The endothelin receptor and axonal degeneration in a model of diffuse brain injury

TBI induces profound vasoreactive and neuronal injury changes. Endothelin-1 acting via its receptors A and B can mediate vasoconstriction and cerebral hypoperfusion. Axonal changes are marked by alterations in axonal transport and cytoskeleton proteins. However, studies related to the expression and distribution of ET-1 receptors A and B, the temporal profile of changes in proteins related to diffuse axonal injury following TBI are limited. Moreover, knowledge on the putative interaction between these co-pathologies is limited. Therefore, the aims of this dissertation research are to determine (1) The expression, regional and sub-cellular localization of ETrA and B post-TBI; (2) The temporal profile of DAI proteins (APP and tau); (3) The effects of selective ETrA antagonism on the expression of DAI proteins and on histological outcome of DAI. TBI was induced by an impact acceleration injury device in male Sprague Dawley rats. ETrA and B, APP and tau protein expression was characterized by western blot, immunocytochemistry and immunofluorescence. APP and tau WB was also performed to ascertain interaction between co-pathologies following the administration of selective ETrA antagonist, BQ123 (i.v, 1 mg/kg) in a separate group. While, DAI histology also was assessed in an additional group. ETrA and ETrB are present in blood vessels and neurons in non-injured and TBI brains. The immunocyto and fluorescence data reveals that, both the receptors are selectively up-regulated in neurons post-TBI and was supported by WB. ETrA also was upregulated in a sub-population of astrocytes. APP expression increased in sensorimotor cortex and hippocampus but decreased in corpus callosum with increasing survival time. However, Tau expression increased in all brain regions. Compared to control, ETrA antagonism with BQ123 did not significantly alter the expression of either protein in any of the brain regions and also resulted in a significant reduction of DAI in CC. The cellular shifts of the receptors appear to correlate temporally with changes in vasoreactivity suggesting a putative role for ETrA and B. The notion of co-pathology interaction in cell injury outcome post-TBI is also supported. As TBI induced vasorecativity may impinge on DAI, ETr modulation may provide amelioration in a clinical setting.