Nutritional Intervention And Modeling Of Acute Ischemic Stroke

by Rink, Cameron L.

This dissertation describes nutrient based interventions for risk factors and outcomes affecting acute ischemic stroke and the development of a robust pre-clinical stroke model. Objective: The objectives of this dissertation were three-fold: (i) To characterize a basis for nutritional intervention of acute ischemic stroke risk factors by using niacin-bound chromium in the prevention of metabolic syndrome; (ii) to determine the in vivo significance of the natural vitamin E, ?-tocotrienol (?T3), in neuroprotection following acute ischemic stroke; and (iii) to develop a pre-clinical model of acute ischemic stroke in a large animal setting to bridge the translational gap that exists between laboratory and clinical stroke research. Experimental approach and results: Prophylactic supplementation of niacin-bound chromium (NBC) complex significantly improved the lipid profile of obese mice exhibiting stroke risk factors associated with metabolic syndrome. Examination of the adipose tissue transcriptome using genome-wide microarray analysis revealed a myogenic response to NBC supplementation. Rodents subjected to acute ischemic stroke via middle cerebral artery occlusion (MCAO) had significantly reduced infarct volume when supplemented with the natural vitamin E ?T3 as compared to placebo controls. The mechanism of neuroprotection by ?T3 in cell culture study was related to inhibition of the cytosolic target 12-lipoxygenase (12-Lox). The active form of 12-Lox was reduced in stroke affected tissue of orally administered ?T3 rats as compared to placebo controls. 12-Lox metabolizes arachidonic acid into 12-S-hydroperoxyeicosatetraenoic acid (12-S-HPETE). The rate of respiration in isolated cortical mitochondria was inhibited by incubation with 12-S-HPETE. Furthermore,12-S-HPETE promoted mitochondrial dysfunction by reducing inner membrane potential, and exacerbating permeability transition pore opening (PTP). 12-S-HPETE induction of PTP was inhibited in isolated brain mitochondria by co-treating them with ?T3. Finally, we developed a minimally invasive, pre-clinical model of transient MCAO in canines which benefits from high inter-animal reproducibility due to the ability to visualize the occlusion event in real-time under guided c-arm fluoroscopy. Conclusions: This dissertation describes prospective nutritional interventions for stroke-related risk factors and stroke-induced infarction. Development of a pre-clinical model of stroke bridges the gap between laboratory benchwork and clinical study so that potential stroke therapeutics can be translated to the clinical setting.