Neuroprotective Activity of Ethanolic Extract of Leea macrophylla Against Scopolamine-Induced Cognitive Impairment: Modulation of Cholinergic, Oxidative Stress and Neuroinflammatory Pathways

Background: Alzheimer’s disease (AD) is characterised by cholinergic deficit, oxidative stress and neuroinflammation, yet available drugs offer only symptomatic relief. Leea macrophylla Roxb. ex Hornem. is used in Indian traditional medicine for memory enhancement, but its neuroprotective potential has not been evaluated. Objective: To evaluate the neuroprotective effect of the ethanolic extract of L. macrophylla rhizome (EELM) against scopolamine-induced cognitive impairment in rats and to examine the underlying cholinergic, antioxidant and anti-inflammatory mechanisms. Methods: EELM was prepared by cold maceration (70% ethanol) and characterised by phytochemical screening and HPLC. Acute oral toxicity followed OECD 423. Male Wistar rats (n = 30; six per group) received vehicle, donepezil (5 mg/kg) or EELM (200 or 400 mg/kg, p.o.) for 28 days, with scopolamine (1 mg/kg, i.p.) on days 22–28. Cognition was assessed by the Morris water maze (MWM), elevated plus maze (EPM) and novel object recognition (NOR) tests. Brain AChE, MDA, SOD, CAT, GSH, TNF-α, IL-1β, IL-6 and NF-κB p65 were quantified, and hippocampal histology was examined. Results: EELM (yield 8.42% w/w) was non-toxic up to 5000 mg/kg. Scopolamine impaired all behavioural endpoints (p < 0.001). EELM 400 mg/kg reduced day-5 escape latency (13.4 vs 48.3 s), increased probe-trial quadrant time (36.1 vs 12.8 s) and discrimination index (0.59 vs 0.21), and shortened transfer latency (33.6 vs 74.3 s; all p < 0.001). It inhibited AChE by ~35%, lowered MDA by ~47%, restored SOD, CAT and GSH, suppressed TNF-α, IL-1β, IL-6 and NF-κB p65 by 53–57%, and preserved CA1 neuronal density (272 vs 148 cells/mm²). Conclusion: EELM produced dose-dependent, multi-target neuroprotection comparable to donepezil on most endpoints, supporting L. macrophylla as a candidate for further development against cognitive disorders.