SPACE PROVIDED. Stroke is the third leading cause of death and the leading cause of adult disability in the United States. It especially targets the elderly population which experiences a higher overall incidence and neurological detriment as a result of stroke. As of yet, no widely successful treatments of stroke have been implemented. Thus, we emphasize the importance of examining the brain's own endogenous neuroprotective mechanisms in order to elucidate potential molecular pathways that may be the target of future therapeutic strategies particularly suited for the aged brain. NPD1, a derivative of DMA omega-3 fatty acid, is a lipid messenger shown to be anti-inflammatory and neuroprotective. It is produced in the brain in response to ischemia-reperfusion damage and has been shown to attenuate destruction of neurons resulting from oxidative cascades (Marcheselli et al.,2003). Because advanced age is a primary risk factor for stroke, this study will investigate the variation in NPD1 synthesis and utilization with respect to age. Our broad aim will be to trigger the brain's endogenous NPD1 synthesis pathways via a Middle Cerebral Artery occlusion (MCAo) model on young and aged Sprague- Dawley rats followed by neurobehavioral testing, quantification of NPD1 synthesis via HPLC-ESI-MS-MS lipidomic-based analysis, and immunohistochemical studies. Specifically, we will examine: 1) How does endogenous NPD1 synthesis vary with respect to age in response to MCAo? 2) To what degree does cerebrally infused NPD1 or DMA (NPDI's lipid precursor) rescue aged neurons from MCAo induced cell death and reduce infarct size? 3) What is the therapeutic window of protection for NPD1 infusion in aged brains? If NPD1 synthesis and utilization does in fact vary with age, it may prove to be a crucial factor resulting in the increased susceptibility of stroke in our aged population and, thus, NPD1 may be prove to be an optimal target for future stroke therapy. This research training experience will provide an opportunity to learn and master the MCAo surgery on young and aged rats, cardiac perfusion, mass spectrometer analysis on lipid extracts from whole brain, direct ventricular infusion of NPD1 and DMA, and H&E staining procedures to determine infarct volume.
|Eady, Tiffany N; Belayev, Ludmila; Khoutorova, Larissa et al. (2012) Docosahexaenoic acid signaling modulates cell survival in experimental ischemic stroke penumbra and initiates long-term repair in young and aged rats. PLoS One 7:e46151|
|Belayev, Ludmila; Khoutorova, Larissa; Atkins, Kristal D et al. (2011) Docosahexaenoic Acid therapy of experimental ischemic stroke. Transl Stroke Res 2:33-41|
|Niemoller, Tiffany D; Bazan, Nicolas G (2010) Docosahexaenoic acid neurolipidomics. Prostaglandins Other Lipid Mediat 91:85-9|