4-O-methylhonokiol attenuated β-amyloid-induced memory impairment through reduction of oxidative damages via inactivation of p38 MAP kinase.

Oxidative stress induced neuronal cell death by accumulation of β-amyloid (Aβ) is a critical pathological mechanism of Alzheimer's disease (AD). Intracerebroventrical infusion of Aβ(1-42) (300 pmol/day per mouse) for 14 days induced neuronal cell death and memory impairment, but pre-treatment of 4-O-methylhonokiol (4-O-MH), a novel compound extracted from Magnolia officinalis for 3 weeks (0.2, 0.5 and 1.0 mg/kg) prior to the infusion of Aβ(1-42) and during the infusion dose dependently improved Aβ(1-42)-induced memory impairment and prevented neuronal cell death. Additionally, 4-O-MH reduced Aβ(1-42) infusion-induced oxidative damages of protein and lipid but reduced glutathione levels in the cortex and hippocampus. Aβ(1-42) infusion-induced activation of astrocytes and p38 mitogenic activated protein (MAP) kinase was also prevented by 4-O-MH in mice brains. In further study using culture cortical neurons, p38 MAP kinase inhibitor abolished the inhibitory effect of 4-O-MH (10 μM) on the Aβ(1-42) (5 μM)-induced reactive oxidative species generation and neuronal cell death. These results suggest that 4-O-MH might prevent the development and progression of AD through the reduction of oxidative stress and neuronal cell death via inactivation of p38 MAP kinase pathway.