PURPOSE Loss of retinal ganglion cells (RGCs) during retinal ischemia is the potentially blinding mechanism that underlies several sight-threatening disorders. Fluctuations in extracellular pH are associated with such pathological conditions. It has been demonstrated that the retina is a functionally distinct region of central neurons that are known to contain acid-sensing ion channels (ASICs), which are depolarizing conductance channels that are directly activated by protons. This study was conducted to determine whether ASIC1a channels in RGCs are essential for ischemia-induced cell death.
METHODS Expression ofASIC1a channels was detected in primary cultures of rat RGCs and in retinal sections. The patch-clamp technique in the conventional whole-cell configuration was used to examine the currents evoked by acid in the cultured RGCs. Simultaneously, we used the middle cerebral artery occlusion modelin ASIC1+/+ and ASIC1–/– mice to examine the role of ASIC1a channels under ischemic conditions. Furthermore, hypoxia-induced cell death in RGC cultures was measured by MTT assay.
RESULTS RGCs expressed a high density of ASIC1a channels. The function of ASIC channels was upregulated after hypoxia in cultured RGCs. Acute blockade of ASIC1a channels with the specific inhibitor PcTX1 reduced RGC death in vitro. Genetic suppression of ASIC1a channels in ASIC1a –/– mice attenuated RGC death in vivo.
CONCLUSIONS Based on these novel findings, we conclude that ASIC1a plays a role in RGC death induced by hypoxia. Therefore, neuroprotective strategies in glaucoma could include tools to improve the ability of these neurons to survive the cytotoxic consequences of ASIC1a activation.
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