Zingerone attenuates aluminum chloride/D-galactose-induced hippocampal neurotoxicity in mice: Modulation of oxidative stress, astrogliosis, cholinergic function, ATP hydrolysis, and neurotrophic signaling.

Neurodegenerative disorders constitute a growing global health concern, with oxidative stress, cholinergic dysfunction, and compromised neuroplasticity identified as key pathological contributors. Zingerone, a bioactive phenolic compound from ginger (Zingiber officinale), possesses antioxidant and anti-inflammatory properties, but its neuroprotective capacity against combined aluminum chloride (AlCl₃) and D-galactose (D-Gal)-induced hippocampal neurotoxicity remains poorly characterized. This study evaluated the neuroprotective effects of zingerone (100 mg/kg) on spatial memory, brain antioxidant enzyme activities, acetylcholinesterase (AChE) activity, ATP hydrolysis and nitric oxide levels, together with hippocampal neuronal integrity, astrocytic reactivity, and brain-derived neurotrophic factor (BDNF) expression, in mice co-exposed to AlCl₃ and D-Gal, with donepezil (10 mg/kg) as the standard reference drug. Twenty male Swiss mice were randomly assigned to four groups (n = 5): Control, AlCl₃/D-Gal, AlCl₃/D-Gal + Zingerone, and AlCl₃/D-Gal + Donepezil. AlCl₃/D-Gal co-exposure significantly impaired Y-maze and Morris water maze performance, depleted catalase and superoxide dismutase activities, elevated AChE activity, ATP hydrolysis, and nitric oxide levels, reduced Nissl substance staining, increased glial fibrillary acidic protein (GFAP) immunoreactivity, and suppressed BDNF expression. Zingerone significantly reversed these deficits, producing significantly greater restoration of superoxide dismutase activity than donepezil (p < 0.01) and numerically greater catalase and BDNF responses, whereas donepezil produced greater AChE inhibition and a greater reduction in nitric oxide. These contrasting profiles indicate complementary mechanisms rather than therapeutic superiority of either agent, and provide a rationale for evaluating a zingerone-donepezil combination in future studies. These findings position zingerone as a promising multi-target neuroprotective agent.