Protective role of neuronal KATP channels in brain hypoxia

During severe arterial hypoxia leading to brain anoxia, most mammalian neurons undergo a massive depolarisation terminating in cell death. However, some neurons of the adult brain and most immature nervous structures tolerate extended periods of hypoxia-anoxia. An understanding of the mechanisms underlying this tolerance to oxygen depletion is pivotal for developing strategies to protect the brain from consequences of hypoxic-ischemic insults. ATP-sensitive K+ (K-ATP) channels are good subjects for this study as they are activated by processes associated with energy deprivation and can counteract the terminal anoxic-ischemic neuronal depolarisation. This review summarises in vitro analyses on the role of K-ATP channels in hypoxia-anoxia in three distinct neuronal systems of rodents. In dorsal vagal neurons, blockade of (KATP) channels with sulfonylureas abolishes the hypoxic-anoxic hyperpolarisation. However, this does not affect the extreme tolerance of these neurons to oxygen depletion as evidenced by a moderate and sustained increase of intracellular Ca2+ (Ca-i). By contrast, a sulfonylurea-induced block of K-ATP channels shortens the delay of occurrence of a major Ca-i rise in cerebellar Purkinje neurons. In neurons of the neonatal medullary respiratory network, K-ATP channel blockers reverse the anoxic hyperpolarisation associated with slowing of respiratory frequency. This may constitute an adaptive mechanism for energy preservation. These studies demonstrate that K-ATP channels are an ubiquituous feature of mammalian neurons and may, indeed, play a protective role in brain hypoxia.