Protective effects of Salidroside against ferroptosis through PPARG-dependent mechanism in diabetes-related cognitive impairment

Abstract

Objective

This study focused on investigating the benefits and potential mechanism of Sal in Leptin gene knockout mice (db/db) and primary hippocampal neurons.

Methods

In the current investigation, male db/db mice were administered Sal via oral gavage. Cognitive functions and learning and memory capacities were assessed through the Morris Water Maze (MWM) tests, respectively. Nissl, Fluoro-Jade C (FJC) staining techniques were employed to gauge hippocampal neuronal damage. Transmission electron microscopy facilitated the observation of mitochondrial alterations within hippocampal neurons of db/db mice. We further quantified Fe²⁺ levels, oxidative stress, and lipid peroxidation both in vivo & vitro. Western blotting got utilized to ascertain the relative levels of GPX4, PPARG, Nrf2 protein expressions.

Results

According to the study results, Sal supplement could dramatically relieve db/db mice’ cognitive impairment and protect neurons, through the inhibition of oxidative stress and the reduction of neuronal ferroptosis. According to further research, Sal could achieve a direct binding with peroxisome proliferator-activated receptor gamma (PPARG) for promoting it to be expressed. When culturing hippocampus-derived primary neurons, adding PPARG antagonist GW9662 or Nrf2 antagonist ML385 could eliminate the effect of Sal.

Conclusion

Taken together, the study is the first one that demonstrates the effectiveness of Sal in improving the cognitive impairment deficits of db/db mice as well as its inhibitory effect on oxidative stress and neuronal ferroptosis via PPARG-dependent mechanism.