The aim of this research proposal is to examine whether alpha1-adrenergic receptors are involved in the secondary tissue death associated with experimental brain injury. The Fluid-Percussion Injury Model is an experimental model employed to understand the pathophysiology as well as the biochemical mechanisms associated with traumatic brain injury. The major biochemical events such as phospholipid degradation, proteolysis, free radical generation, and prostaglandin production are implicated in the neuronal death associated with central nervous system injury. It is likely that these biochemical changes are interrelated and arise, in part, from release or activation of endogenous """"""""autodestructive"""""""" pathophysiology factors such as excitatory amino acids (EAA) in response to trauma. Several in vitro and in vivo studies suggest the involvement of receptors and cellular second messengers, such as inositol trisphosphate (IP3), diacyl glycerol, protein kinase C (PKC), and Ca2+, between the pathophysiological factors and biochemical reactions. In contrast to EAA, the endogenous catecholamines thorough alpha-adrenergic receptor appears to protect neuronal damage associated with CNS injury. The long-term objective of the proposal is to (a) target alpha-adrenergic receptors in the treatment of experimental brain injury and (b) identify cellular second messengers and their biochemical responses to follow biochemical neuronal damage associated with traumatic brain injury. The main objectives of this research plan are to (1) evaluate the pharmacological targeting of alpha1-adrenergic receptor in traumatic brain injury by examining the histopathological, neurological motor and memory, and biochemical outcome of FP brain injury, after the administration alpha1 adrenergic receptor agonists and antagonists; (2) examine regional changes in the alpha1-adrenergic receptors, lactate acidosis, phospholipid degradation and levels of IP3, and PKC activities in the traumatized brain, (3) examine the action of alpha1-adrenergic agonists on the depolarization-dependent calcium uptake and degradation of phospholipids in brain slices isolated from traumatized animals. The results of these studies will reveal the involvement of alpha1-adrenergic receptors in secondary tissue death associated with traumatic brain injury, as well as the efficacy of alpha1-adrenergic receptor agonists in improving the neurological and memory functions, and neuronal death after traumatic brain injury. The results of these studies will also reveal (a) the timely appearance of biochemical neuronal damage in several regions of brain after FP brain injury, (b) the involvement of phospholipid degradation, cellular second messengers IP3 and PKC activation neuronal injury associated with trauma and (c) mechanisms such as peripheral cardiovascular action and cellular second messengers in alpha1-agonist and alpha1-receptor mediated outcome of brain injury.
