Inhibition of Na/H exchange by SM-20220 attenuates free fatty acid efflux in rat cerebral cortex during ischemia–reperfusion injury

The Na⁺/H⁺ exchanger (NHE) is activated during ischemia–reperfusion in an effort to restore intracellular pH to normal levels. Inhibition of NHE with non-selective amiloride derivatives has been shown to be neuroprotective and to attenuate free fatty acid efflux during ischemia–reperfusion. We evaluated the effects of SM-20220 (20 μM), a highly selective and specific NHE inhibitor, applied topically onto rat cerebral cortex prior to and during a 20-min period of ischemia. SM-20220 application significantly reduced the ischemia-evoked efflux of myristic, palmitic, and arachidonic acids during both ischemia and reperfusion with significant decreases in linoleic and docosahexaenoic levels during reperfusion. This study confirms the importance of NHEs in eliciting free fatty acid efflux, inhibition of which may be an essential component of the neuroprotective benefits of NHE inhibitors in ischemia–reperfusion injury.