Integrated GC–MS Characterization, Behavioral and Biochemical Assessment, and Multi-Target Molecular Docking Reveal the Neuro-Protective Mechanisms of Lavandula angustifolia Essential Oil Against Alzheimer’s Disease

This study evaluated the potential neuroprotective activity of Lavandula angustifolia essential oil (LAEO) using chemical characterization, in vitro antioxidant and cholinesterase assays, a battery of behavioral tests (open field test, Y-maze, and novel object recognition), in vivo biochemical assessment in a D-galactose/aluminum chloride (D-gal/AlCl3)-induced Alzheimer’s disease (AD)-like rat model, multi-target molecular docking, and in silico ADMET prediction. GC–MS analysis revealed a terpene-rich profile dominated by linalyl acetate (37.02%), linalool (36.31%), and eucalyptol (11.23%). LAEO exhibited concentration-dependent antioxidant activity and preferential acetylcholinesterase (AChE) inhibition (IC50 41.8 µg/mL; selectivity index 1.88). Molecular docking against AChE (PDB: 7E3H) and BChE (PDB: 7AMZ) revealed constituent-specific predicted binding modes: the sesquiterpene hydrocarbon cis-caryophyllene showed the most favorable predicted docking scores (−8.6 and −7.6 kcal/mol), engaging hydrophobic, π–alkyl, and van der Waals contacts within the AChE aromatic gorge, whereas the major monoterpene esters (±)-lavandulyl acetate and linalyl acetate showed preferential predicted AChE engagement (−7.4 and −7.0 kcal/mol). ADMET predictions indicated favorable oral absorption and predicted blood–brain barrier permeation for the major constituents. In vivo, LAEO dose-dependently attenuated oxidative stress-associated alterations and improved antioxidant defense parameters in brain tissue, with the effects being more pronounced at 200 mg/kg/day. Behavioral assessment revealed that LAEO improved exploratory, working memory, and recognition memory performance in AD-like rats. These findings support LAEO as a promising multi-target candidate for further preclinical development, while underscoring that mechanistic conclusions remain hypothesis-generating pending direct molecular validation.