EVIDENCE FOR THE INVOLVEMENT OF CORTICOTROPIN-RELEASING HORMONE IN THE PATHOGENESIS OF TRAUMATIC BRAIN INJURY

The aim of this study was to investigate the role of the neuropeptide corticotrophin-releasing hormone (CRH) in neurodegeneration induced by traumatic brain injury, using a well characterized model of lateral f luid percussion injury in male, Sprague-Dawley rats. In the first seri es of experiments, CRH gene expression was assessed by in situ hybridi zation after traumatic brain injury, A bilateral increase in CRH mRNA in the paraventricular nucleus was observed in rats subjected to traum atic brain injury compared with sham-operated controls, A maximal (40% ) increase in hybridization signal was detected 2 h after trauma compa red with control rat brains. In addition, marked induction of CRH tran scripts was found in the ipsilateral amygdala after trauma, but no inc rease was detected in the ipsilateral cortex around the area of damage . In a separate experiment, the effects of the CRH antagonist, D-Phe C RH(12-41) (25 mu g total dose), or appropriate vehicle injected intrac erebroventricularly, was tested on infarct volume caused by brain inju ry. Repeated intracerebroventricular injection of D-Phe CRH(12-41) sig nificantly reduced, by 45%, the volume of cortical damage in injured r ats compared with vehicle-treated, trauma animals. The rapid upregulat ion of CRH gene expression in the paraventricular nucleus and amygdala following lateral fluid percussion injury and the marked neuroprotect ion achieved by inhibiting CRH action suggest that CRH is involved dir ectly in the pathogenesis of traumatic brain injury. This observation may have important implications for the development of novel therapeut ic strategies for treating the neurological consequences of brain trau ma and related conditions.