Neuroprotective Potential of Pinostrobin in a Rat Model of Huntington's Disease: Behavioural, Biochemical, and...

Huntington's disease (HD) is an enormously destructive autosomal hereditary neurodegenerative disease that results in malfunction of motor, psychological, and cognitive deficits. The neurotoxin 3-nitropropionic acid (3-NPA) is known to induce HD-like signs in the in vivo rat model. The current research is aimed at defining the defensive properties of pinostrobin (PSB) against 3-NPA-induced HD in rats. Wistar rats were used as a test model, and PBS (10, 20, and 40 mg/kg, per oral) was administered before 3-NPA (10 mg/kg i.p.) treatment for 15 days. To assess neurodegeneration, behavioural tests such as the narrow beam walk, rotarod test, open field test, and grip strength test were performed. The effect of PSB on 3-NPA induced alterations on lipid peroxidation and oxidative stress markers (malondialdehyde, superoxide dismutase, reduced glutathione, and catalase), neurotransmitter levels (dopamine serotonin, glutamate, and GABA), Complex I (ATP generation) and Complex II (succinate dehydrogenase) cytokines levels (tumour necrosis factor-α, interleukin-1β, and IL-6), programmed cell-death marker levels (Caspase-3 and Caspase-9), and brain-derived neurotrophic factor (BDNF) was assessed by brain striatum homogenate. In silico analyses, including molecular docking, molecular dynamics (MD) simulations, MM-GBSA binding free energy calculations, principal component analysis, dynamic cross-correlation mapping, and free energy landscape profiling, were conducted to clarify the molecular interactions between PSB and relevant HD-related targets. Results showed that the 3-NPA-induced group of rats had significantly decreased behavioural activity, oxidative stress, neurotransmitter levels, and neuroinflammatory indices. Treatment with PSB improves cognitive functions, increases antioxidant marker levels, modulates inflammatory marker expression, and provides neuroprotection against the tested neurotoxin. Computational analyses, including MD, molecular dynamics, and MM-GBSA free energy profiling, demonstrated favourable binding affinity of PSB with target proteins involved in SDH and BDNF. Thus, PSB may be a promising neuroprotective candidate for managing 3-NPA-induced brain dysfunction and cognitive deficits, which are similar to those observed in Huntington's disease.