Pharmacological Evaluation and In-Silico Study of Sabinene as a Potential Anti-Alzheimer’s Drug in AlCl3-Induced Rat Model via BACE-1 and GSK3β Modulation

Alzheimer’s disease (AD) is a progressive and debilitating neurodegenerative disorder. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and glycogen synthase kinase-3β (GSK3β) contribute to Aβ plaque development, tau hyperphosphorylation, neurofibrillary tangles, and neuronal dysfunction in AD pathogenesis. This study aimed to investigate the neuroprotective potential of sabinene in an Aluminum chloride (AlCl₃)-induced model of AD in male Wistar rats. Thirty male Wistar rats were randomly divided into six groups (n = 6 per group). Group I (control) received normal saline for 30 days. Groups II–V were administered only AlCl₃ (100 mg/kg, orally) for 20 consecutive days to induce AD-like pathology, which was confirmed through behavioral assessments. Following induction, Group II (AD control) received 1% Tween 80; Group III (standard treatment) was administered rivastigmine (2.5 mg/kg); while Groups IV–VI received sabinene at doses of 5, 10, and 20 mg/kg, respectively, for 10 days 1 h prior to AlCl₃. Behavioral evaluations were conducted on days 0, 20, and 31. On the 31st day, animals were sacrificed for biochemical and molecular analyses. In silico molecular docking studies revealed that sabinene exhibited a higher binding affinity towards AD-related targets (BACE1, GSK-3β, TACE, and AChE) compared to rivastigmine. In vivo, sabinene treatment significantly mitigated oxidative stress, restored antioxidant enzyme activities, reduced pro-inflammatory cytokine levels, AChE, BACE1, and GSK3β expression, and ameliorated histopathological alterations in the rat brain. Thus, sabinene exerts potent neuroprotective and disease-modifying effects in AlCl₃-induced AD via AchE, BACE-1, and GSK3β Modulation.

Graphical Abstract