New Strike against Stroke
Neuronal damage has a new culprit
Context: Strokes kill neurons by depriving them of oxygen. Without oxygen, neurons have difficulty producing the molecule ATP, their source of energy. This prevents them from performing housekeeping chores, including the important task of pulling glutamate, a message-transmitting chemical, back into the neuron after its message has been received; glutamate keeps sending signals to neighboring neurons, resulting in a deadly influx of calcium ions. However, drugs designed to curb stroke damage by blocking glutamate’s effects have shown disappointing results in clinical trials. New research, led by Zhigang Xiong at the Legacy Clinical Research and Technology Center in Portland, OR, shows another strategy that seems more promising.
Methods and Results: To make ATP without oxygen, cells use an inefficient method that produces lactic acid and protons as by-products. Neurons using this method become more acidic; they also become more susceptible to damage, but it wasn’t clear why. Xiong and his colleagues speculated that acid-sensing ion channels (ASICs) might move calcium into the cell, thereby accelerating neuronal damage. After showing that strokelike conditions activated ASICs, and that ASICs allowed calcium into the neuron, they studied mice lacking the gene for ASIC1a, which is highly expressed in the brain. When subjected to simulated strokes, mice without the gene fared better than mice with it, even when treated with memantine, a drug that blocks the actions of glutamate. The researchers also discovered that small molecules that block ASICs can protect against stroke injury. In rats treated with one such molecule before simulated strokes, the rate of neuronal death was less than half that among untreated rats.
Why it matters: Drugs that block ASICs will likely face many of the same challenges as those that block glutamate: they must be administered quickly after a stroke and could have unintended effects on brain function. Nonetheless, small molecules have already shown the capacity to prevent the type of brain damage caused by this newly described mechanism. Thus, these results offer hope against a devastating cause of disability and the third-leading cause of death in the United States.
Source: Xiong, Z. G. et al. (2004) Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell 118: 687-698.