Effects of protein-energy malnutrition on outcome from global cerebral ischemia

The goal of my thesis was to elucidate the impact of protein-energy malnutrition (PEM, a condition commonly found in aging stroke patients) on outcomes from global ischemia. I first examined the hypothesis that PEM will impair working memory in the adult gerbil as measured in the T-maze. Gerbils were fed an adequate (12.5%) or low protein (2%; PEM) diet for 6wk. Stringent assessment of T-maze performance indicated an improvement with PEM although I was unable to reconcile whether this was increased motivation for the food reward or enhanced working memory. The second hypothesis tested was PEM will decrease expression of plasticity-associated hippocampal mRNA and protein expression following global ischemia in the gerbil. The plasticity markers brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (trkB), and growth-associated protein-43 (GAP-43) were examined in the CA1 hippocampal region post-ischemia. PEM induced in gerbils for 4wk did not alter the global ischemia-induced decrease in CA1 neurons. Ischemia resulted in increased CA1 pyramidal expression of BDNF and trkB mRNA at 1, 3, and 7d post-ischemia and increased trkB protein expression at 3 and 7d. PEM further elevated the increased trkB protein detected at 7d in the fibres. Ischemia resulted in increased GAP-43 protein at 3 and 7d post-ischemia with PEM increasing this expression at 3d in the CA3 and hilar regions in addition to CA1. These findings suggest an increased stress-response and/or hyperexcitability state in the hippocampus of malnourished ischemic animals. Since the reliability of the gerbil model of global ischemia has come into question, the third part of my thesis tested the hypothesis that the influence of pre-existing PEM on global ischemia-induced hippocampal injury can be reliably studied with the 2-vessel occlusion rat model. The impact of PEM on CA1 neuronal death and dendritic damage was examined. Rats received protein adequate (18%) or deficient (2%; PEM) diet for 7-8d prior to global ischemia. PEM did not worsen the decrease in CA1 neurons and dendrites observed at 7d post-ischemia. Importantly, I found that PEM altered blood glucose and acid-base balance during surgery and caused brief hypothermia post-surgically, factors which are important for consistent brain injury. Taken together, these findings reveal (i) that nutritional care, although frequently ignored, can have robust effects on recovery mechanisms after brain ischemia; and (ii) the challenges of studying pre-existing PEM in an established rodent model of stroke