The Regulation of Autophagy by p38 MAPK-PPARγ Signaling During the Brain Ischemic Tolerance Induced by Cerebral Ischemic Preconditioning.

Several studies indicated that autophagy activation participates in brain ischemic tolerance (BIT) induced by cerebral ischemic preconditioning (CIP). However, the mechanism of autophagy activation during the process still remains unclear. The present study aimed to evaluate the role of p38 MAPK-peroxisome proliferator-activated receptor γ (PPARγ) signaling cascade in autophagy during the CIP-induced BIT. The results shown that, initially, autophagy activation was observed after CIP in the model of global cerebral ischemia in rats, as was indicated by the upregulation of Beclin 1 expression, an increase in LC3-II/LC3-I ratio, the enhanced LC3 immunofluorescence, and a rise in the number of autophagosomes in the neurons of the hippocampal CA1 area. Besides, the inhibitor of autophagy 3-methyladenine obliterated the neuroprotection induced by CIP. Furthermore, the upregulation of p-p38 MAPK and PPARγ expressions was earlier than autophagy activation after CIP. In addition, pretreatment with SB203580 (the inhibitor of p38 MAPK) reversed CIP-induced PPARγ upregulation, autophagy activation, and neuroprotection. Pretreatment with GW9662 (the inhibitor of PPARγ) reversed autophagy activation and neuroprotection, while it had no effect on p-p38 MAPK upregulation induced by CIP. These data suggested that the p38 MAPK-PPARγ signaling pathway participates in autophagy activation during the induction of BIT by CIP.