Ischemic neuroprotection afforded by
sevoflurane preconditioning has been previously demonstrated, yet the underlying mechanism is poorly understood and likely affects a wide range of cellular activities. Several individual
microRNAs have been implicated in both the pathogenesis of
cerebral ischemia and cellular survival, and are capable of affecting a range of target
mRNA. Conceivably,
sevoflurane preconditioning may lead to alterations in
ischemia-induced
microRNA expression that may subsequently exert
neuroprotective effects. We first examined the
microRNA expression profile following
transient cerebral ischemia in rats and the impact of
sevoflurane preconditioning. Microarray analysis revealed that 3
microRNAs were up-regulated (>2.0 fold) and 9 were down-regulated (< 0.5 fold) following
middle cerebral artery occlusion (MCAO) compared to
sham controls. In particular, miR-15b was expressed at significantly high levels after MCAO. Preconditioning with
sevoflurane significantly attenuated the upregulation of miR-15b at 72h after reperfusion. Bcl-2, an anti-apoptotic gene involved in the pathogenesis of
cerebral ischemia, has been identified as a direct target of miR-15b. Consistent with the observed downregulation of miR-15b in
sevoflurane-preconditioned brain, postischemic Bcl-2 expression was significantly increased by
sevoflurane preconditioning. We identified the 3'-UTR of Bcl-2 as the target for miR-15b. Molecular inhibition of miR-15b was capable of mimicking the
neuroprotective effect of
sevoflurane preconditioning, suggesting that the suppression of miR-15b due to
sevoflurane contributes to its ischemic neuroprotection. Thus,
sevoflurane preconditioning may exert its anti-apoptotic effects by reducing the elevated expression of miR-15b following ischemic injury, allowing its target
proteins, including Bcl-2, to be translated and expressed at the
protein level.