Diazoxide preconditioning alleviates caspase-dependent and caspase-independent apoptosis induced by anoxia-reoxygenation of PC12 cells

Abstract

Although there is increasing evidence that the ATP sensitive potassium channel (K(ATP)) opener exhibits neuroprotective effects against ischaemic neural damage, little is known about the mechanism. Mitochondria play a key role in apoptosis by releasing many important factors, including cytochrome c and apoptosis-inducing factor, which in turn initiate the caspase-dependent and -independent mitochondrial pathway, respectively. In the present study, we sought to determine the locus that K(ATP) opener uses to mediate this protection in PC12 cells. We found that pre-treatment of PC12 cells with diazoxide (DZX), a mitochondrial ATP sensitive potassium channel (mitoK(ATP)) opener, dose-dependently increased cell viability under conditions of oxygen glucose deprivation (OGD). The protective effect of this pre-conditioning was attenuated by 5-hydroxydecanoic acid, a selective mitoK(ATP) blocker. The results showed that DZX inhibits the release of cytochrome c, the activation of caspase-3 and the release of AIF evoked by OGD. Taken together, our results demonstrate for the first time that activation of the mitoK(ATP) channel elicits protective effects against OGD-induced cell apoptosis by caspase-dependent and -independent mitochondrial pathways.

Abnormal Neurodevelopmental Outcomes are Common in Children with Transient Congenital Hyperinsulinism

“…Theoretically, it is possible that the positive correlation of diazoxide dose and abnormal neurodevelopment indicates that diazoxide itself may be detrimental to the neonatal brain. However, there have been no clinical reports of brain injury from diazoxide use, and there are several studies in animals demonstrating neuroprotective effects of diazoxide (Zhang et al, 2010, Huang et al, 2010). It is possible that diazoxide unresponsiveness represents an independent adverse marker for abnormal neurodevelopment, due to relative drug inactivity at the level of neuronal K ATP channels, which are important for brain neuronal survival.…”

Protective Effect of Delayed Remote Limb Ischemic Postconditioning: Role of Mitochondrial KATP Channels in a Rat Model of Focal Cerebral Ischemic Reperfusion Injury

“…Opening of K ATP channels has been shown to be a prerequisite event for the induction of protection against ischemia–reperfusion injury by RIPC, IPost, and RIPost (Schmidt et al , 2007; Steensrud et al , 2010; Yang et al , 2004). Zhang et al (2010) used an in-vitro model of PC12 cells undergoing oxygen glucose deprivation to reveal that activation of K ATP channels elicits protective effects against oxygen glucose deprivation-induced cell apoptosis by caspase-dependent and -independent mitochondrial pathways. In addition, Loukogeorgakis et al (2007) revealed that transient limb ischemia induces RIPost in humans by a K ATP channel-dependent mechanism.…”

CrossTalk proposal: Cell volume changes are an essential step in the cell death machinery

“…The organic osmolytes stabilize intracellular proteins (Burg et al 2007; Lang & Hoffmann, 2012). The stabilisation of the permeability transition pore by organic osmolytes counteracts mitochondrial depolarization (Zhang et al 2010). The protein stabilisation contributes to the inhibitory effect of organic osmolytes on apoptotic cell death (Burg et al 2007; Zhang et al 2010).…”