Elevated extracellular glutamate is known to play a central role in ischemic brain damage. The current proposal stems from key preliminary data demonstrating that induction of Glutamate Oxaloacetate Transaminase (iGOT) can metabolize extracellular glutamate ([Glu]o) via a truncated TCA cycle to sustain cell viability in the face of hypoglycemic challenge. Here, two strategies to achieve iGOT protection in the brain are employed. (1) Supplemental oxygen is used as a tool to study mechanisms of GOT induction. We propose that when supplemental oxygen is used to correct stroke-induced hypoxia while hypoglycemia remains, GOT metabolizes [Glu]o to serve as life-sustaining energy source for neural cells. (2) Biochanin A, a phytoestrogen isoflavone is investigated as a small molecule that induces GOT expression and protects against ischemic stroke injury in vivo. As a safe and natural dietary factor with an established track record of clinical testing for other indications (i.e. cholesterol lowering), biochanin A represents a therapeutic target that can quickly be translated to clinical study. The following three specific aims will be addressed:
Aim 1 : Identify endogenous and therapeutic pathways of GOT induction in neural cells.
Aim 2 : In vivo functional spectroscopy to characterize the significance of iGOT in handling brain tissue Gly, corresponding ATP levels and lesion volume at the stroke-affected site.
Aim 3 : Determine the neuroprotective efficacy of iGOT targeting therapy. The focus of the proposal is to address a central hypothesis which is conceptually innovative in highlighting the significance of iGOT on [Glu]o metabolism during ischemic stroke.
This proposal identifies therapeutic strategies to induce expression of an enzyme, Glutamate Oxaloacetate Transaminase (GOT), that can metabolize otherwise harmful glutamate at the site of ischemic brain injury. We hypothesize that GOT metabolism of glutamate protects neural cells from brain injury by two mechanisms: (1) reducing excitotoxic levels of extracellular glutamate caused by ischemic injury, (2) providing neurons an alternative source of energy in ischemic brain tissue challenged by hypoglycemia.