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SARA SHAABAN SHARKAWI SAYED
Department of Pharmacology
College of Medicine and Health Sciences
Title
Role of Tumor Necrosis Factor Alpha (TNF-α) in Hippocampal Neurodegeneration
Faculty Advisor
Prof. Abdu Adem
Defense Date
2 May 2016
Abstract
Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine with homeostatic and pathological
roles in the central nervous system. Previous studies suggested a neuroprotective role for TNF-α
mediated through TNF-receptor1. The main objective of this dissertation is to study the role of TNF-α
in kainic acid (KA)-induced neurotoxicity and to find out a possible mechanism(s) underlying its effects.
Compared with wild-type (Wt-mice), TNF-α knockout (TNF-Ko) mice were more susceptible to KA-induced
neurotoxicity, showing more severe seizures, measurable behavior changes and greater hippocampal
neurodegeneration. Neuroinflammation was evident by increased hippocampal IL-1β, IL-6 and IL-12 levels
and decreased IL-10 levels. TNF-Ko mice hippocampi showed more oxidative stress, lower IGF-I, and
higher β-NGF levels compared to Wt-mice. GSH was elevated only in Wt-mice, while catalase and SOD
were elevated more in TNF-Ko mice. Hippocampal microglial activation and astrogliosis were enhanced in
TNF-Ko mice. Additionally, the expression of hippocampal NFκB was significantly up-regulated in TNF-Ko
mice. Altogether, this study showed that deficiency of TNF-α worsens KA-induced neurotoxicity resulting
in uncontrolled oxidative stress, glial over-activation, lack of neuroprotective mechanisms and results
in a vicious cycle of chronic neuroinflammation, oxidative stress and neurodegeneration. These results
highlighted the protective effects of TNF-α in KA-induced neurotoxicity that may be mediated via the
regulation of NFκB signaling pathway.
Dissertation