Preserving Neurogenesis and Cognition with NSAID'S

Stanford University, Stanford CA

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Abstract

DESCRIPTION (provided by applicant): Cranial radiation therapy is associated with progressive deficits in cognitive function; particularly in children treated a very young age. Although cancer therapies can yield promisingly high cure rates, the quality of life after therapy declines and most children eventually require special education programs or even institutionalization. Hippocampal deficits in learning and memory are a predominant aspect of the cognitive decline and observations in animal models suggest that a chronic inflammatory response induced by irradiation may significantly contribute to hippocampal dysfunction. Adult neurogenesis in one aspect of normal hippocampal biology that is severely impacted by inflammation and recent work shows neurogenesis can be sheltered from these effects by oral administration of the non-steroidal anti-inflammatory drug (NSAID) indomethacin. Pilot studies show that hippocampal function is also normalized by indomethacin and the ease with which inflammation can be modulated with NSAIDs suggests that inflammatory blockade may have utility in sparing cognitive function following cranial radiotherapy. However, there may be risks associated with the use of indomethacin that might be avoided by more selective NSAIDs. The anti-inflammatory effects of Indomethacin are mediated via Cox-1, Cox-2 and PPAR(. Cox-1 inhibition also impairs platelets and the protective function of gastric mucosa. Since megakaryocytes and mucosal epithelium are also particularly sensitive to chemotherapy, concurrent Cox-1 inhibition could conceivably place a patient at higher risk of spontaneous and possibly life-threatening hemorrhage. The more selective inhibition of Cox-2 (celecoxib) and/or activation of PPAR( (rosiglitazone) may offer equally effective strategies that minimize risks associated with Cox-1 inhibition. Here we propose to evaluate these drugs in genetically manipulated mice to determine the relative importance of Cox-1, Cox-2 and PPARgamma in normalizing hippocampal function following inflammatory challenge.