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Limiting Stroke-Induced Damage by Targeting an Acid Channel
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     Why are brain neurons so much more susceptible to ischemic injury than, say, muscle or skin tissue? A clue is provided by work showing that the activation of neuronal acid-sensing ion channel 1 (ASIC1) can lead to neuronal death.1,2,3 A recent study by Xiong et al.3 places this observation in the context of stroke by showing that the activation of ASIC1 during the metabolic acidosis accompanying experimental stroke contributes substantially to subsequent brain injury.

    Excessive loading of calcium into neurons through N-methyl-D-aspartate (NMDA) receptors and voltage-dependent calcium channels is thought to be one of the triggers of neuronal injury after ischemic stroke. ASIC1 contributes to this process and is a member of the family of epithelial sodium channels located in the brain. Protein subunits (e.g., the ASIC1 splice variant ASIC1a) assemble as multimeric complexes to form voltage-insensitive, amiloride-sensitive channels in the surface membrane. In contrast to many calcium-permeable neurotransmitter-receptor channels, such as nicotinic acetylcholine receptors and glutamate receptors, which are inhibited as pH falls, acid-sensing ion channels are activated as pH falls. ASIC1a begins to open when the pH falls below approximately 7.0, and its activation is half maximal at a pH of 6.2 — a pH range that should occur within the penumbra and core of an infarct. Moreover, the activation of acid-sensing ion channels is promoted by stretching of the membrane, the release of arachidonic acid, the production of lactate,1,4 or a drop in extracellular calcium concentrations5 — conditions that occur within an infarct as cells swell, calcium-dependent phospholipases are activated, and calcium influx occurs.

    Xiong et al.3 used both in vitro and in vivo methods to determine whether acidosis or an ischemic insult could cause the calcium-dependent death of neurons through ASIC1. Using the release of lactate dehydrogenase to measure the incidence of neuronal death in cortical cultures, they showed that the neurotoxic effect of exposure to a medium with a pH of 6.0 was inhibited by both amiloride and the ASIC1a-specific antagonist psalmotoxin 1 (PcTX1), a component of the venom of a Trinidad Chevron tarantula. Acid-mediated neurotoxicity was absent in mice deficient in the ASIC1 gene. Taken together, these results suggest that ASIC1 can cause a clinically significant incidence of calcium-mediated death of neurons in the presence of acidosis in vitro.

    Excess influx of calcium is known to trigger neuronal degeneration, but whether ASIC1 itself is an important portal for the entry of calcium is a matter of controversy. We know that acidosis induces a cytoplasmic increase in calcium concentrations in ASIC1-transfected cells.2 Xiong et al.3 show that brief exposure of cortical neurons to a medium with a pH of 6.0 in the presence of a cocktail of glutamate and calcium-channel blockers leads to an increase in calcium concentrations within the cytoplasm that can be blocked by exposure to amiloride or PcTX1. The acidosis-triggered increase in calcium was absent in neurons isolated from mice that were deficient in ASIC1. The authors conclude that calcium enters directly through the acid-sensing ion channels under acidic conditions, although other routes of calcium entry are probably also involved.

    Finally, using genetic and pharmacologic strategies, Xiong et al.3 showed that ASIC1 mediates neuronal death in vivo in a mouse model of stroke (Figure 1). The volume of infarcts caused by transient occlusion of the middle cerebral artery could be reduced by intraventricular injections of amiloride or PcTX1 and was also smaller in mice lacking the ASIC1 gene than in wild-type mice. The addition of PcTX1 or a deficiency of ASIC1 conferred additional neuroprotection in mice treated with memantine (which blocks the NMDA receptor), suggesting that ASIC1 has a direct role in mediating neurotoxicity.

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    Figure 1. Involvement of the ASIC1 Channel during Stroke.

    In a recent study, Xiong et al.3 used a mouse model of ischemic stroke, in which occlusion of the middle cerebral artery leads to ischemia, acidosis, and ultimately, stroke, to evaluate the influence of an acidosis-sensitive ion channel on the size of the resulting infarct. The middle cerebral artery of wild-type mice or mice in which the ASIC1 gene had been knocked out was occluded for 1 hour, and the volume of the infarct was assayed 24 hours later by staining coronal sections (bottom panels) with a vital dye. Wild-type mice had larger infarcts than the ASIC1-knockout mice. Other evidence obtained by Xiong et al.3 suggests that neurotoxicity is partially mediated through the activation of ASIC1a, which, in turn, causes an increase in intracellular calcium concentrations, possibly through the acid-sensing ion channel itself, with or without the assistance of other calcium-permeable channels (middle panels). CSF denotes cerebrospinal fluid.

    The report by Xiong et al.3 points the way to a neuroprotective strategy for stroke — namely, to develop a small-molecule inhibitor of ASIC1 or its components. The current treatment of stroke relies on the use of thrombolytic agents, which are of demonstrable value only if delivered within three hours after the onset of stroke. Although potential side effects must be considered, a small-molecule inhibitor of acid-sensing ion channels could be an attractive option, because these channels should be relatively quiescent under nonacidotic conditions. The context-dependent activation of ASIC1 with acidification makes this cation channel a particularly intriguing target for new stroke therapies.

    Dr. Dingledine reports holding equity in NeurOp.

    Source Information

    From the Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel (M.B.); and the Department of Pharmacology, Emory University School of Medicine, Atlanta (M.B., R.D.).

    References

    Allen NJ, Attwell D. Modulation of ASIC channels in rat cerebellar Purkinje neurons by ischaemia-related signals. J Physiol 2002;543:521-529.

    Yermolaieva O, Leonard AS, Schnizler MK, Abboud FM, Welsh MJ. Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. Proc Natl Acad Sci U S A 2004;101:6752-6757.

    Xiong ZG, Zhu XM, Chu XP, et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell 2004;118:687-698.

    Immke DC, McCleskey EW. Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons. Nat Neurosci 2001;4:869-870.

    Immke DC, McCleskey EW. Protons open acid-sensing ion channels by catalyzing relief of Ca2+ blockade. Neuron 2003;37:75-84.(Morris Benveniste, Ph.D.,)