New Insight into Reducing Stroke Damage

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Stroke is the third most common cause of death in the developed world and is also the leading cause of serious long-term adult disability; many survivors never recover sufficient function to live independently. Although rapid intervention to restore blood flow to the affected area can improve outcomes, the brain has limited capacity for repair and there is currently no treatment that helps recovery. The zone immediately surrounding the damaged area is critically important for recovery since motor and sensory neurons in this region can make new connections and compensate for those killed by the stroke.

L-655,708 structure

L-655,708

Immediately after a stroke, tonic inhibition in the affected area increases to reduce excitability and limit the extent of the damage, but this increased tonic inhibition also has the effect of reducing plasticity in surrounding areas. Researchers at UCLA and the University of Otago have now shown that the increased tonic inhibition can persist for weeks and eventually hinder recovery. In experimentally induced stroke in mice, tonic neural inhibition was found to be increased in the area surrounding the stroke damage and shown to be mediated by extrasynaptic GABAA receptors. After a stroke in the motor cortex, six weeks treatment with L-655,708, a subtype-selective inverse agonist of the α5-subunit-containing extrasynaptic GABAA receptor, restored tonic inhibition to pre-stroke levels and led to a sustained improvement of motor function. In keeping with a protective role of tonic inhibition immediately after a stroke, the treatment was only effective if delayed until three days after the stroke; initiating treatment too early increased the damage caused by the stroke.

The results suggest that reduction of tonic inhibition by reducing extrasynaptic GABAA receptor function could be beneficial in promoting recovery after stroke and possibly other brain traumas. A treatment that is effective following delayed administration would offer a significant advantage over existing interventions which must be carried out within a few hours of the stroke occurring.

The study is published in the journal Nature.


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