The proposed experiments are planned in cats and in human patients to examine the hypothesis that oxygen radicals are generated during and after prolonged seizures and that they may produce microvascular injury analogous to that seen in experimental fluid- percussion brain injury and in experimental acute severe hypertension. In earlier experiments it was found that microvascular injury consisting of sustained arteriolar dilation, abnormal vascular responsiveness, and increased blood-brain barrier permeability to proteins occurred during seizures induced by drugs in animals. Similar alterations are also seen in patients with prolonged seizures. In earlier studies in acute hypertension and in fluid-percussion brain injury we showed that the microvascular injury in these conditions is due to the generation of oxygen radicals. The planned experiments will find out whether during seizures there is production of superoxide and other radicals derived from it, such as hydrogen peroxide and hydroxyl radical. We will identify what factor determine the production of these radicals and some of the mechanisms which allow them to gain access to the extracellular fluid compartment. These studies will make use of appropriate scavengers and of specific inhibitors of the anion channel. We will also identify the enzymatic source of oxygen radicals during and after prolonged seizures. Particular emphases will be placed on the xanthine oxidase reaction, on metabolism of arachidonate via cyclooxygenase and lipoxygenase, and on the accumulation of activated leukocytes. These experiments will be carried out on anesthetized cats equipped with cranial windows for the direct observation of the cerebral microcirculation and for the measurement of regional cerebral blood flow. Parallel experiments will be carried out in patients with status epilepticus to identify products of lipid peroxidation in the CSF. Preliminary experiments showed that the CSF of such patient products contains conjugated dienes suggesting strongly the occurrence of lipid peroxidation from oxygen radicals.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
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