Acetylcholinesterase (AChE) holds significance in Alzheimer's disease (AD), where cognitive impairment correlates with insufficient acetylcholine levels. AChE's role involves the breakdown of acetylcholine, moderating cholinergic neuron activity to prevent overstimulation and signal termination. Hence, inhibiting AChE emerges as a potential treatment avenue for AD. A library of 2500 compounds, derived from 25 traditionally used medicinal plants, was constructed using the IMPAAT database of traditional medicinal plants. The canonical SMILES of these compounds were collected and underwent virtual screening based on physicochemical properties, with subsequent determination of IC₅₀ values for the screened compounds followed by analysis using machine learning (ML). Subsequently, a molecular docking study elucidated both binding affinity and interactions between these compounds and AChE. The top three compounds, exhibiting robust binding affinities, underwent MM-GBSA analysis for molecular docking validation, succeeded by pharmacokinetics and toxicity evaluations to gauge safety and efficacy. These three compounds underwent MD simulation studies to assess protein–ligand complex conformational stability. Additionally, Density Functional Theory (DFT) was employed to ascertain HOMO, LUMO, energy gap, and molecular electrostatic potential. Among 2500 compounds, physicochemical properties-based virtual screening identified 80 with good properties, of which 32 showed promising IC₅₀ values. Molecular docking studies of these 32 compounds revealed various binding energies with AChE, with the best three compounds (CID 102267534, CID 15161648, CID 12441) selected for further analysis. MM-GBSA studies confirmed the promising binding energies of these three compounds, validating the molecular docking study. Further, the MD simulation studies have confirmed the structural and conformational stability of these three protein–ligand complexes. Finally, DFT calculations revealed favorable chemical features of these compounds. Thus, we can conclude that these three compounds (CID 102267534, CID 15161648, CID 12441) may inhibit the activity of AChE and can be useful as a treatment for Alzheimer's disease.

Microglia, the unique and motile immune cells of the central nervous system (CNS), function as a security guard in maintaining CNS homeostasis, primarily through calcium signaling. The calcium dynamics in microglia control important functions such as phagocytosis, cytokine release, and migration. Calcium dysregulation in microglia has been linked to several CNS disorders, like Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and ischemic stroke (IS). Calcium entering through channels such as voltage-gated calcium channels (VGCCs), store-operated calcium entry (SOCE), and transient receptor potential (TRP) channels is essential for microglial activation and pro-inflammatory responses. Under pathological conditions, like the formation of amyloid-β plaques in AD, aggregation of α-synuclein in PD, and oxidative stress in MS, calcium dysregulation exacerbates neuroinflammation, mitochondrial dysfunction, and neurodegeneration. Therapeutic strategies targeting calcium signaling pathways, using calcium channel blockers and antioxidant interventions, show promise for alleviating microglial activation and slowing down disease progression. This review summarizes the underlying mechanisms of microglial calcium dysregulation and potential therapeutic benefits for restoring microglial calcium balance in CNS disorders.

COVID-19 has raised significant concern regarding its neurological impact, particularly during the early pandemic waves when severe systemic inflammation and neuroimmune dysregulation were more common. Although SARS-CoV-2 has been extensively studied, the precise mechanisms underlying its neurological effects remain incompletely understood, and much of the available evidence is derived from early variants with higher pathogenicity. Current research indicates that neuroinflammatory processes—driven primarily by systemic cytokine elevation, microglial activation, and blood–brain barrier dysfunction—contribute to a wide range of neurological symptoms. Severe complications such as encephalopathy, stroke, and cognitive impairment were predominantly reported in critically ill patients infected with the Wuhan, Alpha, or Delta variants, while such manifestations are considerably less frequent in the Omicron era. Most proposed mechanisms, including ACE2-mediated viral entry into the central nervous system, are supported mainly by experimental or preclinical studies rather than definitive human evidence. Biomarkers such as IL-6 and TNF-α, along with neuroimaging modalities including MRI and PET, offer useful but indirect indicators of neuroinflammation. Therapeutic approaches continue to focus on controlling systemic inflammation through immunomodulatory agents, complemented by targeted non-pharmacological strategies—such as physical rehabilitation, cognitive support, and psychological interventions—for the minority of patients with persistent neurological deficits. Overall, current evidence supports a variant-dependent neuroinflammatory profile and underscores the need for longitudinal, mechanism-focused studies to better characterize long-term neurological outcomes and refine therapeutic strategies.

Ethnopharmacological Relevance: Nypa fruticans (Arecaceae) has long been used in traditional medicine for the management of anxiety, insomnia, and depressive symptoms. However, scientific validation of its neuropharmacological activities and active constituents is limited. Aim of the Study: This study evaluated the anxiolytic, antidepressant, and sedative activities of the ethyl acetate fraction of Nypa fruticans (NF) leaves (EaNFL) through in vivo behavioral models and in silico molecular docking (MD) and molecular dynamics simulations (MDS) to provide scientific support for its traditional CNS use. Materials and Methods: Neuropharmacological activities of EaNFL were assessed in mice using elevated plus maze (EPM), hole board test (HBT), open field test (OFT), hole cross test (HCT), tail suspension test (TST), and forced swimming test (FST). Major phytochemicals identified from EaNFL were subjected to MD analysis against voltage‐gated potassium channels (PDB: 4UUJ), GABA‐A receptors (PDB: 6X3X), and human serotonin transporter (PDB: 5I6X). Top‐binding compounds were further analyzed using MDS to assess receptor–ligand stability. Results: EaNFL (400 mg/kg) showed significant anxiolytic activity in EPM and HBT, dose‐dependent sedative properties in HCT and OFT, and notable antidepressant‐like effects in TST and FST. However, reduced locomotor activity may have contributed to some of the observed behavioral outcomes. MD revealed that myricetin (CID 5281672) and quercetin (CID 5280343) predicted stable interactions and favorable binding affinities with major CNS‐related receptors, as suggested by MDS analysis. Additionally, (−)‐epicatechin (CID 72276) and rosmarinic acid (CID 5281792) exhibited favorable receptor interactions, suggesting therapeutic potential in anxiety, insomnia, and depression. Conclusions: EaNFL possesses notable anxiolytic, sedative, and antidepressant‐like effects, supporting its traditional use in CNS disorders. MD and MDS findings suggest that myricetin, quercetin, and (−)‐epicatechin acid may be key bioactive constituents underlying these effects. Further studies are warranted to elucidate molecular mechanisms and explore its pharmaceutical potential.