INHIBITION OF CPB-MEDIATED NEUROLOGICAL DYSFUNCTION

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DESCRIPTION (provided by applicant): Cerebral injury remains one of the most frequent and devastating complications of heart surgery, for which there is no known therapy. These injuries, ranging from stroke to cognitive dysfunction, are a long-term problem for a substantial percentage of patients undergoing cardiopulmonary bypass (CPB), resulting in lower quality of life, decreased likelihood of employment, and a substantial cost burden to patients, as well as the healthcare system. Evidence from clinical and experimental studies indicate that apolipoprotein E (apoE) attenuates central nervous system (CNS) response to injury by modulating glial activation and the associated release of glutamate, reactive oxygen species, and inflammatory cytokines which can exacerbate the primary neuronal injury. ApoE exerts direct neuroprotective effects as well. We have created and characterized a small peptide derived from the receptor-binding region of apoE (COG-133) and demonstrated, in vitro and in vivo, that it retains the neuroprotective properties exhibited by the holo-apoE protein. While, the exact mechanisms underlying CPB-induced neurological dysfunction are not clear, it has been demonstrated that CPB induces a systemic inflammatory response. Therefore, the neuroprotective properties of COG-133, its ability to down regulate the secretion of inflammatory cytokines in particular, make It a strong candidate for use as a therapeutic intervention in the arena of CPB-induced neurological dysfunction. We hypothesize that the apoE mimetic peptide, COG-133, will exhibit neuroprotective effects in the arena of cerebral injury stemming from cardiac surgery. We will use a repeated measures design in which we will examine the following endpoints for saline and COG-133 treated rats that have undergone CPB: neuromotor functioning, rotorod test, Morris Water Maze task, and fluoro-jade and glial fibrillary acidic protein staining of the hippocampus to examine degenerating neurons and astrocyte proliferation, respectively. Currently, there are no definitive neuroprotective agents available to prevent or treat cardiac surgery-related cerebral injuries. We believe that our apoE mimetic peptide represents a novel therapeutic strategy for the prevention and treatment of neurological dysfunction, thereby fulfilling a currently unmet medical need.