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Alzheimer's disease (AD) is progressive brain amyloidosis that damages brain regions associated with memory, thinking, behavioral and social skills. Neuropathologically, AD is characterized by intraneuronal hyperphosphorylated tau inclusions as neurofibrillary tangles (NFTs), and buildup of extracellular amyloid-beta (Aβ) peptide as senile plaques. Several biomarker tests capturing these pathologies have been developed. However, for the full clinical expression of the neurodegenerative events of AD, there exist other central molecular pathways. In terms of understanding the unidentified underlying processes for the progression and development of AD, a complete comprehension of the structure and composition of atypical aggregation of proteins is essential. Presently, to aid the prognosis, diagnosis, detection, and development of drug targets in AD, neuroproteomics is elected as one of the leading essential tools for the efficient exploratory discovery of prospective biomarker candidates estimated to play a crucial role. Therefore, the aim of this review is to present the role of neuroproteomics to analyze the complexity of AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Excessive activation of microglia and subsequent release of proinflammatory cytokines play a crucial role in neuroinflammation and neurodegeneration in Parkinson's disease (PD). Components of the nucleotide-binding oligomerization domain and leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome complex, leucine-rich-repeat- and pyrin-domain-containing 3, caspase-1, and apoptosis-associated speck-like protein containing a CARD, are highly expressed in activated microglia in PD patient brains. Findings suggest that neurotoxins, aggregation of α-synuclein, mitochondrial reactive oxygen species, and disrupted mitophagy are the key regulators of microglial leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome activation and release of interleukin-1β and interleukin-18 caspase-1-mediated pyroptotic cell death in the substantia nigra of the brain. Although this evidence suggests the leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome may be a potential drug target for treatment of PD, the exact mechanism of how the microglia sense these stimuli and initiate leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome signaling is unknown. Here, the molecular mechanism and regulation of microglial leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome activation and its role in the pathogenesis of PD are discussed. Moreover, the potential of both endogenous and synthetic leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome modulators, long noncoding RNA, microRNA to develop novel therapeutics to treat PD is presented. Overall, we recommend that the microglial leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome can be a potential target for PD treatment. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Quercetin (QC) is a flavonoid and crucial bioactive compound found in a variety of vegetables and fruits. In preclinical studies, QC has demonstrated broad activity against several diseases and disorders. According to recent investigations, QC is a potential therapeutic candidate for the treatment of nervous system illnesses because of its protective role against oxidative damage and neuroinflammation. QC acts on several molecular signals, including ion channels, neuroreceptors, and inflammatory receptor signaling, and it also regulates neurotrophic and anti-oxidative signaling molecules. While the study of QC in neurological disorders has focused on numerous target molecules, the role of QC on certain molecular targets such as G-protein coupled and nuclear receptors remains to be investigated. Our analysis presents several molecular targets of QC and its derivatives that demonstrate the pharmacological potential against cognitive impairment. Consequently, this article may guide future studies using QC and its analogs on specific signaling molecules. Finding new molecular targets of QC and its analogs may ultimately assist in the treatment of cognitive impairment., Competing Interests: The authors declare no conflict of interest.

Aging plays a significant role in the progression of vascular diseases and vascular dysfunction. Activation of the ADP-ribosylation factor 6 and small GTPases by inflammatory signals may cause vascular permeability and endothelial leakage. Pro-inflammatory molecules have a significant effect on smooth muscle cells (SMC). The migration and proliferation of SMC can be promoted by tumor necrosis factor alpha (TNF-α). TNF-α can also increase oxidative stress in SMCs, which has been identified to persuade DNA damage resulting in apoptosis and cellular senescence. Peroxisome proliferator-activated receptor (PPAR) acts as a ligand-dependent transcription factor and a member of the nuclear receptor superfamily. They play key roles in a wide range of biological processes, including cell differentiation and proliferation, bone formation, cell metabolism, tissue remodeling, insulin sensitivity, and eicosanoid signaling. The PPARγ activation regulates inflammatory responses, which can exert protective effects in the vasculature. In addition, loss of function of PPARγ enhances cardiovascular events and atherosclerosis in the vascular endothelium. This appraisal, therefore, discusses the critical linkage of PPARγ in the inflammatory process and highlights a crucial defensive role for endothelial PPARγ in vascular dysfunction and disease, as well as therapy for vascular aging.

Neuroinflammation, apoptosis, and oxidative stress are connected to the pathogenesis of neurodegenerative diseases (NDDs). Targeting these three factors, the intervention of neuroprotective agents may have great potential in the treatment of NDDs. In the current study, the anti-inflammatory effects of the methanol extract of Allium cepa (MEAC) in lipopolysaccharide (LPS)-induced BV-2 microglial cells were investigated. MEAC has been studied in regard to the regulation of the antiapoptotic gene (Bcl-2) and various antioxidant enzyme (HO-1, NQO-1, and catalase) expressions in N27-A cells. Additionally, the protective action of MEAC has also been studied against MPP + -induced death in N27-A cells. The results suggest that MEAC is significantly protected from NO release and increase iNOS expression at the mRNA and protein levels in LPS-stimulated BV-2 microglial cells. MEAC treatment also protects COX-2 expression at the mRNA and protein levels. Furthermore, MEAC treatment prevents LPS-stimulated increases of proinflammatory cytokines, including TNF-α, IL-6, and IL-1β. In N27-A cells, MEAC treatment significantly upregulates antiapoptotic gene (Bcl-2) and antioxidant enzyme (HO-1, NQO1, and catalase) expressions. Moreover, MEAC treatment protects against MPP + -induced death in N27-A cells. To conclude, A cepa extract takes protective action against LPS and MPP + , and upregulates the antioxidant enzymes that could potentially be used in the therapy of NDDs.

NR4A2 is a nuclear receptor and a transcription factor, with distinctive physiological features. In the cell nuclei of the central nervous system, it is widely expressed and identified as a crucial regulator of dopaminergic (DA) neuronal differentiation, survival, and maintenance. Importantly, it has regulated different genes crucial for dopaminergic signals, and its expression has been diminished in both aged and PD post-mortem brains and reduced in PD patients. In microglia and astrocytes, the expression of NR4A2 has been found where it can be capable of inhibiting the expression of proinflammatory mediators; hence, it protected inflammation-mediated DA neuronal death. In addition, NR4A2 plays neuroprotective role via regulating different signals. However, NR4A2 has been mainly focused on Parkinson's research, but, in recent times, it has been studied in Alzheimer's disease (AD), multiple sclerosis (MS), and stroke. Altered expression of NR4A2 is connected to AD progression, and activation of its may improve cognitive function. It is downregulated in peripheral blood mononuclear cells of MS patients; nonetheless, its role in MS has not been fully clear. miR-145-5p known as a putative regulator of NR4A2 and in a middle cerebral artery occlusion/reperfusion model, anti-miR-145-5p administration promoted neurological outcomes in rat. To date, various activators and modulators of NR4A2 have been discovered and investigated as probable therapeutic drugs in neuroinflammatory and neuronal cell death models. The NR4A2 gene and cell-based therapy are described as promising drug candidates for neurodegenerative diseases. Moreover, microRNA might have a crucial role in neurodegeneration via affecting NR4A2 expression. Herein, we present the role of NR4A2 in neuroinflammation and neuronal cell death focusing on neurodegenerative conditions and display NR4A2 as a promising therapeutic target for the therapy of neuroprotection.

Medicinal plants are the backbone of modern medicine. In recent times, there is a great urge to discover nootropic medicinal plants to reverse cognitive dysfunction owing to their less adverse effects. Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the inevitable loss of cognitive function, memory and language impairment, and behavioral disturbances, which turn into gradually more severe. Alzheimer's has no current cure, but symptomatic treatments are available and research continues. The number of patients suffering from AD continues to rise and today, there is a worldwide effort under study to find better ways to alleviate Alzheimer's pathogenesis. In this review, the nootropic and anti-Alzheimer's potentials of 6 medicinal plants (i.e., Centella asiatica, Clitoria ternatea, Crocus sativus, Terminalia chebula, Withania somnifera, and Asparagus racemosus) were explored through literature review. This appraisal focused on available information about neuroprotective and anti-Alzheimer's use of these plants and their respective bioactive compounds/metabolites and associated effects in animal models and consequences of its use in human as well as proposed molecular mechanisms. This review progresses our existing knowledge to reveal the promising linkage of traditional medicine to halt AD pathogenesis. This analysis also avowed a new insight to search the promising anti-Alzheimer's drugs.

Taurine is a sulfur-containing amino acid and known as semi-essential in mammals and is produced chiefly by the liver and kidney. It presents in different organs, including retina, brain, heart and placenta and demonstrates extensive physiological activities within the body. In the several disease models, it attenuates inflammation- and oxidative stress-mediated injuries. Taurine also modulates ER stress, Ca 2+ homeostasis and neuronal activity at the molecular level as part of its broader roles. Different cellular processes such as energy metabolism, gene expression, osmosis and quality control of protein are regulated by taurine. In addition, taurine displays potential ameliorating effects against different neurological disorders such as neurodegenerative diseases, stroke, epilepsy and diabetic neuropathy and protects against injuries and toxicities of the nervous system. Several findings demonstrate its therapeutic role against neurodevelopmental disorders, including Angelman syndrome, Fragile X syndrome, sleep-wake disorders, neural tube defects and attention-deficit hyperactivity disorder. Considering current biopharmaceutical limitations, developing novel delivery approaches and new derivatives and precursors of taurine may be an attractive option for treating neurological disorders. Herein, we present an overview on the therapeutic potential of taurine against neurological disorders and highlight clinical studies and its molecular mechanistic roles. This article also addresses the neuropharmacological potential of taurine analogs., (Copyright © 2019. Published by Elsevier B.V.)

Neuronal dysfunction initiates several intracellular signaling cascades to release different proinflammatory cytokines and chemokines, as well as various reactive oxygen species. In addition to neurons, microglia, and astrocytes are also affected by this signaling cascade. This release can either be helpful, neutral or detrimental for cell survival. Toll-like receptors (TLRs) activate and signal their downstream pathway to activate NF-κB and pro-IL-1β, both of which are responsible for neuroinflammation and linked to the pathogenesis of different age-related neurological conditions. However, herein, recent aspects of polyphenols in the treatment of neurodegenerative diseases are assessed, with a focus on TLR regulation by polyphenols. Different polyphenol classes, including flavonoids, phenolic acids, phenolic alcohols, stilbenes, and lignans can potentially target TLR signaling in a distinct pathway. Further, some polyphenols can suppress overexpression of inflammatory mediators through TLR4/NF-κB/STAT signaling intervention, while others can reduce neuronal apoptosis via modulating the TLR4/MyD88/NF-κB-pathway in microglia/macrophages. Indeed, neurodegeneration etiology is complex and yet to be completely understood, it may be that targeting TLRs could reveal a number of molecular and pharmacological aspects related to neurodegenerative diseases. Thus, activating TLR signaling modulation via natural resources could provide new therapeutic potentiality in the treatment of neurodegeneration.

Common features of neurodegenerative diseases (NDDs) include progressive dysfunctions and neuronal injuries leading to deterioration in normal brain functions. At present, ginseng is one of the most frequently used natural products. Its use has a long history as a cure for various diseases because its extracts and active compounds exhibit several pharmacological properties against several disorders. However, the pathophysiology of NDDs is not fully clear, but researchers have found that various ion channels and specific signaling pathways might have contributed to the disease pathogenesis. Apart from the different pharmacological potentials, ginseng and its active compounds modulate various ion channels and specific molecular signaling pathways related to the nervous system. Here, we discuss the signal modulating potential of ginseng and its active compounds mainly focusing on those relevant to NDDs.

Bacterial type II secretion system has now become an attractive target for antivirulence drug development. The aim of the present study was to characterize the binding site of the type II secretion system traffic ATPase GspE R of Pseudomonas aeruginosa, and identify potent inhibitors using extensive computational and virtual screening approaches. Initially, the designed platform focused on the evolutionary relationship of ATPase GspE R of P. aeruginosa, followed by protein-protein interaction network analysis to characterize its function. In addition, homology modeling, virtual screening and molecular dynamics simulation have been performed to identify potent hits and understand the ligand binding properties of ATPase GspE R. According to the evolutionary relationship, high level of genetic change was observed for P. aeruginosa, bearing orthology relationships with P.alcaligenes and P.otitidis. Concurrently, the binding site analysis represented residue Gly268, Ser267, Thr270, Thr271and Lys269 in Walker A motif directly formed hydrogen bonds with the ATP, which modulates the function of ATPase GspE R in the secretion process, is also validated by the molecular docking analysis and molecular dynamics simulation. Furthermore, ZINC04325133 is one of the most potent hits has been identified from virtual screening approach followed by molecular dynamics simulation and MM-GBSA binding energy analysis. These results may provide new knowledge for the development of novel therapeutic strategies against P. aeruginosa, as well as inhibiting secretion system process of a wide range of gram-negative bacteria., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Cognitive impairment is a state that affects thinking, communication, understanding, and memory, and is very common in various neurological disorders. Among many factors, age-related cognitive decline is an important area in mental health research. Research to find therapeutic medications or supplements to treat cognitive deficits and maintain cognitive health has been ongoing. Ginseng and its active components may have played a role in treating chronic disorders. Numerous preclinical studies have confirmed that ginseng and its active components such as ginsenosides, gintonin, and compound K are pharmacologically efficacious in different models of and are linked to cognitive impairment. Among their several roles, they act as an anti-neuroinflammatory and help fight against oxidative stress and modulate the cholinergic signal. These roles may be involved in enhancing cognition and attenuating impairment. There have been some clinical studies on the activity of ginseng in cognitive impairment, but many ginseng species and active compounds remain to be investigated. In addition, new formulations of active ginseng components such as nanoparticles and liposomes could be used for preclinical and clinical models of cognitive impairment. Here, we discuss the therapeutic potential of active ginseng components in cognitive impairment and their chemistry and pharmacokinetics and consider prospects for their delivery and clinical study with respect to cognitive impairment., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

Glutamate receptors play a crucial role in the central nervous system and are implicated in different brain disorders. They play a significant role in the pathogenesis of neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although many studies on NDDs have been conducted, their exact pathophysiological characteristics are still not fully understood. In in vivo and in vitro models of neurotoxic-induced NDDs, neurotoxic agents are used to induce several neuronal injuries for the purpose of correlating them with the pathological characteristics of NDDs. Moreover, therapeutic drugs might be discovered based on the studies employing these models. In NDD models, different neurotoxic agents, namely, kainic acid, domoic acid, glutamate, β- N -Methylamino-L-alanine, amyloid beta, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1-methyl-4-phenylpyridinium, rotenone, 3-Nitropropionic acid and methamphetamine can potently impair both ionotropic and metabotropic glutamate receptors, leading to the progression of toxicity. Many other neurotoxic agents mainly affect the functions of ionotropic glutamate receptors. We discuss particular neurotoxic agents that can act upon glutamate receptors so as to effectively mimic NDDs. The correlation of neurotoxic agent-induced disease characteristics with glutamate receptors would aid the discovery and development of therapeutic drugs for NDDs.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with impairment of cognition, memory deficits and behavioral abnormalities. Accumulation of amyloid beta (Aβ) is a characteristic hallmark of AD. Microglia express several GPCRs, which, upon activation by modulators, mediate microglial activation and polarization phenotype. This GPCR-mediated microglial activation has both protective and detrimental effects. Microglial GPCRs are involved in amyloid precursor protein (APP) cleavage and Aβ generation. In addition, microglial GPCRs are featured in the regulation of Aβ degradation and clearance through microglial phagocytosis and chemotaxis. Moreover, in response to Aβ binding on microglial Aβ receptors, they can trigger multiple inflammatory pathways. However, there is still a lack of insight into the mechanistic link between GPCR-mediated microglial activation and its pathological consequences in AD. Currently, the available drugs for the treatment of AD are mostly symptomatic and dominated by acetylcholinesterase inhibitors (AchEI). The selection of a specific microglial GPCR that is highly expressed in the AD brain and capable of modulating AD progression through Aβ generation, degradation and clearance will be a potential source of therapeutic intervention. Here, we have highlighted the expression and distribution of various GPCRs connected to microglial activation in the AD brain and their potential to serve as therapeutic targets of AD.

Thymoquinone (TQ) is an active ingredient isolated from Nigella sativa and has various pharmacological activities, such as protection against oxidative stress, inflammation, and infections. In addition, it might be a potential neuropharmacological agent because it exhibits versatile potential for attenuating neurological impairments. It features greater beneficial effects in toxin-induced neuroinflammation and neurotoxicity. In various models of neurological disorders, it demonstrates emergent functions, including safeguarding various neurodegenerative diseases and other neurological diseases, such as stroke, schizophrenia, and epilepsy. TQ also has potential effects in trauma mediating and chemical-, radiation-, and drug-induced central nervous system injuries. Considering the pharmacokinetic limitations, research has concentrated on different TQ novel formulations and delivery systems. Here, we visualize the neuropharmacological potential, challenges, and delivery prospects of TQ, specifically focusing on neurological disorders along with its chemistry, pharmacokinetics, and toxicity.

Background: The superior genus Jacquemontia belongs to Convolvulaceae, with around 120 species, and is also considered taxonomically difficult. The aim of this experiment was to assess the sedative and hypnotic activities of methanol extract from the leaves of Jacquemontia paniculata (Burm.f.) Hallier f., Methods: The sedative and hypnotic activities were evaluated by hole-cross, open field, hole-board, elevated plus maze (EPM), and thiopental sodium-induced sleeping time determination tests in mice at doses of 200 and 400 mg/kg., Results: In this investigation, we found that methanol extract of Jacquemontia paniculata (MEJP) produced a significant dose-dependent inhibition of spontaneous activity of mice both in hole-cross and open field tests. In addition, it also decreased the number of head dips in hole-board test. In the case of EPM test, this crude extract induced an anxiogenic-like effect rather than anxiolytic effect in mice. Moreover, MEJP significantly decreased the induction time to sleep and prolonged the duration of sleeping, induced by thiopental sodium., Conclusions: To conclude, these results suggest that the MEJP leaves possess potent sedative and hypnotic activities, which supported its therapeutic use for sleep disorders like insomnia.