Ellagic acid prevents streptozotocin-induced hippocampal damage and memory loss in rats by stimulating Nrf2 and nuclear factor-κB, and activating insulin receptor substrate/PI3K/Akt axis.

Abstract

This study examined the protective effect of ellagic acid (EA) against streptozotocin (STZ)-induced hippocampal damage and memory loss and investigated some mechanisms of action. Adult male rats were divided into 4 groups (n = 12) as control, control + EA (50 mg/kg), STZ-DM, and STZ-DM + EA. Treatments were given orally and daily for 8 weeks. Memory function was assessed by the Morris water maze (MWM) and passive learning avoidance test. In addition, blood samples were used to measure glucose and insulin levels. Also, the hippocampus was used to measure markers of oxidative stress, inflammation, and insulin signaling. Associated with the improved memory, EA preserved the structure of the CA1 area of rats' hippocampus and suppressed the hippocampal expression of Bax and cleaved caspase 3. Concomitantly, EA increased rats' weekly weights gain and fasting plasma insulin levels and reduced the hippocampal levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and plasma glucose levels in diabetic rats. In both the control and STZ-DM rats, EA significantly lowered the hippocampal levels of reactive oxygen species (ROS) and malondialdehyde (MDA) but significantly increased the hippocampal levels of glutathione (GSH) and manganese superoxide dismutase (MnSOD), as well as the nuclear levels of NF-κB and nuclear factor-erythroid 2-related factor (Nrf-2). Besides, and in the hippocampus of both groups, EA increased the phosphorylation of insulin receptor substrate (IRS), PI3K, Akt, GS3Kβ, and CREB, and increased levels of BDNF and Bcl-2. In conclusion, these data suggest that the neuroprotective effect of EA on rats' hippocampus and memory function is associated with upregulation of Nrf2 and Bcl-2, suppression of NF-κB, and activation of CREB and IRS/PI3K/Akt/ GS3Kβ axis.