Despite the major clinical importance of brain edema, most treatments remain non-specific and directed at reducing elevated lntracranial pressure rather than inhibiting edema formation. Our long-term goal is to better understand the mechanisms of brain edema formation so that specific therapy can be developed. We have chosen to study edema during cerebral ischemia because the two primary types of brain edema, cytotoxic and vasogenic, occur during ischemia. Using animal models of focal ischemia, we have demonstrated that the development. of edema is closely related to the movement of sodium and chloride from the blood to the brain. Based upon these findings, we hypothesize that brain edema formation can be controlled by blocKing the influx of sodium from blood to brain. When the blood-brain barrier (BBB) is intact, sodium enters brain via specific transport pathways in the brain capillary endothelial cell and, therefore, it should be possible to reduce sodium influx into brain by inhibiting these transport systems. However, once the BBB opens, sodium is free to diffuse from the blood to the brain. The treatment of brain edema in this vasogenic phase must focus on preventing. BBB opening so that transport inhibitors can be effective. In support of the hypothesis, our preliminary studies show that treatment with dimethylamiloride, an inhibitor of the BBB Na/H exchanger, and benzamil, an inhibitor of the BBB-Na channel, reduce edema formation during early focal ischemia.
Tee specific aims of this proposal are to 1) identify the transport pathways that mediate BBB sodium and chloride transport and determine how they are regulated, 2) identify the mechanisms that produce BBB opening in ischemia, and 3) determine whether the formation of ischemic brain edema can be reduced by inhibition of BBB sodium transporters and/or by inhibiting breakdown of the BBB. We will study the mechanisms- of BBB ion transport using in situ perfusion of the rat brain and identification of transporter isoforms in isolated brain capillaries by protein and mRNA analysis. The mechanisms of BBB opening will be studied using pharmacologic agents to attenuate BBB disruption following middle cerebral artery occlusion in rats. Finally, the effect on brain edema formation of transport inhibitors and agents that prevent BBB opening will be determined also in the middle cerebral artery occlusion model. By better understanding the mechanisms of BBB ion transport and BBB disruption, we believe that it will be possible to develop effective therapies that limit the formation of brain edema during ischemia and following other types of brain injuries.
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