Elabela-APLNR Inhibits Cerebral Ischemia/Reperfusion Injury Through AMPK/SIRT3/PGC-1α and Akt/Nrf2 Pathways

Abstract

Inhibiting mitochondrial dysfunction and oxidative stress has benefits effects for the treatment of cerebral ischemia/reperfusion injury (CI/RI). Elabela/APLENR system had showed to be protective against ischemia/reperfusion induced injury in other tissue. However, whether Elabela had protective effects against CI/RI and its possible mechanisms were largely unknown. This study was designed to evaluate the effects of Elabela 32 (ELA32) against CI/RI. In vivo, behavioral test, infarct size and brain edema were evaluated on rats middle cerebral artery occlusion/reperfusion (MCAO/R) model after treated by ELA32. In vitro, HT22 cells were subjected to glucose deprivation/reperfusion (OGD/R) and treated with ELA32 in presence of SIRT3-siRNA, or AMPK-siRNA, or Nrf2-siRNA. Cell viability, cell apoptosis, ROS and ATP levels, mitochondrial related proteins and oxidative related cytokines were measured by relative methods.As the results showed, neurological scores, infarct size, brain edema and injury cytokines were improved by ELA32 treatment in rats. Subsequently, we found that ELA32 inhibited cell apoptosis, mitochondrial dysfunction, and oxidative stress in a dose dependent manner in brain and HT22 cell. Western blotting results showed that ELA32 induced the deacetylation and phosphorylation of PGC-1α, the expression of Nrf2, SIRT3 and APLNR, and the phosphorylation of AMPK and Akt. Further, the crosstalk relationship between APLNR, SIRT3, AMPK, PGC-1α, Akt and Nrf2 were verified by the specific targeted siRNA transfection. The same effects on APLNR related pathways were also observed in rats.In conclusion, ELA32 improved mitochondrial dysfunction and oxidative stress through regulating APLNR mediated AMPK/SIRT3/PGC-1α pathway and Akt/Nrf2 pathway. These results indicated that ELA32/APLNR system plays some role in central nervous system, and more studies should be performed to confirm these effects.

The neuroprotection of electro-acupuncture via the PGC-1α/TFAM pathway in transient focal cerebral ischemia rats

“…The PGC-1α/TFAM is a major upstream signaling pathway of MRCC (Fu et al, 2016;Yang et al, 2018). Wang et al (2020a) found that low expression of PGC-1α and TFAM protein led to a reduction of ATP, Complex I and V in MCAO rats. Geng et al (2017) reported that poor expression of PGC-1α decreased the ATP content, and PGC-1α may be a therapeutic target for the treatment of cerebral ischemia/reperfusion injury.…”