Na+/h+ exchangers as therapeutic targets for cerebral ischemia

Abstract

The Na+/H+ exchangers (NHE) are a family of membrane transporters that catalyzes the exchange of intracellular H+ with extracellular Na+ and plays a role in regulating intracellular pH and cell volume. Following cerebral ischemia, the "housekeeping" NHE isoform 1 (NHE-1) is stimulated by intracellular acidosis to remove excess H+. Overstimulation of NHE-1 causes accumulation of Na+ and Ca2+ inside the cell through the reversal mode of Na+/Ca2+ exchange (NCX) and eventually contributes to cell death. Pharmacological inhibition or genetic knockdown of NHE-1 is neuroprotective in both in vitro and in vivo ischemia models as shown by reduced neuronal death and blockade of intracellular Ca2 + and Na+ accumulation. Inhibition of NHE-1 not only reduces brain infarct volume but also improves longterm neurological functions. Inhibition of NHE-1 also has a profound effect on neuroinflammation and edema formation, providing a longer treatment time window for stroke therapy. Therefore, NHE-1 merges as an important target for developing new therapeutics for stroke treatment.