PHARMACOLOGICAL EVALUATION OF ISOXANTHOHUMOL IN ALCL3 INDUCED ALZHEIMER DISEASE

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and neuronal loss, with limited disease-modifying therapeutic options available. The present study investigated the neuroprotective potential of isoxanthohumol in an aluminium chloride induced AD-like mice model using an integrated approach involving in silico, in vitro, and in vivo evaluations. Blood–brain barrier (BBB) permeability was predicted using SwissADME, confirming favorable physicochemical properties and potential central nervous system penetration. Molecular docking studies demonstrated strong binding affinity of isoxanthohumol toward acetylcholinesterase and moderate interaction with brain-derived neurotrophic factor, indicating dual involvement in cholinergic and neurotrophic pathways. In vitro cholinesterase assays revealed significant inhibitory activity against both acetylcholinesterase and butyrylcholinesterase, supporting its role in enhancing cholinergic neurotransmission. These effects were comparable, although slightly lower, than those observed with donepezil treatment. In vivo, cognitive performance was assessed using the novel object recognition test, where isoxanthohumol-treated mice showed significant improvement in recognition memory compared to the disease control group.  The AlCl₃-induced model successfully replicated AD-like behavioral deficits, confirming oxidative and neurotoxic impairment. Collectively, the findings suggest that isoxanthohumol exerts multi-target neuroprotective effects through modulation of cholinergic activity and neurotrophic signaling, potentially supported by antioxidant and anti-inflammatory mechanisms. This study provides preliminary evidence that isoxanthohumol may serve as a promising natural therapeutic candidate for the management of AD. However, further mechanistic and translational studies are requires to validate its clinical applicability