Date of Graduation

2015

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Neurology

Committee Chair

James W Simpkins

Committee Co-Chair

Taura Barr

Committee Member

Paul Chantler

Committee Member

Valeriya Gritsenko

Committee Member

Xeufang Ren

Committee Member

Rosana Schafer

Abstract

TNF-alpha is known to exacerbate infarct volume in animal models and elevated levels of TNF-alpha are correlated with worse outcomes in stroke patients. However, the mechanism is not well understood. TNF-alpha has been shown to be neurotoxic at high doses and after long exposure times which is not clinically relevant. Thus, we show for the first time that TNF-alpha at clinically relevant concentrations seen in the serum of stroke patients rapidly and profoundly decreases mitochondrial function resulting in neuronal cell death through activation of caspase 8 and cytochrome c release. A slight decrease in mitochondrial function is detrimental to neurons due to their high energy demand. Since TNF-alpha is known to be increased during ischemia and correlated with negative outcomes, it is important to understand the neurotoxic mechanism of TNF-alpha to develop potential therapeutic targets for stroke. Moreover, TNF-alpha is increased during infections, and 30-40% of strokes occur during an active infection. We show that having a stroke during an active bacterial infection mimic results in an increased infarct volume, worsened neurological deficits, and prolonged sickness behavior. TNF-alpha's rapid and profound effect on mitochondrial function may be one mechanism by which stroke severity is exacerbated, neurological deficits are worsened, and recovery delayed. Thus, enhancing mitochondrial function acutely post-stroke could be a potential therapeutic intervention.

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