Injury to the brain caused by cerebral ischemia (i.e. stroke) is a major public health concern. Studies have determined that the brain damage associated with cerebral ischemia is mediated by over-stimulation of excitatory amino acid receptors, oxidative stress, as well as inflammatory factors. Preliminary results obtained during the last/current grant period as well as supporting data from the literature demonstrate a link between leukocyte-type 12/15 lipoxygenase (L-12/15 LO) activation in cerebral ischemic neuronal injury in vivo and oxidative stress-induced neuronal injury in vitro. Thus, the objectives of this following 5 yr research plan of study are as follows: 1) To determine the extent to which L-12/15 LO is involved in cerebral ischemic injury. Animals genetically null for L-12/15 LO and those genetically engineered to over-express L-12/15 LO will be used to determine its contribution to cerebral ischemic damage over a detailed time course. 2) To determine whether the decreased susceptibility of L-12/15 LO null mutants to cerebral ischemic damage results from a change in cerebrovasculature function and/or a reduction in glutamate receptor-mediated damage. To assess the former, relative and absolute regional cerebral blood flow changes occurring during and at end-stage cerebral ischemia will be measured to determine whether L-12/15 LO animals (null mutants and over-expressers) sustain a similar intra-ischemic insult as compared to wild-type mice. To assess the latter, a comparison of the damage induced by direct microinjection of NMDA into brain parenchyma between L- 12/15 LO animals and wild-type controls will be made. 3) To identify an orally active, pharmacological inhibitor of the L-12/15-LO pathway for the treatment cerebral ischemic damage. Using structurally distinct, proprietary lipoxygenase inhibitors developed by Onconova Therapeutics, studies will be undertaken to identify compounds that effectively prevent injury induced by middle cerebral artery occlusion (MCAo) and/or direct hippocampal injection of NMDA as well as to elucidate their therapeutic time window. Results from this study will elucidate the contribution of L-12/15 LO to cerebral ischemic damage and could aid in the development of a novel stroke therapeutic.
Morbidity associated with stroke remains a huge emotional and economic burden due in large part to a void in treatment options to protect against secondary injury. It is our contention that successful completion of this proposal will advance and refine our knowledge about an important new therapeutic target (L-12/15 LO) that complements other ongoing efforts to reduce injury following cerebral ischemic insult.
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