Journal
CELLULAR AND MOLECULAR NEUROBIOLOGY
Volume 43, Issue 3, Pages 1355-1367Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10571-022-01255-y
Keywords
Cerebral ischemic preconditioning; Brain ischemic tolerance; Klotho; PPAR gamma; Hippocampus
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This study discovered that Klotho plays an important role in cerebral ischemic tolerance induced by CIP, and it is upregulated via PPAR gamma. This finding contributes to a better understanding of the mechanisms behind cerebral ischemic tolerance and may provide new targets for the development of therapeutic strategies.
Cerebral ischemic preconditioning (CIP)-induced brain ischemic tolerance protects neurons from subsequent lethal ischemic insult. However, the specific mechanisms underlying CIP remain unclear. In the present study, we explored the hypothesis that peroxisome proliferator-activated receptor gamma (PPAR gamma) participates in the upregulation of Klotho during the induction of brain ischemic tolerance by CIP. First we investigated the expression of Klotho during the brain ischemic tolerance induced by CIP. Lethal ischemia significantly decreased Klotho expression from 6 h to 7 days, while CIP significantly increased Klotho expression from 12 h to 7 days in the hippocampal CA1 region. Inhibition of Klotho expression by its shRNA blocked the neuroprotection induced by CIP. These results indicate that Klotho participates in brain ischemic tolerance by CIP. Furthermore, we tested the role of PPAR gamma in regulating Klotho expression after CIP. CIP caused PPAR gamma protein translocation to the nucleus in neurons in the CA1 region of the hippocampus. Pretreatment with GW9962, a PPAR gamma inhibitor, significantly attenuated the upregulation of Klotho protein and blocked the brain ischemic tolerance induced by CIP. Taken together, it can be concluded that Klotho upregulation via PPAR gamma contributes to the induction of brain ischemic tolerance by CIP.
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