Acid sensing ion channels - novel therapeutic targets for ischemic brain injury

Nov 28, 2006Frontiers in bioscience : a journal and virtual library

Acid sensing ion channels as new treatment targets for brain injury caused by lack of blood flow

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Abstract

Blockade of ASIC1a protects against ischemic brain injury and offers a prolonged therapeutic time window.

Ischemic stroke is a major cause of death and disability, with limited treatment options currently available.
Acidosis, characterized by decreased tissue pH, is commonly observed in ischemic brain conditions and may contribute to neuronal injury.
Activation of acid-sensing ion channels (ASICs) occurs in response to lowered extracellular pH, leading to membrane depolarization and increased intracellular calcium levels.
Acid-induced neuronal injury can occur independently of glutamate receptor activation.
Inhibiting ASIC1a can prevent acid-induced currents, membrane depolarization, and neuronal injury.
Both ASIC1a blockade and gene knockout show protective effects in focal ischemia, suggesting ASIC1a is a potential therapeutic target.

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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.

Abstract

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