The role of Na+/Ca2+ countertransport and other Na+-entry routes in the pathophysiology of stroke

Abstract

Na+ has a crucial role in neuronal osmoregulation and, therefore, its intracellular concentrations are strictly controlled by several homeostatic systems, the most important of which is the Na+/K+ ATPase. A marked increase in [Na+]i takes place after ischemic insults in neurons where it has a crucial role in triggering necrotic and, perhaps, also apoptotic cell death. While the impairment in Na+/K+ ATPase activity contributes to this process, it is not sufficient per se to cause the massive intracellular Na+ overload observed after ischemia which requires, instead, also a significant increase in Na+ influx into the cell or an impairment of Na+ efflux. Traditionally, the increase in Na+ permeability occurring in ischemic neurons was ascribed to the activation of voltage-gated Na+ channels and/or of glutamate receptors, and their pharmacological blockade was proposed as a therapeutic strategy in stroke but did not meet the expectations. More recently, the spotlight was turned on NCX, ASICs, NHE, and NKCC, a group of ion channels and transporters, which, because of their specific mechanisms of activation, could represent a preferential Na+ influx or efflux route in ischemic neurons. Evidence suggesting their involvement in stroke and the possible benefits of their pharmacological modulation in this condition are reviewed in the present chapter.