LAUSR

Aim: In the present study, attempts have been made to evaluate the potential role of fisetin, a caloric restriction mimetic (CRM), for neuroprotection in D‐galactose (D‐gal) induced accelerated and natural aging models of rat. Main methods: Fisetin was supplemented (15 mg/kg b.w., orally) to young, D‐gal induced aged (D‐gal 500 mg/kg b.w subcutaneously) and naturally aged rats for 6 weeks. Standard protocols were employed to measure pro‐oxidants, antioxidants and mitochondrial membrane potential in brain tissues. Gene expression analysis with reverse transcriptase‐polymerase chain reaction (RT‐PCR) was performed to assess the expression of autophagy, neuronal, aging as well as inflammatory marker genes. We have also evaluated apoptotic cell death and synaptosomal membrane‐bound ion transporter activities in brain tissues. Key findings: Our data demonstrated that fisetin significantly decreased the level of pro‐oxidants and increased the level of antioxidants. Furthermore, fisetin also ameliorated mitochondrial membrane depolarization, apoptotic cell death and impairments in the activities of synaptosomal membrane‐bound ion transporters in aging rat brain. RT‐PCR data revealed that fisetin up‐regulated the expression of autophagy genes (Atg‐3 and Beclin‐1), sirtuin‐1 and neuronal markers (NSE and Ngb), and down‐regulated the expression of inflammatory (IL‐1&bgr; and TNF‐&agr;) and Sirt‐2 genes respectively in aging brain. Significance: The present study suggests that fisetin supplementation may provide neuroprotection against aging‐induced oxidative stress, apoptotic cell death, neuro‐inflammation, and neurodegeneration in rat brain.