UCLA researchers from the Department of Neurology have discovered a molecular compound that promotes activation of parvalbumin neurons in the brain, enhancing behavioral recovery after stroke.
BACKGROUND: Stroke is a leading cause of death and disability worldwide. According to the World Health Organization, approximately 15 million people suffer from stroke each year, with nearly 5 million deaths and another 5 million patients left permanently disabled. A stroke occurs when the blood supply to part of the brain is interrupted or reduced, preventing brain tissue from getting oxygen and nutrients. There is no medical therapy currently available for stroke, and rehabilitation efforts can be fraught due to the type, intensity, and/or duration of rehabilitation therapies hindering patient accessibility. Additionally, rehabilitation effort for stroke is at most modestly effective even if patients have full access and participate. These setbacks highlight a major unmet need for stroke recovery. Understanding stroke mechanisms in the brain responsive to rehabilitation would lead to progress in developing more effective therapies. It is recently understood that spinal projections to the brain after stroke may be important for rehabilitation, however it is unknown where in the brain it projects to and what its involvement in rehabilitation might be. A therapeutic drug that could exhibit rehabilitative effects seen in neural circuits involved in rehabilitation after stroke would be greatly impactful for clinical use.
INNOVATION: The Carmichael Lab at UCLA discovered a molecular compound that activates a stroke-related neural circuit in the brain. First, using a newly developed in-house mouse model of stroke and rehabilitation, they discovered that the rostral forelimb area (RFA), a brain area in the premotor cortex, mediates the rehabilitation process on the same (ipsilateral) side of the brain where the stroke occurred. The RFA is a key area for recovery in stroke in humans. Specifically, they identified a neural pathway that is lost by stroke and regained during rehabilitation – neural projections from parvalbumin neurons in the RFA. This pathway has clinical relevance, as they developed a molecular compound that enhances the activity of parvalbumin neurons (a type of inhibitory neuron) in the RFA, promoting behavioral recovery after stroke. This molecular compound is a negative allosteric modulator of the GABA^A receptor in parvalbumin neurons, which disinhibits the activity of this rehabilitation pathway in the brain, allowing it to function in a more enhanced way. This therapeutic drug discovery is novel – no drugs on the market to aid in stroke recovery – and has great clinical potential considering that existing methods for stroke rehabilitation are only mildly effective.
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DEVELOPMENT-TO-DATE: All work has been done in vivo in novel stroke mice model.