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Neurodegenerative disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce psycho-motor malfunctions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-β, huntingtin, and tau, and accumulation of the associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation. Cannabidiol (CBD) is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo. CBD has gained attention as a promising drug candidate for the management of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as the clinical applications of CBD in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sesamol, one of the key bioactive ingredients of sesame seeds ( Sesamum indicum L.), is responsible for many of its possible nutritional benefits. Both the Chinese and Indian medical systems have recognized the therapeutic potential of sesame seeds. It has been shown to have significant therapeutic potential against oxidative stress, inflammatory diseases, metabolic syndrome, neurodegeneration, and mental disorders. Sesamol is a benign molecule that inhibits the expression of inflammatory indicators like numerous enzymes responsible for inducing inflammation, protein kinases, cytokines, and redox status. This review summarises the potential beneficial effects of sesamol against neurological diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Recently, sesamol has been shown to reduce amyloid peptide accumulation and attenuate cognitive deficits in AD models. Sesamol has also been demonstrated to reduce the severity of PD and HD in animal models by decreasing oxidative stress and inflammatory pathways. The mechanism of sesamol's pharmacological activities against neurodegenerative diseases will also be discussed in this review., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Parkinson's disease (PD) is the second most common neurodegenerative disorder. The degeneration of dopaminergic neurons in the midbrain is primarily responsible for the onset of the disease. The major challenge faced in the treatment of PD is the blood-brain barrier (BBB), which impedes the delivery of therapeutics to targeted locations. To address this issue, lipid nanosystems have been used for the precise delivery of therapeutic compounds in anti-PD therapy. In this review, we will discuss the application and clinical significance of lipid nanosystem in delivering therapeutic compounds for anti-PD treatment. These medicinal compounds include ropinirole, apomorphine, bromocriptine, astaxanthin, resveratrol, dopamine, glyceryl monooleate, levodopa, N-3,4-bis(pivaloyloxy)- dopamine and fibroblast growth factor, which have significant potential to treat PD in the early stage. This review, in a nutshell, will pave the way for researchers to develop diagnostic and potential therapeutic approaches using nanomedicine to overcome the challenges posed by the BBB in delivering therapeutic compounds for PD., Competing Interests: Declaration of Competing Interest No., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The phytochemicals have antioxidant properties to counter the deleterious effects of oxidative stress in the central nervous system and can be a promising drug candidate for neurodegenerative diseases. Among various phytochemicals, constituents of spice origin have recently received special attention for neurodegenerative diseases owing to their health benefits, therapeutic potential, edible nature, and dietary accessibility and availability. Carvacrol, a phenolic monoterpenoid, has garnered attention in treating and managing various human diseases. It possesses diverse pharmacological effects, including antioxidant, anti-inflammatory, antimicrobial and anticancer. Alzheimer's disease (AD) and Parkinson's disease (PD) are major public health concerns that place a significant financial burden on healthcare systems worldwide. The global burden of these diseases is expected to increase in the next few decades owing to increasing life expectancies. Currently, there is no cure for neurodegenerative diseases, such as AD and PD, and the available drugs only give symptomatic relief. For a long time, oxidative stress has been recognized as a primary contributor to neurodegeneration. Carvacrol enhances memory and cognition by modulating the effects of oxidative stress, inflammation, and Aβ25-35- induced neurotoxicity in AD. Moreover, it also reduces the production of reactive oxygen species and proinflammatory cytokine levels in PD, which further prevents the loss of dopaminergic neurons in the substantia nigra and improves motor functions. This review highlights carvacrol's potential antioxidant and anti-inflammatory properties in managing and treating AD and PD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Quercetin is a naturally occurring bioactive flavonoid abundant in many plants and fruits. Quercetin and its derivatives have shown an array of pharmacological activities in preclinical tests against various illnesses and ailments. Owing to its protective role against oxidative stress and neuroinflammation, quercetin is a possible therapeutic choice for the treatment of neurological disorders. Quercetin and its derivatives can modulate a variety of signal transductions, including neuroreceptor, neuroinflammatory receptor, and redox signaling events. The research on quercetin and its derivatives in neurology-related illnesses mainly focused on the targets, such as redox stress, neuroinflammation, and signaling pathways; however, the function of quercetin and its derivatives on specific molecular targets, such as nuclear receptors and proinflammatory mediators are yet to be explored. Findings showed that various molecular targets of quercetin and its derivatives have therapeutic potential against psychological and neurodegenerative disorders., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The Japanese encephalitis virus (JEV) is the most common cause of neurodegenerative disease in Southeast Asia and the Western Pacific region; approximately 1.15 billion people are at risk, and thousands suffer from permanent neurological disorders across Asian countries, with 10-15 thousand people dying each year. JEV crosses the blood-brain barrier (BBB) and forms a complex with receptors on the surface of neurons. GRP78, Src, TLR7, caveolin-1, and dopamine receptor D2 are involved in JEV binding and entry into the neurons, and these receptors also play a role in carcinogenic activity in cells. JEV binds to GRP78, a member of the HSP70 overexpressed on malignant cells to enter neurons, indicating a higher chance of JEV infection in cancer patients. However, JEV enters human brain microvascular endothelial cells via an endocytic pathway mediated by caveolae and the ezrin protein and also targets dopamine-rich areas for infection of the midbrain via altering dopamine levels. In addition, JEV complexed with CLEC5A receptor of macrophage cells is involved in the breakdown of the BBB and central nervous system (CNS) inflammation. CLEC5A-mediated infection is also responsible for the influx of cytokines into the CNS. In this review, we discuss the neuronal and macrophage surface receptors involved in neuronal death.

Alzheimer's, a progressive neurodegenerative disease affects brain and neurons through enormous reduction in nerve cell regenerative capacity. Dementia and impairment of cognitive functions are more prevalent in Alzheimer's disease (AD) patients in both industrialized and non-industrialized countries. Various factors play significant role in molecular cascades that leads to neuronal inflammation, dementia and thereby AD progression. Current medications are symptomatic that alleviates pain while lack in absolute cure, urging researchers to explore targets and therapeutics. Interestingly, nanomedicines developed due to the onset of nanotechnology, are being extensively investigated for the treatment of AD. This review presents the advancement in nanotherapeutic strategies, involving the emergence of nanomaterials that offers advantage to pass through the blood-brain barrier and acts as a therapeutic modality against AD., (© 2021 The Author(s). Published by BRI.)

The pharmacological activation of cannabinoid type 2 receptors (CB2R) gained attention due to its ability to mitigate neuroinflammatory events without eliciting psychotropic actions, a limiting factor for the drugs targeting cannabinoid type 1 receptors (CB1R). Therefore, ligands activating CB2R are receiving enormous importance for therapeutic targeting in numerous neurological diseases including neurodegenerative, neuropsychiatric and neurodevelopmental disorders as well as traumatic injuries and neuropathic pain where neuroinflammation is a common accompaniment. Since the characterization of CB2R, many CB2R selective synthetic ligands have been developed with high selectivity and functional activity. Among numerous ligands, JWH133 has been found one of the compounds with high selectivity for CB2R. JWH133 has been reported to exhibit numerous pharmacological activities including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, and immunomodulatory. Recent studies have shown that JWH133 possesses potent neuroprotective properties in several neurological disorders, including neuropathic pain, anxiety, epilepsy, depression, alcoholism, psychosis, stroke, and neurodegeneration. Additionally, JWH133 showed to protect neurons from oxidative damage and inflammation, promote neuronal survival and neurogenesis, and serve as an immunomodulatory agent. The present review comprehensively examined neuropharmacological activities of JWH133 in neurological disorders including neurodegenerative, neurodevelopmental and neuropsychiatric using synoptic tables and elucidated pharmacological mechanisms based on reported observations. Considering the cumulative data, JWH133 appears to be a promising CB2R agonist molecule for further evaluation and it can be a prototype agent in drug discovery and development for a unique class of agents in neurotherapeutics. Further, regulatory toxicology and pharmacokinetic studies are required to determine safety and proceed for clinical evaluation., (Copyright © 2021. Published by Elsevier B.V.)

Limonene is a monoterpene confined to the family of Rutaceae , showing several biological properties such as antioxidant, anti-inflammatory, anticancer, antinociceptive and gastroprotective characteristics. Recently, there is notable interest in investigating the pharmacological effects of limonene in various chronic diseases due to its mitigating effect on oxidative stress and inflammation and regulating apoptotic cell death. There are several available studies demonstrating the neuroprotective role of limonene in neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis, epilepsy, anxiety, and stroke. The high abundance of limonene in nature, its safety profile, and various mechanisms of action make this monoterpene a favorable molecule to be developed as a nutraceutical for preventive purposes and as an alternative agent or adjuvant to modern therapeutic drugs in curbing the onset and progression of neurodegenerative diseases. This manuscript presents a comprehensive review of the available scientific literature discussing the pharmacological activities of limonene or plant products containing limonene which attribute to the protective and therapeutic ability in neurodegenerative disorders. This review has been compiled based on the existing published articles confined to limonene or limonene-containing natural products investigated for their neurotherapeutic or neuroprotective potential. All the articles available in English or the abstract in English were extracted from different databases that offer an access to diverse journals. These databases are PubMed, Scopus, Google Scholar, and Science Direct. Collectively, this review emphasizes the neuroprotective potential of limonene against neurodegenerative and other neuroinflammatory diseases. The available data are indicative of the nutritional use of products containing limonene and the pharmacological actions and mechanisms of limonene and may direct future preclinical and clinical studies for the development of limonene as an alternative or complementary phytomedicine. The pharmacophore can also provide a blueprint for further drug discovery using numerous drug discovery tools.

Excessive exposure to toxic substances or chemicals in the environment and various pathogens, including viruses and bacteria, is associated with the onset of numerous brain abnormalities. Among them, pathogens, specifically viruses, elicit persistent inflammation that plays a major role in Alzheimer's disease (AD) as well as dementia. AD is the most common brain disorder that affects thought, speech, memory and ability to execute daily routines. It is also manifested by progressive synaptic impairment and neurodegeneration, which eventually leads to dementia following the accumulation of Aβ and hyperphosphorylated Tau. Numerous factors contribute to the pathogenesis of AD, including neuroinflammation associated with pathogens, and specifically viruses. The human immunodeficiency virus (HIV) is often linked with HIV-associated neurocognitive disorders (HAND) following permeation through the blood-brain barrier (BBB) and induction of persistent neuroinflammation. Further, HIV infections also exhibited the ability to modulate numerous AD-associated factors such as BBB regulators, members of stress-related pathways as well as the amyloid and Tau pathways that lead to the formation of amyloid plaques or neurofibrillary tangles accumulation. Studies regarding the role of HIV in HAND and AD are still in infancy, and potential link or mechanism between both is not yet established. Thus, in the present article, we attempt to discuss various molecular mechanisms that contribute to the basic understanding of the role of HIV-associated neuroinflammation in AD and HAND. Further, using numerous growth factors and drugs, we also present possible therapeutic strategies to curb the neuroinflammatory changes and its associated sequels.

For the maintenance of cellular homeostasis and energy metabolism, an uninterrupted supply of oxygen (O2) is routinely required in the brain. However, under the impaired level of O2 (hypoxia) or reduced blood flow (ischemia), the tissues are not sufficiently oxygenated, which triggers disruption of cellular homeostasis in the brain. Hypoxia is known to have a notable effect on controlling the expression of proteins involved in a broad range of biological processes varying from energy metabolism, erythropoiesis, angiogenesis, neurogenesis to mitochondrial trafficking and autophagy, thus facilitating neuronal cells to endure in deprived O2. On the contrary, hypoxia to the brain is a major source of morbidity and mortality in humans culminating in cognitive impairment, gradual muscle weakness, loss of motor activity, speech deficit, and paralysis as well as other pathological consequences. Further, hypoxia resulting in reduced O2 deliveries to brain tissues is supposed to cause neurodegeneration in both in vivo and in vitro models. Similarly, chronic exposure to hypoxia has also been reportedly involved in defective vessel formation. Such vascular abnormalities lead to altered blood flow, reduced nutrient delivery, and entry of otherwise restricted infiltrates, thereby limiting O2 availability to the brain and causing neurological disabilities. Moreover, the precise mechanistic role played by hypoxia in mediating key processes of the brain and alternatively, in triggering pathological signals associated with neurodegeneration remains mysterious. Therefore, this review elucidates the intricate role played by hypoxia in modulating crucial processes of the brain and their severity in neuronal damage. Additionally, the involvement of numerous pharmacological approaches to compensate hypoxia-induced neuronal damage has also been addressed, which may be considered as a potential therapeutic approach in hypoxia-mediated neurodegeneration.

Mounting evidence suggests a link between metabolic syndrome (MetS) such as diabetes, obesity, non-alcoholic fatty liver disease in the progression of Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases (NDDs). For instance, accumulated Aβ oligomer is enhancing neuronal Ca 2+ release and neural NO where increased NO level in the brain through post translational modification is modulating the level of insulin production. It has been further confirmed that irrespective of origin; brain insulin resistance triggers a cascade of the neurodegeneration phenomenon which can be aggravated by free reactive oxygen species burden, ER stress, metabolic dysfunction, neuorinflammation, reduced cell survival and altered lipid metabolism. Moreover, several studies confirmed that MetS and diabetic sharing common mechanisms in the progression of AD and NDDs where mitochondrial dynamics playing a critical role. Any mutation in mitochondrial DNA, exposure of environmental toxin, high-calorie intake, homeostasis imbalance, glucolipotoxicity is causative factors for mitochondrial dysfunction. These cumulative pleiotropic burdens in mitochondria leads to insulin resistance, increased ROS production; enhanced stress-related enzymes that is directly linked MetS and diabetes in neurodegeneration. Since, the linkup mechanism between mitochondrial dysfunction and disease phenomenon of both MetS and NDDs is quite intriguing, therefore, it is pertinent for the researchers to identify and implement the therapeutic interventions for targeting MetS and NDDs. Herein, we elucidated the pertinent role of MetS induced mitochondrial dysfunction in neurons and their consequences in NDDs. Further, therapeutic potential of well-known biomolecules and chaperones to target altered mitochondria has been comprehensively documented. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy., (Copyright © 2016 Elsevier B.V. All rights reserved.)