Traumatic brain injury (TBI) kills and disables more young people every year than any other cause. Decades of preclinical and clinical studies have not produced an effective medical treatment for TBI. Brain trauma initiates a series of sequelae that may result in secondary injuries long after the initial traumatic event. Secondary injuries worsen clinical outcomes and increase the brain's vulnerability to subsequent insults. Epidemiological evidence shows TBI to be a major risk factor for early onset dementia and progressive neurodegenerative disease. Thus, the cost to society is great for young and old alike. Unfortunately, the neuropathological mechanisms underlying these long lasting injuries are poorly understood. After brain injury, arachidonic acid is released from cell membranes and converted into many different bioactive eicosanoids. Vasoactive prostanoids formed early after injury appears to be adaptive, reducing bleeding in the brain or enhancing circulation. However, prolonged prostanoid formation produces excessive free radicals and has been associated with secondary injuries. Another set of arachidonic acid metabolites, cytochrome P450 (CYP) eicosanoids, are also increased in the injured brain. We recently have shown that an inhibitor of prostanoid synthesis improves recovery after TBI in a rat model. This drug does more than just reduce prostaglandins, it markedly increases P450 eicosanoids, epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs) in the injured brain. Selected EETs have antiinflammatory activities in vitro, and certain HETEs protect cultured neurons from glutamate-mediated excitotoxicity. We hypothesize that two P450 eicosanoids that exhibit potentially beneficial activities are elevated in brain regions associated with cognitive and neurological deficits after TBI. We will determine the contribution of these eicosanoids in reducing neuroinflammation, cell death, and promoting functional recovery after TBI.
Our first Aim i s to confirm that increased P450 eicosanoids improve functional recovery after TBI. We employ rodent models, using both pharmacologic and genetic manipulations to achieve conditions that favor (or limit) P450 eicosanoid formation.
Our second Aim i s to determine the specific P450 eicosanoids and CYP genes amplified in the injured brain, along with their neuroanatomical and temporal changes. To this end, we have developed a novel method to quantify trace levels of eicosanoids in milligram quantities of brain tissue.
Our third Aim i s to determine how increasing P450 eicosanoids improve neuroinflammation and cell death after TBI. These results will establish a new class of drugs that enhance P450 eicosanoid activity in the central nervous system, with the potential to improve outcomes in human brain injuries.
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