ADSC-Exosomes Alleviate MTX-induced Rat Neuronal Damage by Activating Nrf2-ARE Pathway

The aim of this study was to analyze the efficacy and underlying mechanism of adipose-derived mesenchymal stem cell exosome (ADSC-exosomes)–mediated protection on methotrexate (MTX)–induced neuronal damage. We established a H(2)O(2)­induced oxidative stress model in vitro, as well as an MTX-induced neuronal damage rat model in vivo. We analyzed the effects of ADSC-exosomes on neuronal damage and Nrf2-ARE signaling pathway in rats and related mechanisms. The morphological and functional recovery of rat hippocampal neurons by ADSC-exosomes was examined by Nissl staining and modified neurological severity score (mNSS) score. The activation of Nrf2-ARE pathway effectively inhibited H(2)O(2)-induced oxidative stress. ADSC-exosomes treatment restored the activity of hippocampal neuronal cells, reduced ROS production, and inhibited hippocampal neuronal cells apoptosis. In in vivo experiments, ADSC­exosomes ameliorates MTX-induced hippocampal neuron damage by triggering Nrf2­ARE pathway, decreasing IL-6, IFN-, and TNF-a levels and TUNEL positive cells in hippocampus, and repairing hippocampal neuronal cell damage. ADSC­exosomes ameliorated MTX-induced neuronal damage and suppressed oxidative stress induced by neuronal damage through the activation of Nrf2-ARE signaling pathway.