Date of Award

5-2016

Document Type

Dissertation

Degree Name

Doctor of Psychology (PsyD)

Department

Medical Education

First Advisor

Prof. Abdu Adem

Second Advisor

Abderrahim Nemmar

Third Advisor

Dr. Shreesh K. Ojha

Abstract

Tumor necrosis factor alpha (TNF= α) is a proinflammatory cytokine with homeostatic and pathological roles in the central nervous system. The main objective of this dissertation is to study the impact of presence and absence of TNF – α on kainic acid (KA) - induced neurotoxicity a several time points (0.5 and 4 hr. as well as 1.3, 5.15 and 30 days) to find out the possible mechanisms underlying its effects. KA (40) mg/kg) was given intranasal to TNF – α knockout (KO) mice and C57BL/6 wild-type (Wt.) mice Seizure severity was scored and behavioral tests including Elevated plus maze (EPM) open –field and Y-maze were performed . The hippocampal levels of cytokines (IL- Iβ-IL-6, I2, IL-10). Insulin like growth factor –I (IGP-I) and nerve growth factor (NGF) were assessed. Hippocampal oxidative stress makers including malondialdehyde. Nitric oxide glutathione (GSH) catalase and superoxide dismutase (SOD) were evaluated immunohistochemical methods used to assess neurodegeneration and glial activation

Compared with Wt-mice TNF- α Ko mice were more susceptible to KA- induced neurotoxicity by showing rapid onset (Р < 0.001)and severe seizures (Р < 0. 01) IN EPM. TNF- α Ko mice showed changed risk assessment performance (Р

In the Y-maze at 30 days, post KA. TNF- α Ko mice showed significantly lower percent alternation compared to the respective KA –treated WT- mice increased levels of proinflammatory cytokines (IL –Iβ. IL 6 and IL 12) as well as decreased levels of anti-inflammatory cytokines (IL- 10) were observed in both strains following KA- treatment. KA treated TNF Ko mice showed more severe oxidative stress (Р < 0.01). Lower IGF-1 levels (РAnd higher levels of (β-NGF (Р compared to WT-mice. Hippocampal GSH levels were significantly elevated in WT mice but not in TNF- α KO mice. Hippocampal microglial activation and astrogliosis were significantly enhanced and persisted up to 30 days in TNF –α Ko mice compared with WT-mice moreover significant hippocampal CA# neurodegeneration was

Observed 3 days post KA- treatment in both TNF-α Ko and Wt.-mice compared to controls. The neurodegeneration was progressive and more significant (Р

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