These studies are a continuation and extension of investigations initiated in the Brain Trauma Center feasibility grant, which has been active for 2 years. During this period we have successfully addressed and extended the specific aims of the initial grant and have found in humans: 1) marked upregulation of interleukin-1Beta (IL, 1Beta) in the SCF following head injury; 2) remarkable suppression of IL-1Beta in CSF under conditions of moderate hypothermia. Utilizing two rat models of traumatic brain injury (TBeta1; the Lighthall cortical confusion and weight drop) we have found: 1) A marked elevation in IL-1Beta RNA in cortical tissue, 2) A marked elevation of nerve growth factor (NGF) and NGF RNA in cortical tissue; 3) Total suppression of the elevation of NGF and NGF RNA by 4 hours of post-trauma hypothermia; 4) Suppression of the NGF response by administration of IL-1Beta receptor antagonist protein (IRAP), suggesting that IL-1Beta mediates NGF expression after trauma. Based on our findings, the proposed studies will examine IL-1Beta, NGF, and the NGF receptor, p75NGFR in the Lighthall model of rat TBeta1, and assess the therapeutic value of several intervention therapies. We will assess the effects of TBeta1 on the time course of expression of IL-1Beta RNA in the rat brain, and the effect of specific interventions on this time course; post-trauma hypothermia, administration of IRAP or interleukin-4 (IL-4) via implantation of protein-secreting transfected fibroblasts, and combination of hypothermia and either IRAP or IL-4 therapy. We will also determine the time course of expression of NGF protein and RNA and p75NGFR RNA in the cortex following cortical confusion. We will also employ the four therapeutic strategies used in the IL-1Beta studies, to determine their efforts on NGF/p75NGFR expression following TBeta1, and explore the mechanisms relating cytokine expression and NGF regulation. We will also explore the hypothesis that upregulation of NGF, following trauma, induces increased antioxidant enzyme activity by measuring the antioxidant enzymes glutathione peroxidase, glutathione reductase, catalase, and superoxide dismutase following TBeta1. Furthermore, we will examine the effect of purified NGF protein injected into the cortex and hippocampus on the production of the same antioxidant enzymes and employ the four therapeutic strategies used above to investigate the relationship among IL,-1Beta, NGF, and the induction of antioxidant enzymes. Finally, we will assess cerebral edema and lesion volume utilizing the TBeta1 model with and without the interventions outlined above. We will determine the capability of magnetic resonance imaging (MRI) to non-invasively measure these changes, comparing MRI measurements to traditional histological determinants of brain water and lesion size. This in vivo methodology should enable us to develop a model for rapid reliable assessment of TBeta1 interventions in fewer animals (each animal will be assessed at multiple time points) without the confound of interanimal variations and cohort differences. Collaborations will extend these studies of NGF and IL-1Beta to other inflammatory cascades and reactive oxygen species in secondary injury.
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