Intracellular signaling pathway of fisetin attenuates learning and memory impairments in mouse model of Alzheimer's disease

Abstract

Objective To explore the effects of fisetin on the learning and memory abilities impairments induced by Aβ in mice. Methods Alzheimer's disease (AD) animal model was made by single intracerebroventricular infusion of Aβ (1-42) through guide cannula. Fisetin was orally administered 7 days before Aβ infusion once a day, and continued throughout the experimental period. Water maze test began on day 3 after Aβ infusion. All mice were sacrificed and hippocampi were dissected immediately after behavioral test. The protein expression of hippocampal nuclear Nrf2 and the mRNA level of HO-1, GCLC and GCLM were examined by western blotting and RT-RCR techniques respectively. Results (1) Aβ (1-42) significantly increased escape latency in hidden platform test ((25.4±3.33)s), and decreased the number of crossings in probe test(1.70±0.25) compared with control ((9.05±1.37)s) for hidden plat form; 4.50±0.41 for probe test) and Aβ (42-1)-treated group((10.80±1.38)s) for hidden platform test; 4.10±0.39 for probe test; P<0.01). The prolonged treatment with fisetin dose-dependently reversed the changes (10 mg/kg: 17.54±3.56s for hidden platform test; 2.50±0.40 for probe test, P<0.05, 20 mg/kg: (13.04±2.36)s for hidden platform test; 3.60±0.36 for probe test, P<0.01). (2) Aβ (1-42) significantly decreased the nuclear Nrf2 protein level (0.07±0.02), and mRNA level (0.45±0.04) of HO-1, GCLC (0.41±0.04) and GCLM (0.26±0.03) in the hippocampus of mice compared with control (0.18±0.02 for Nrf2; 0.83±0.09 for HO-1; 1.01±0.10 for GCLC; 0.65±0.07 for GCLM) and Aβ (42-1)-treated group (0.21±0.02 for Nrf2; 0.90±0.08 for HO-1; 1.11±0.11 for GCLC; 0.72±0.07 for GCLM)(P<0.05 or P<0.01). However, fisetin administration significantly counteracted these changes (10 mg/kg: 0.11±0.01 for Nrf2; 0.56±0.06 for HO-1; 0.61±0.04 for GCLC; 0.35±0.04 for GCLM; 20 mg/kg: 0.16±0.02 for Nrf2; 0.79±0.10 for HO-1; 0.86±0.09 for GCLC; 0.51±0.04 for GCLM; P<0.05). Conclusion Fisetin attenuates learning and memory impairments induced by Aβ (1-42) through activation of Nrf2 antioxidant signaling pathway. Key words: Fisetin; Alzheimer's disease; β-amyloid; Nuclear factor (erythroid-derived 2)-like 2