Ischemic Preconditioning in the Hippocampus of a Knockout Mouse Lacking SUR1-Based K ATP Channels

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Abstract
Background and Purpose— ATP-sensitive K + (K ATP ) channels have been implicated in the mechanism of neuronal ischemic preconditioning. To evaluate the role of neuronal/β–cell-type K ATP channels, SUR1 null (Sur1KO) mice lacking (K IR 6.x/SUR1) 4 K ATP channels were subjected to a preconditioning protocol with the use of double carotid occlusion. Methods— Wild-type C57BL/6 and Sur1KO mice were subjected to a double carotid block for 40 minutes with or without a 20-minute preconditioning block. After a 10-day reperfusion period, damage was assessed histologically in the hippocampal CA1, CA2, and CA3 areas and in the dentate gyrus. The neuroprotective effects of intracerebroventricular injections of diazoxide, which selectively affects mitochondria versus opening SUR1-type K ATP channels, and 5-hydroxydecanoate, a selective blocker of mitoK ATP channels, were evaluated with the same protocol. Results— Neurons in the CA1 region of both Sur1KO and wild-type animals subjected to a 20-minute ischemic insult were protected equally from neuronal damage produced by a subsequent 40-minute ischemic period. Pretreatment with diazoxide protected both Sur1KO and wild-type neurons, while 5-hydroxydecanoate augmented neurodegeneration in both strains of animals when administered before a 20-minute bout of ischemia. Conclusions— SUR1-based K ATP channels are not obligatory for neuronal preconditioning or augmentation of neurodegeneration by 5-hydroxydecanoate.