Traumatic brain injury (TBI) causes the brain to susceptible to secondary insults. The secondary insult model that we have developed directly mimics the circumstances of a mild TBI patient who may have systemic injuries that may result in hypotension or hypoxia. The secondary insult model also represent the circumstance in moderate and severe TBI patients who have areas in the brain that are injured and vulnerable to secondary insults, but potentially salvageable if managed optimally. The primary mechanism for the increased vulnerability of traumatized brain to secondary insults appears to be vascular. One possible cause of these findings is impairment of the normal vasodilatory mechanisms, in particular nitric oxide. Another possible cause is release by the trauma of vasoconstrictive substances that prevent vasodilation. We have preliminary evidence that alterations in nitric oxide function play a role in the reduction in rCBF, and treat treatment with L-arginine reverses these findings and improves outcome after severe cortical impact injury. Interestingly, the increase in CBF induced by L-arginine infusion is not associated with an increase in ICP; in fact the ICP is lower with L- arginine treatment than in the saline controls. This is uncharacteristic for vasodilating agents, such as nitroprusside and nitroglycerin. which typically raise ICP in the injured brain. The studies that we propose in this project will extend these studies into the secondary insult model, and examine in more detail how trauma alters nitric oxide metabolism. and how L-arginine ameliorates the situation. The 4 specific aims for the project are: 1. To study the effect of L-arginine and D-arginine on physiological, histological and behavioral measures after the 3m/sec impact injury complicate by a secondary insult. 2. To study the mechanism of the reduced CBF after traumatic brain injury and the L-arginine effect of increasing the reduced CBF. 3. To study the effect of timing of L-arginine dosage on behavior and histological outcome. 4. To study the effect of L-arginine infusion on endothelial and neuronal isoforms of NOS after TBI.
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