Therapeutic implications of purinergic receptor P2X4 in ischemic stroke

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Summary: Stroke remains a leading cause of disability in the United States. Stroke is a heterogeneous multifactorial disorder. Prior attempts at developing new therapies have failed in clinics due to imperfect target validation, unrealistic therapeutic windows and lack of age appropriate models. Thus, there is an opportunity and a need to identify new medical treatment for stroke. The immune cells move to stroke area in the brain and contribute to damage. We have recently shown that the purinergic P2X4 receptor is excessively stimulated by adenosine triphosphate (ATP) released by dying brain cells during stroke. This receptor protein then causes activation of the immune cells and results in greater stroke injury. We have assembled the necessary tools such as animals lacking P2X4 receptors as well as blockers that selectively inhibit the receptor. The proposal, using these new tools, aims to investigate whether this receptor protein is a novel target to develop treatment for subjects with stroke. Our initial data suggest that blocking or deleting this receptor protein during the acute phase of stroke is beneficial. However, it is unknown how this protein works and what its potential adverse effects might be. Answering these questions is the overall goal here and should define the correct approach in pursuing a new stroke treatment