The long-term objective of this proposal is improved therapy for traumatic brain injury. Fluid percussion (FP) brain injury model produces several of pathophysiologic, morphologic and neurologic changes observed in closed human injury. The neurochemical and pharmacological studies in the experimental brain injury indicate that excitatory neurotransmitters such as amino acids and acetyl choline through overactivation of their receptors contribute to secondary neuronal damage and associated neurologic motor and cognitive (behavioral) deficits. The immediate goal of this application is to determine if these excitatory neurotransmitter receptor-coupled phospholipase and leukotriene C4 are involved in the pathophysiology of traumatic brain injury in the rat. We have recently shown that lateral FP brain injury in the rat activates 1) phospholipase C activity on phosphatidylinositol-bisphosphate (PIP2) and generate cellular second messengers, which can produce secondary injury factors through calcium and activation of protein kinase C (PKC), and 2) phospholipase A2 activity on the other membrane phospholipids that generate secondary injury factors such as arachidonic acid and leukotrienes.
The specific aims of this application are to determine in the lateral FP brain injury in the rat: 1) if the activations of phospholipase C activity of PIP2 and phospholipase A2 on the other membrane phospholipides correlate with the blood brain barrier (BBB) breakdown and with neuronal loss in the cortex and CA3 region of the hippocampus (morphologic damage) after brain injury, 2) if specific blockade of phospholipase C activity reduces morphologic damage and BBB breakdown, and improves behavioral outcome of brain injury, 3) if specific blockade of phospholipase A2 activity reduces morphologic damage and BBB breakdown, and improves behavioral outcome of brain injury, and 4) if specific blockade of leukotrienes C4 synthesis improves behavioral outcome of brain injury. Another goal of this application is to determine if the activation of PIP2 is involved in the glutamate-induced neuronal death in an in vitro model of primary cortical neuron culture. Measurements of substrates and metabolic products of phospholipase C and A2 activities, leukotriene C4 and PKC activity, neurologic motor and cognitive functions, and morphologic analysis of brain are the tolls to be used in the current proposal. Completion of these studies will increase our understanding of the potentially harmful metabolic events of phospholipase C, phospholipase A2, and leukotrienes C4 after FP brain injury leading to improved therapies to limit neurologic motor and cognitive dysfunction.
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