INVOLVEMENT OF THE ENDOTHELIN RECEPTOR SUBTYPE-A IN NEURONAL PATHOGENESIS AFTER TRAUMATIC BRAIN INJURY

Endothelin-1 (ET-1) is a 21 amino acid peptide that has been closely l inked to cerebral vasospasm and more recently to oxidative stress afte r traumatic brain injury. In this study, we have examined the effects of the endothelin receptor subtype A antagonist, Ro 61-1790, on acute cortical neuronal injury and delayed neuronal death in the cerebellum after mild traumatic brain injury. Rats were administered Ro 61-1790 o r vehicle for 24 h after injury and euthanized at 1 day, 3 days, or 7 days. Heat shock protein70 (HSP70), a marker of neuronal stress/injury , was immunolocalized in the cortex. Induction of heme oxygenase-1 (HO -1) and enhanced immunoexpression of the complement C3bi receptor, bot h of which are indicators of cerebellar glial reactivity, and Purkinje cell loss were evaluated in the cerebellum. There was maximal inducti on of HSP70 in cortical neurons at 24 h postinjury in all animals. Dru g treated animals showed significantly fewer HSP70 labeled cortical ne urons at this time point. There were fewer reactive glia in the cerebe llum of drug treated animals as compared to vehicle controls at 3 days postinjury. However, at 7 days postinjury glial reactivity and Purkin je cell loss were similar in both groups. These findings demonstrate t hat Ro 61-1790, when administered for the first 24 h postinjury, limit s acute neuronal injury in the cortex, transiently influences glial re activity in the cerebellum, and does not attenuate delayed Purkinje ce ll death. The latter finding may reflect the duration of infusion of t he drug. (C) 1998 Elsevier Science B.V. All rights reserved.