Ischemic stroke is a leading cause of death and long-term disability in the United States. Unfortunately there is no effective therapeutic intervention other than the use of thrombolytics, which has a limited therapeutic time window of approximately 3 h and the potential side effect of
intracranial hemorrhage. The absence of neuroprotective
therapy is particularly apparent following the failure of multiple clinical trials using
glutamate antagonists as therapeutic agents. Understanding the detailed biochemical changes associated with
brain ischemia and the cellular mechanisms involved in ischemic
brain injury are critical for establishing new and effective neuroprotective strategy. Dramatically decreased tissue pH, or
acidosis, is a common feature of ischemic brain, and has been suggested to play a role in neuronal injury. However, the detailed cellular and molecular mechanisms of such
acid induced injury remain elusive. The recent finding that
acidosis activates a distinct family of
cation channels, the
acid-sensing ion channels (ASICs), in both peripheral and central neurons has dramatically changed the landscape of
brain ischemia neurochemistry and provided a novel therapeutic target. In CNS neurons, lowering extracellular pH to the level commonly seen in ischemic brain activates inward ASIC currents resulting in membrane depolarization. In the majority of these neurons, ASICs are also permeable to Ca2+. Therefore, activation of these channels induces an increase of [Ca2+]i. Incubation of neurons with acidic solutions reproduces Ca2+-dependent neuronal injury independent of
glutamate receptor activation. The
acid-induced currents, membrane depolarization, [Ca2+]i increase, and neuronal injury can be inhibited by the blockade of ASIC1a. In focal
ischemia, ASIC1a blockade, or ASIC1a gene knockout both protect brain from injury. The blockers of ASIC1a also demonstrate a prolonged therapeutic time window, beyond that of the
glutamate antagonists. Thus, Ca2+-permeable ASIC1a may represent a novel therapeutic target for ischemic
brain injury.