Dexmedetomidine Protects Mouse Brain from Ischemia-Reperfusion Injury via Inhibiting Neuronal Autophagy through Up-Regulating HIF-1α

Abstract

Stroke is the leading cause of death in China and produces a heavy socio-economic burden in the past decades. Previous studies have shown that dexmedetomidine (DEX) is neuroprotective after cerebral ischemia. However, the role of autophagy during DEX-mediated neuroprotection after cerebral ischemia is still unknown. In this study, we found that post-conditioning with DEX and DEX+3-methyladenine (3-MA) (autophagy inhibitor) reduced brain infarct size and improved neurological deficits compared with DEX+RAPA (autophagy inducer) 24 h after transient middle cerebral artery artery occlusion (tMCAO) model in mice. DEX inhibited the neuronal autophagy in the peri-ischemic brain, and increased viability and decreased apoptosis of primary cultured neurons in oxygen-glucose deprivation (OGD) model. DEX induced expression of Bcl-1 and p62, while reduced the expression of microtubule-associated protein 1 light chain 3 (LC3) and Beclin 1 in primary cultured neurons through inhibition of apoptosis and autophagy. Meanwhile, DEX promoted the expression of hypoxia-inducible factor-1α (HIF-1α) both in vivo and in vitro, and 2-Methoxyestradiol (2ME2), an inhibitor of HIF-1α, could reverse DEX-induced autophagic inhibition. In conclusion, our study suggests that post-conditioning with DEX at the beginning of reperfusion protects mouse brain from ischemia-reperfusion injury via inhibition of neuronal autophagy by upregulation of HIF-1α, which provides a potential therapeutic treatment for acute ischemic injury.

Icariside II, a phosphodiesterase 5 inhibitor, attenuates cerebral ischaemia/reperfusion injury by inhibiting glycogen synthase kinase‐3β‐mediated activation of autophagy

“…Notably, neuronal cell death after OGD/R was attenuated and aggravated with 3‐methylamphetamine and rapamycin, respectively. These results were consistent with the hypothesis that activation of autophagy in cerebral I/R does not provide neuroprotection but triggers cell death (Luo et al, ). Most importantly, icariside II significantly inhibited autophagosome formation (a special double‐membrane structure) in neurons upon cerebral I/R stress, which was observed by ultrastructural analysis.…”

Suppression of REDD1 attenuates oxygen glucose deprivation/reoxygenation‐evoked ischemic injury in neuron by suppressing mTOR‐mediated excessive autophagy

“…Autophagy involves the formation of autophagosomes that will fuse with lysosomes to degrade proteins and damaged organelles by regulating autophagy‐related protein, such as microtubule‐associated protein light chain 3 (LC3), Beclin 1, and p62. Recently, increasing evidence has supported the dysregulated autophagy as a mechanism in various diseases, including ischemia/reperfusion (I/R) injury . However, its role in ischemic diseases is controversial.…”

Dexmedetomidine attenuates cerebral ischemia/reperfusion injury in neonatal rats by inhibiting TLR4 signaling

“…7,11,12 Inhibition of the TLR4 pathway has been suggested as the major underlying working mechanism responsible for the neuroprotective effects of DEX. Kim et al.…”