-inflammatory cytokines, prevents Lewy bodies formation and regulates autophagy along with apoptosis. By exhibiting the aforementioned effects, quercetin protects against the neuronal toxicity induced by various neurotoxins through multiple mechanisms to improve motor and non-motor functions. This highlights quercetin as a potential multifaceted therapeutic candidate for PD intervention. We searched for the published data on quercetin related to PD and summarized them in the current review. This review aims to address the understanding of mechanisms, therapeutic effects of quercetin and various models using neurotoxins to induce PD. This review aims to elucidate the underlying cellular and molecular mechanisms and therapeutic effects of quercetin, as well as to explore the various neurotoxin-induced models of PD used to investigate its efficacy. The major part of this review article discusses the roles of quercetin in the management of PD in animals of several experimental models used by many research studies. Overall, quercetin represents a promising, safe, effective and potentially neuroprotective candidate for disease disease-modifying strategy to combat neurological disorders such as PD.

Glial-mediated neuroinflammation significantly contributes to major neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Inhibition of glial-mediated neuroinflammation is effective in treating neurodegenerative diseases. Although no permanent cure exists, considerable research aims to identify natural compounds that may slow the disease progression. Icariin is a naturally occurring flavonoid derived from the herb Herba epimedii and has been shown to have several medicinal benefits, including anti-aging, antioxidant, anti-inflammatory, and anti-apoptotic properties. Recent studies have indicated that Icariin, a potent prenylated flavonol glycoside, exhibits neuroprotective effects against glial-mediated neuroinflammation. Icariin attenuates glial pro-inflammatory responses and prevents neurotoxicity in cellular and animal models. Additionally, Icariin is speculated to facilitate neuronal functioning and survival in experimental conditions. The present review highlights the remarkable role of glial cells in neuroinflammatory processes subsequently neurodegeneration, and the potential of icariin to suppress glial-mediated neuroinflammation. We hope that this review will accelerate the pharmacological development of icariin as a potential therapeutic compound against glial-mediated neuroinflammation, which triggers the pathogenesis of several neurodegenerative disorders.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive declination, neuronal loss, multifaceted pathological mechanisms. Despite extensive scientific research, no definitive cure exists, but recent advancements in clinical trials highlight promising therapeutic strategies targeting multiple pathways involved in AD progression. Early-phase trials (Phases I and II) focus primarily on amyloid-beta (Aβ) and tau pathologies, with monoclonal antibodies like Aducanumab, Lacanemab, and Remternetug targeting Aβ clearance, while tau-directed agents such as E2814 and Bepranemab aim to reduce neurofibrillary tangle formation. Additionally, some novel approaches addressing neuroinflammation, bioenergetic disturbances, neurotransmitter modulation, and synaptic plasticity are emerging. In Phase III, late-stage candidates like Aducanumab, Donanemab, and Lecanemab have advanced, with some receiving regulatory approval, though their long-term clinical efficacy remains under evaluation. Phase IV studies further assess the long-term safety effectiveness of approved treatments in real world populations. The evolving landscape of AD therapeutics underscores a paradigm shift towards combination therapies and personalized medicine, recognizing AD as a multifactorial disorder.

Globally, Alzheimer's Disease (AD) is the most common neurological disorder that affects the older population. However, the intricacy of AD pathophysiology causes disparities in our knowledge of the disease and could be the primary cause of the medication development failure for AD. Thankfully, several preclinical and clinical research projects are still in progress, which will continue to pave the way for the discovery of disease processes and direct approaches to AD diagnosis and medication development. For instance, because of the exceptional preclinical outcomes, immunotherapeutic approaches targeting the tau and amyloid-β (Aβ) proteins were originally thought to be almost successful in clinical treatment. This strategy has been called into question due to the numerous failures in clinical studies involving vaccinations and humanized anti-tau monoclonal, anti-Aβ antibodies. However, immunotherapy targeting Aβ may still have potential, as evidenced by the United States Food and Drug Administration (USFDA) recent endorsement of Aducanumab, a novel anti-Aβ monoclonal antibody. Immunotherapies targeting various targets, including microglia, tau, and the gut-brain axis, are also being developed in the meantime. To improve the accuracy and efficacy of immunotherapeutic treatments, more inspection is required to clarify the targeted proteins' structures and epitopes. In this review, we concentrate on the mechanisms of action of immunotherapies focused on microglia, tau, and Aβ in AD. We also discuss current developments and prospects for immunotherapeutic approaches to AD.

Betanin is widely consumed around the globe either as beetroot directly or as one of the key ingredients in food and pharmaceutical preparations. The health benefits of Betanin, including the treatment of numerous neurological diseases and brain cancer, have been reported extensively. Betanin has gained global attention due to notable anti-inflammatory, antioxidant, and anti-cancer activities. Recently, there has been growing attention on the usage of Betanin to prevent or delay the onset of neurodegenerative disorders. This review recapitulates available information from various recent pre-clinical studies on Betanin in several neurological diseases, such as Parkinson's disease, Alzheimer's disease, aging, brain stroke, anxiety, and neuropathic pain. Betanin exhibits remarkable neuroprotective effects via activation of the Nrf2 signaling pathway, inhibition of the production and expression of pro-inflammatory mediators and reactive oxygen species, along with suppression of the NF-κB signaling pathway. Taking betanin as part of a healthy diet may aid in the management of various brain-related disorders. This review focuses on the neurological conditions for which betanin has shown therapeutic potential, highlighting its beneficial properties, cellular and molecular mechanisms of action, and its relevance in light of current research. Based on the available evidence, betanin could be considered a promising candidate and lead compound in the drug development process for the prevention, treatment, and management of several neurological disorders in the future.

Melanocytes are highly specialized dendritic cells that deliver melanin to keratinocytes in melanosomes, which are subcellular organelles where melanin is produced and stored. Mammal's skin, hair, and eyes all contain the complex pigment melanin, which gives them color and ultraviolet protection. Melanins have the potential to be free radical sinks and are strong cation chelators. Amino acid tyrosine and its metabolite, dopa, are the precursors to complex metabolic processes that end with melanin production. Melanocytes generate different types and amounts of melanin, which is defined genetically and is impacted by several extrinsic and intrinsic factors such as hormone fluctuations, inflammation, age, and ultraviolet radiation exposure, leading to the stimulation of numerous melanogenesis pathways. Melasma, a common skin pigmentation condition, is associated with the overproduction of melanin and is characterized by brown to gray-brown and black spots that mostly affect the face. The present review addresses the regulatory mechanisms and signaling pathways involved in skin pigmentation with an emphasis on the altered melanogenesis that causes melasma and hyperpigmentation. The current study also illustrates the available treatment options with cellular and molecular mechanisms for the management of melasma. Understanding the mechanism of the pigmentation process may help researchers develop new therapeutic strategies and novel drugs for the management of melasma.

The PI3K/AKT and Nrf2 signaling systems are essential for neurogenesis, synaptic plasticity, and cellular survival, and their dysregulation has been linked to the progression of Alzheimer's disease (AD). Due to its complex pathophysiology, currently approved therapeutic agents only provide symptomatic relief and are often associated with serious side effects. Researchers have increasingly focused on natural bioactive compounds as potential therapies, with flavonoids emerging as promising candidates due to their diverse neuroprotective properties. These polyphenolic compounds exhibit notable anti-inflammatory, anti-apoptotic, and antioxidant effects, making them attractive therapeutic agents against AD. A key mechanism by which flavonoids exert neuroprotection is through modulation of the PI3K/AKT and Nrf2 signaling pathways. By enhancing neuronal resilience, reducing oxidative stress, inhibiting apoptosis, and regulating autophagy, flavonoids can mitigate neurodegenerative processes associated with AD. Additionally, they attenuate Aβ accumulation and tau hyperphosphorylation, both of which contribute to neuronal dysfunction, via PI3K/AKT activation and Nrf2 pathway regulation. In preclinical AD models, numerous flavonoids-including epicatechin, kaempferol, quercetin, and luteolin- have demonstrated neuroprotective effects through regulation of the PI3K/AKT and Nrf2 pathways. Despite these encouraging findings, further research is needed to determine optimal dosages, strategies for enhancing bioavailability, and the long-term effects of flavonoid-based therapies in AD. Future studies should focus on translating preclinical evidence into clinical trials, which could improve patient outcomes and quality of life. A deeper understanding of the molecular mechanisms underlying flavonoid activity, particularly their interaction with PI3K/AKT and Nrf2 pathways, may pave the way for novel neuroprotective therapies.

Brain related disorders are a set of medical ailments that cause motor incoordination, cognitive and memory problems due to neurodegeneration in the brain. Although current therapies alleviate symptoms, they fail to target the fundamental pathological processes driving the disorders. A hematopoietic growth factor, Erythropoietin, stimulates erythroid cell formation and is therapeutically applied for the treatment of anemia. Furthermore, Erythropoietin has shown improved neurological outcomes in preclinical models and is being investigated as a potential therapeutic agent for neurodegenerative disorders. Erythropoietin is potential target for the regulation of numerous cellular signal pathways to enhance the neuronal survival, promote neuronal differentiation via binding of Erythropoietin-to-Erythropoietin receptor to stimulate the protein Janus-tyrosine kinase 2 followed by regulation of protein kinase B, signal transducer and stimulators of transcription 5, protein tyrosine phosphatases, mitogen-activated protein kinases, nuclear factor kB and Wnt1. Numerous research studies have evaluated the therapeutic potential of Erythropoietin against several neurological disorders including Alzheimer's disease, Parkinson's disease, neuroinflammation and epilepsy and highlight that Erythropoietin exhibits significant neuroprotective effects by counteracting apoptosis, neuroinflammatory process, reactive oxygen species overburden and neuronal death, consequently, prevent the progression of such diseases. However, two major challenges in developing erythropoietin as a neuroprotective agent include optimizing its therapeutic window and addressing safety concerns, particularly its adverse interaction with tissue plasminogen activator, which has been shown to increase the risk of hemorrhagic complications in ischemic stroke patients. In present review, we discuss the neurotherapeutic applications of Erythropoietin against brain related disorders beyond erythropoiesis. In conclusion, it can be assumed that Erythropoietin could be an alternative therapeutic option for the management of neurological disorders.

The KEAP1-Nrf2 pathway plays a pivotal role in redox homeostasis and cellular stress. Abnormal regulation of this pathway results in neurodegenerative diseases, including Alzheimer's Disease and Parkinson's Disease, cancer and diabetes. Targeting the KEAP1 Kelch domain presents a promising therapeutic strategy to regulate Nrf2 activity. Structural insights acquired from macromolecular crystallography have enabled the development of potent inhibitors disrupting the KEAP1-Nrf2 interaction. This article focuses exclusively on compiling studies of the 112 KEAP1 structures co-crystallized with peptides and small molecule ligands over the last 20 years, investigating interactions that govern inhibitory potency. After a thorough review, small molecule ligands have been classified according to their chemical structures, including naphthalene, isoquinoline, benzotriazole, pyrazole, and azabicyclic, along with their biological efficacies to investigate the decisive interactions at the orthosteric site. Among all the reported PDB records of KEAP1, hydrogen bonding, cation-π, π-π stacking, and salt-bridge interactions predominantly contribute to stabilizing protein-ligand complexes. These insights will pave the way for the design and development of selective peptide and small molecule-based ligands for regulating the KEAP1-Nrf2 pathway, providing breakthroughs for the management of various diseases.

Alzheimer's Disease (AD), a prevalent neurodegenerative disorder, poses a significant global health challenge with complicated pathogenesis. Pathological characteristics of AD include increasing loss of cholinergic neurons, oxidative stress, mitochondrial dysfunction, and amyloid beta accumulation. Due to the limited availability of effective therapeutic options with only symptomatic relief and their severe adverse effects, there is a significant need to search and explore new agents for the management of AD. Recently, natural products and/or phytoconstituents of plants have gained notable attention as potential sources of neuroprotective agents due to their diverse chemical constituents, mechanism of action, and relatively safe profiles. In view of this, Glycyrrhiza glabra has been recognized for its several therapeutic properties in traditional medicine systems for centuries. Further, neuroactive phytoconstituents of this plant, including glycyrrhizin, liquiritigenin, isoliquiritigenin, glabridin, and glycyrrhizic acid, exhibit significant pharmacological advantages along with potential neuroprotective effects against AD. Glycyrrhiza glabra and its phytoconstituents have gained significant interest due to its ability to exert a neuroprotective impact by influencing multiple signaling pathways, inhibiting AChE and BACE1 activity, reducing Aβ accumulation, plaque formation, and tau phosphorylation, and quenching the free radical in experimentally-induced AD-like brain. The present review summarizes available in vitro and in vivo preclinical studies that have been performed to evaluate the beneficial neuroprotective effect of Glycyrrhiza glabra and its phytoconstituents against AD-like pathology. Based on available facts, it can be concluded that neuroactive phytoconstituents of Glycyrrhiza glabra could be significant lead molecules for the drug discovery of anti-AD medicines in the future.

Abstract: Alzheimer's disease, characterized by cognitive decline, memory impairment, and the presence of abnormal proteins or aberrant proteins like tau tangles and beta-amyloid plaques in the brain, despite intensive scientific efforts, has no known treatment, posing a significant global healthcare challenge. Antibody-based therapies have received more attention recently as possible Alzheimer's disease treatments. An extensive review of the state of research on antibody-based compounds as potential Alzheimer's disease treatments is given in this study. In addition to examining the difficulties and constraints encountered during development, it briefly overviews their mechanisms of action, therapeutic efficacy, and safety profiles. The study also emphasizes important factors to consider when developing antibody-based treatments, including safety concerns, dosage schedules, and patient selection standards. To sum up, antibody-based treatments have a bright future for treating Alzheimer's. Despite current obstacles, mounting data indicates that these treatments have a great deal of promise to either slow or stop the progression of this debilitating condition, which could improve the quality of life for the millions of people and families who suffer from Alzheimer's disease globally.

Glaucoma is a serious eye disease characterized by elevated intraocular pressure, which can ultimately lead to blindness, making it the second leading cause of blindness worldwide, following cataracts. The condition is associated with various risk factors and primarily affects the optic nerve. To treat glaucoma, a range of approaches, both traditional and innovative, have been employed. Recently, there has been a significant focus on nanoemulsions as a promising avenue for treatment. This review underscores the advantages of using oil -in -water nanoemulsions for ocular drug delivery, showcasing their superiority in terms of enhanced bioavailability and stability compared with other dispersion systems. This review also delves into the limitations inherent in traditional drug formulations, elucidates the mechanisms governing drug release, explores the pivotal role of surfactants, and examines the landscape of granted patents in this domain. By addressing these critical aspects, the review offers invaluable insights into the treatment of glaucoma, shedding light on innovative approaches that hold great promise in the fight against this debilitating eye condition. During our search, it was noticed that despite the existence of commendable research in the field of ocular nanoemulsions, particularly in the context of glaucoma along with granted patents, the commercialized nanoemulsion formulations for glaucoma is not yet exist.

Hepatic encephalopathy (HE) is a serious neuropsychiatric disorder caused in patients with both; acute and chronic liver diseases, which consists of various complications ranging from cognitive impairment, disorientation, confusion, and coma. The available therapies mainly focus on decreasing ammonia levels either through increasing its elimination or decreasing its production, some medications may subside the duration and limit the consequences of HE, but there is no complete available treatment for HE-like manifestation. Thus, there is a need to explore new pharmacotherapy for the treatment and management of HE. Flavonoids are polyphenolic compounds easily found in vegetables, fruits, flowers, beverages, and plants based foods. In modern research, flavonoids have gained attention due to their broad pharmacological properties, like anti-oxidant, antiviral, anti-inflammatory, cardioprotective, cytoprotective, and neuroprotective activity. Several preclinical studies suggest that various flavonoids have a potential therapeutic role in a variety of metabolic- related neurological disorders, including HE. This review focuses on all pre-clinical reports that highlight the neuroprotective potential of natural flavonoids for the management of HE. Based on numerous pre-clinical studies and taking into account the therapeutic effects of natural flavonoids, the present study illustrates the cellular and molecular mechanisms responsible for the potential role of natural flavonoids as pharmacotherapy for the management and treatment of HE.

INTRODUCTIONVarious natural phytomedicines originating from Chinese herbs exhibit numerous pharmacological activities. Calotropis procera (CP), communally known as Aak, is a xerophytic perennial shrub in the Apocynaceae family that is found in China. Phytoconstituents of this plant have been used to treat several illnesses including colds, asthma, arthritis, diarrhea, and skin disorders in China and other parts of Asia for a very long time. Apart from these, active constituents of CP also exhibit notable antioxidant and neuroprotective activities. Still, there is a gap between the preclinical and clinical significance of this plant. Thus, the present study has been designed to summarize numerous phytochemical, therapeutic, and pharmacological properties of CP in numerous disorders based on preclinical evidence which will provide a relevant basis for the researcher to investigate its efficacy in clinical studies.METHODSThe current research looks at the literature from 2003 to 2023. Electronic search platforms/media PubMed, Google Scholar, ResearchGate, and Scopus database were used to gather the relevant reports related to this study using keywords such as “Herbal Chinese Medicine”, “Phytoconstituent”, “Therapeutic uses”, “Medicinal uses”, “Antimicrobial activity”, “Antifungal activity”, “Anti-inflammatory activity”, “Antioxidant activity”, “Neuroprotective activity”, “Anti-diabetic activity”, “Cardiac activity”, and “Anti-cancer activity” paired with “Calotropis procera”.RESULTSBased on available research reports, the pharmacological and therapeutic potential of CP are collected and summarized. CP contains numerous phytoconstituents such as flavonoids, steroids, alkaloids, volatile oils, esters, and many more which are responsible for the majority of the pharmacological actions including antioxidant, antibacterial, antifungal, anti-diabetic, anti-cancer, antimicrobial, anti-inflammatory effect and anti-ulcer effects.DISCUSSIONThe current study provides primary data for future research. In-vivo and in-vitro studies were used to make the biosynthetic observation for its numerous ethnopharmacological applications and even pharmacological qualities. This evaluation will give the knowledge required to undertake essential pharmacokinetic and toxicological studies on human models to ensure the effects of active ingredients in the body and confirm their safety problems in clinical settings.

Brain-related disorders include neuroinflammation, neurodegenerative disorders, and demyelination, which ultimately affect the quality of life of patients. Currently, brain-related disorders represent the most challenging health problem worldwide due to complex pathogenesis and limited availability of drugs for their management. Further, the available pharmacotherapy accompanies serious side effects, therefore, much attention has been directed toward the development of alternative therapy derived from natural sources to treat such disorders. Recently, flavonoids, natural phytochemicals, have been reported as a treatment option for preventing brain aging and disorders related to this. Among these flavonoids, dietary luteolin, a flavone, is found in many plant products such as broccoli, chamomile tea, and honeysuckle bloom having several pharmacological properties including neuroprotective activities. Therefore, the objective of this paper is to compile the available literature regarding the neuroprotective potential of luteolin and its mechanism of action. Luteolin exerts notable anti-inflammatory, antioxidant, and antiapoptotic activity suggesting its therapeutic efficacy in different neurological disorders. Numerous in-vivo and in-vitro experiments have revealed that luteolin exhibits neuroprotective potential via up-regulating the ER/ERK, PI3AKT, Nrf2 pathways and down-regulating the MAPK/JAK2STAT and NFκB pathways. Taking into account of available facts regarding the neuroprotective efficacy of luteolin, the current study highlights the beneficial effects of luteolin for the prevention, management, and treatment of different neurological disorders. Thus, luteolin can be considered an alternative for the development of new pharmacophores against various brain-related disorders.

Recently, Parkinson's disease (PD) has become a remarkable burden on families and society with an acceleration of population aging having several pathological hallmarks such as dopaminergic neuronal loss of the substantia nigra pars compacta, α-synucleinopathy, neuroinflammation, autophagy, last but not the least astrogliosis. Astrocyte, star-shaped glial cells perform notable physiological functions in the brain through several molecular and cellular mechanisms including nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. It has been well established that the downregulation of the astrocytic Nrf2 signaling pathway plays a crucial role in the pathogenesis of PD because it is a master regulator of cellular defense mechanism along with a regulator of numerous detoxifying and antioxidant enzymes gene expression. Fascinatingly, upregulation of the astrocytic Nrf2 signaling pathway attenuates the degeneration of nigrostriatal neurons, restores neuronal proliferation, rejuvenates astrocytic functions, and exhibits neuroprotective effects via numerous cellular and molecular mechanisms in the PD-like brain of the experimental animal. Here, we discuss the numerous in-vitro and in-vivo studies that evaluate the neuroprotective potential of the astrocytic Nrf2 signaling pathway against experimentally-induced PD-like manifestation. In conclusion, based on available preclinical reports, it can be assumed that the astrocytic Nrf2 signaling pathway could be an alternative target in the drug discovery process for the prevention, management, and treatment of PD.

Phosphodiesterase type 5 (PDE5) is an enzyme primarily found in the smooth muscle of the corpus cavernosum and also highly expressed in the substantia nigra, cerebellum, caudate, hippocampal regions and cerebellar purkinje cells, responsible for selectively breaking down cyclic guanosine monophosphate (cGMP) into 5'-GMP and regulate intracellular cGMP levels. As a second messenger, cyclic GMP enhances signals at postsynaptic receptors and triggers downstream effector molecules, leading to changes in gene expression and neuronal responses. Additionally, cGMP signaling transduction cascade, present in the brain, is also essential for learning and memory processes. Mechanistically, PDE5 inhibitors share structural similarities with cGMP, competitively binding to PDE5 and inhibiting cGMP hydrolysis. This action enhances the effects of nitric oxide, resulting in anti-inflammatory and neuroprotective effects. Neurodegenerative disorders entail the progressive loss of neuron structure, culminating in neuronal cell death, with currently available drugs providing only limited symptomatic relief, rendering neurodegeneration considered incurable. PDE5 inhibitors have recently emerged as a potential therapeutic approach for neurodegeneration, neuroinflammation, and diseases involving cognitive impairment. This review elucidates the principal roles of 3',5'-cyclic adenosine monophosphate (cAMP) and cGMP signaling pathways in neuronal functions, believed to play pivotal roles in the pathogenesis of various neurodegenerative disorders. It provides an updated assessment of PDE5 inhibitors as disease-modifying agents for conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral ischemia, Huntington's disease, and neuroinflammation. The paper aims to review the current understanding of PDE5 inhibitors, which concurrently regulate both cAMP and cGMP signaling pathways, positing that they may exert complementary and synergistic effects in modifying neurodegeneration, thus presenting a novel direction in therapeutic discovery. Moreover, the review provides critical about biological functions, therapeutic potentials, limitations, challenges, and emerging applications of selective PDE5 inhibitors. This comprehensive overview aims to guide future academic and industrial endeavors in this field.