Nutritional Intervention And Modeling Of Acute Ischemic Stroke
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.
School:The Ohio State University
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:stroke metabolic syndrome chromium vitamin e tocotrienol tocopherol middle cerebral artery pre clinical model
Date of Publication:01/01/2008