Editors' ChoiceSTROKE

Of Acid and Neuronal Injury

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Science's STKE  28 Sep 2004:
Vol. 2004, Issue 252, pp. tw341
DOI: 10.1126/stke.2522004tw341

During an ischemic stroke, the blood supply to the brain is disrupted; the ensuing hypoxia leads to neuronal death after calcium influx, which can result in death or severe brain injury. Because hypoxia leads to an increase in extracellular glutamate, much research has focused on the role of N-methyl-D-aspartate-type glutamate receptors (NMDARs) in mediating toxic calcium influx. However, glutamate receptor antagonists do not appear to be clinically effective in preventing ischemic brain injury (see Huang and McNamara). The switch from oxidative phosphorylation to glycolysis also leads to acidosis of hypoxic tissue. Although acidosis is known to contribute to ischemic brain injury, the precise mechanisms remain unclear. Xiong et al. showed that, in cultured mouse cortical neurons, decreasing extracellular pH activated inward currents through acid-sensing ion channels (ASICs). ASICs were permeable to calcium, and a decrease in pH could elicit a sustained increase in intracellular calcium concentration. Oxygen and glucose deprivation (a model of ischemia) enhanced ASIC currents and glutamate-independent neuronal injury, whereas ASIC blockers protected neurons from glutamate-independent acidosis-mediated injury (elicited in the presence of glutamate receptor antagonists and L-type calcium channel blockers). Moreover, mice lacking ASIC1 or rats injected intraventricularly with ASIC blockers were resistant to ischemic brain injury. This in vivo protection was both greater than and additive to that seen with NMDAR blockade, leading to the hope that ASICs blockers may be therapeutically useful in preventing ischemic brain injury.

Z.-G. Xiong, X.-M. Zhu, X.-P. Chu, M. Minami, J. Hey, W.-L. Wei, J. F. MacDonald, J. A. Wemmie, M. P. Price, M. J. Welsh, R. P. Simon, Neuroprotection in ischemia: Blocking calcium-permeable acid-sensing ion channels. Cell 118, 687-698 (2004). [Online Journal]

Y. Huang, J. O. McNamara, Ischemic stroke: "Acidotoxicity" is a perpetrator. Cell 118, 665-670 (2004). [Online Journal]