👤 Misbahuddin M Rafeeq

Huntington's Disease (HD) is a neurodegenerative ailment characterized by progressive motor, cognitive, and psychiatric decline, linked with mitochondrial dysfunction, oxidative stress, and neuroinflammation. Few effective treatments are available for Huntington's. Additionally, the therapeutic effects of natural polysaccharides against neurodegenerative disorders have not yet been fully explored. This study aimed to investigate the neuroprotective potential of Aloe Polysaccharides (APs) against 3-Nitropropionic Acid (3- NPA)-initiated HD-like symptoms in rats. Adult male rats were allocated to control, 3-NPA-treated, and APs-treated groups (100 and 200 mg/kg orally) following 3-NPA administration. Behavioral assessments (rotarod, open field, narrow beam walking) and biochemical analyses, including neurotransmitters [Acetylcholinesterase (AChE), Acetylcholine (ACh), Dopamine (DA), Norepinephrine (NE), Serotonin (5-HT), Gamma-Aminobutyric Acid (GABA), Glutamate (Glu)], oxidative/nitrative stress markers [Malondialdehyde (MDA, Nitric Oxide (NO)], antioxidant enzymes [Superoxide Dismutase (SOD), Catalase (CAT), Glutathione (GSH)], mitochondrial enzyme [Succinate Dehydrogenase (SDH)], inflammatory mediators [Nuclear Factor Kappa B (NF-κB), Tumor Necrosis Factor Alpha (TNF-α), Interleukin- 1 Beta (IL-1β), Cyclooxygenase-2 (COX-2)], neurotrophic factor [Brain-Derived Neurotrophic Factor (BDNF)], and apoptotic markers (caspase-3, caspase-9, B-Cell Lymphoma 2 (Bcl-2), Bcl-2-Associated X Protein (Bax)] were performed. Additionally, the impact of APs on regulators of mitochondrial biogenesis and antioxidant response [Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), Sirtuin 1 (Sirt1), Heme Oxygenase-1 (HO-1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PGC-1α), Adenosine Monophosphate-Activated Protein Kinase (AMPK), Uncoupling Protein 1 (UCP1), Uncoupling Protein 2 (UCP2)] was evaluated. Histopathological examination of the striatum was conducted. Statistical analysis was performed using one-way ANOVA followed by Tukey's post hoc test. 3-NPA administration induced significant motor deficits, neurotransmitter imbalance, elevated oxidative stress, inflammation, mitochondrial impairment, BDNF depletion, apoptosis, and striatal degeneration (P < 0.01). APs treatment significantly (P < 0.01; P < 0.001) reversed 3-NPA effects and improved behavioral performance (rotarod latency, OFT exploratory activity, and beam walk score); restored neurotransmitter balance; improved antioxidant enzymes (SOD, CAT, and GSH); mitigated MDA and NO effects; suppressed NF-κB, TNF-α, IL-1β, and COX-2; elevated BDNF and SDH activities; mitigated apoptosis (caspase-3 and 9, BAX, and BCl-2); and preserved striatal structure. APs showed neuroprotective potential in 3-NPA-induced HD rats by modulating the BDNF/NF-κB/Nrf2 pathway, controlling oxidative stress and neuroinflammation, restoring neurotransmitter function, and arresting striatal damage. Treatment with Aps markedly upregulated the levels of mitochondrial biogenesis-related proteins (Sirt1, PGC-1α, AMPK, UCP1, and UCP2) and antioxidant defense mediators (HO-1 and NQO1). In addition to behavioral and biochemical improvements, this study uniquely demonstrates that APs upregulate genes central to the mitochondrial biogenesis pathway, suggesting a new mechanistic basis for their neuroprotective effects in 3-NPA-induced HD. The study results showed that Applied Physiology Solution (APS) enhanced behavioural characteristics and neurotransmission function while simultaneously reducing the inflammatory response and cell stress and preserving striatal tissue structure. These findings reveal that APs promote neuroprotection not only by modulating oxidative stress, neuroinflammation, neurotransmission, and apoptosis, but also by specifically upregulating genes in the mitochondrial biogenesis pathway, highlighting their potential as a natural therapeutic candidate for HD management. Show less

Alzheimer's disease (AD) is a significant global healthcare challenge, particularly in the elderly population. This neurodegenerative disorder is characterized by impaired memory and progressive decline in cognitive function. BACE1, a transmembrane protein found in neurons, oligodendrocytes, and astrocytes, exhibits varying levels across different neural subtypes. Abnormal BACE1 activity in the brains of individuals with AD leads to the formation of beta-amyloid proteins. The complex interplay between myelin sheath formation, BACE1 activity, and beta-amyloid accumulation suggests a critical role in understanding the pathological mechanisms of AD. The primary objective of this study was to identify molecular inhibitors that target Aβ. Structure-based virtual screening (SBVS) was employed using the MCULE database, which houses over 2 million chemical compounds. A total of 59 molecules were selected after the toxicity profiling. Subsequently, five compounds conforming to the Egan-Egg permeation predictive model of the ADME rules were selected and subjected to molecular docking using AutoDock Vina on the Mcule drug discovery platform. The top two ligands and the positive control, 5HA, were subjected to molecular dynamics simulation for five nanoseconds. Toxicity profiling, physiochemical properties, lipophilicity, solubility, pharmacokinetics, druglikeness, medicinal chemistry attributes, average potential energy, RMSD, RMSF, and Rg analyses were conducted to identify the ligand MCULE-9199128437-0-2 as a promising inhibitor of BACE1. Show less