Abstract
The purpose of this current study was to evaluate whether improvement of mitochondrial dysfunction was involved in the therapeutic effect of sevoflurane post-conditioning in global cerebral ischemia after cardiac arrest (CA) via the PI3K/Akt pathway. In the first experiment, animals were randomly divided into three groups: a sham group, a CA group, a CA+sevoflurane post-conditioning group (CA+SE). Sevoflurane post-conditioning was achieved by administration of 2.5% sevoflurane for 30 min after resuscitation. Sevoflurane post-conditioning has a significant neuroprotective effect by increasing survival rates and reducing neuronal apoptosis. Additionally, the gene and protein expression of PGC-1α, NRF-1, and TFAM, the master regulators of mitochondrial biogenesis, were up-regulated in the CA+SE group, when compared to the CA group. Similarly, in contrast to the CA group, mitochondria-specific antioxidant enzymes, including heat-shock protein 60 (HSP60), peroxiredoxin 3 (Prx3), and thioredoxin 2 (Trx2) were also increased in the CA+SE group. Finally, administration of sevoflurane ameliorated mitochondrial reactive oxygen species (ROS) formation and maintained mitochondrial integrity. In the second experiment, we investigated the relationship between the PI3K/Akt pathway and mitochondrial biogenesis and mitochondria-specific antioxidant enzymes in sevoflurane-induced neuroprotection. The selective PI3K inhibitor wortmannin not only eliminated the beneficial biochemical processes of sevoflurane by reducing the level of mitochondrial biogenesis-related proteins and aggravating mitochondrial integrity, but also reversed the elevation of mitochondria-specific antioxidant enzymes induced by sevoflurane. Therefore, our data suggested that sevoflurane post-conditioning provides neuroprotection via improving mitochondrial biogenesis and integrity, as well as increasing mitochondria-specific antioxidant enzymes by a mechanism involving the PI3K/Akt pathway.
Highlights
A brief period of global brain ischemia, such as that induced by cardiac arrest (CA) or cardiopulmonary bypass surgery can occur under various perioperative circumstances and result in long-term neurological disability or death
A continually improved outcome after global brain ischemia induced by CA or cardiopulmonary bypass surgery has been achieved in patients, there has been no revolutionary breakthrough
Sevoflurane post-conditioning significantly attenuated the activation of caspase-3 and -9 to reduce post-ischemic neuronal apoptosis
Summary
A brief period of global brain ischemia, such as that induced by cardiac arrest (CA) or cardiopulmonary bypass surgery can occur under various perioperative circumstances and result in long-term neurological disability or death. Compelling evidences have shown that reperfusion after global cerebral ischemia causes severe damage to mitochondria (Zhou et al, 2011; Jiang et al, 2014; Park et al, 2015). It’s well-known that mitochondria play an essential and pivotal role in cellular bioenergetics by regulating energy metabolism, generating reactive oxygen species (ROS), and mediating apoptosis in response to cerebral ischemia (Guo et al, 2016). Several lines of evidence have pointed to altered mitochondrial biogenesis as one of the causal mechanisms of mitochondrial dysfunction, which occurred during the reperfusion period following cerebral ischemia in animals (Wang et al, 2014; Xie et al, 2014). Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a major regulator involved in mitochondrial biogenesis and plays an important role in oxidative metabolism in the brain (Kleiner et al, 2009). Mitochondrial transcriptional factor A (TFAM) is involved in mitochondrial DNA (mtDNA) maintenance and drives the transcription and replication of mtDNA (Escrivá et al, 1999; Scarpulla, 2002)
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