The Regulation of Autophagy by p38 MAPK-PPAR? Signaling During the Brain Ischemic Tolerance Induced by Cerebral Ischemic Preconditioning
The Regulation of Autophagy by p38 MAPK-PPAR? Signaling During the Brain Ischemic Tolerance Induced by Cerebral Ischemic Preconditioning
复制标题
DOI：
10.1089/dna.2022.0087
复制
发表时间：
2022-08-09
影响因子：
3.1
通讯作者：
Zhang，Min
中科院分区：
文献类型：
--
作者：
Su，A-Chou;Zhang，Ling-Yan;Zhang，Min
大量研究表明，自噬激活参与了脑缺血预处理（CIP）诱导的脑缺血耐受（BIT）。然而，在此过程中自噬激活的机制仍不清楚。本研究旨在评估p38 MAPK-过氧化物酶体增殖物激活受体γ（PPARγ）信号级联反应在CIP诱导的BIT期间自噬中的作用。结果显示，在大鼠全脑缺血模型中，CIP后最初观察到自噬激活，如Beclin 1表达上调、LC 3-II/LC 3-I比率增加、LC 3免疫荧光增强以及海马CA 1区神经元中自噬体数量增加所示。自噬抑制剂3-甲基腺嘌呤可消除CIP的神经保护作用。CIP后p-p38 MAPK和PPARγ表达上调早于自噬激活。此外，SB 203580（p38 MAPK抑制剂）预处理可逆转CIP诱导的PPARγ上调、自噬激活和神经保护作用。预先给予GW 9662（PPARγ抑制剂）可逆转CIP诱导的自噬激活和神经保护作用，但对CIP诱导的p-p38 MAPK表达上调无影响。提示p38 MAPK-PPARγ信号通路参与CIP诱导BIT过程中的自噬激活。
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.