Role of Tumor necrosis factor alpha (TNF- α) in Fctor alpha (TNF- α) Hippocampal Neurodegeneration
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 at 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 intranasally 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-1β, IL-6, IL-12, IL-10), Insulin-like growth factor-I (IGF-I), and nerve growth factor (NGF) were assessed. Hippocampal oxidative stress markers including malondialdehyde, nitric oxide, glutathione (GSH), catalase and superoxide dismutase (SOD) were evaluated. Immunohistochemical methods were 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 (P<0.001) and severe seizures (P<0.01). In EPM, TNF-α Ko mice showed changed risk assessment performance (P<0.01) especially at 30 days post KA. In open field test, TNF-α Ko mice showed significant hyperactivity at 3 and 30 days post KA treatment. 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-1β, 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-α Ko mice showed more severe oxidative stress (P<0.01), lower IGF-I levels (P<0.05), and higher levels of β-NGF (P<0.05) compared to Wt-mice. Hippocampal GSH levels were significantly elevated in Wt-mice but not in TNF-α Ko mice, while, catalase and SOD activity were elevated (P<0.001) 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 CA3 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 (P<0.01) in TNF-α Ko mice compared with Wt-mice. Additionally, KA-treatment significantly up-regulated NFκB expression at 5 days post KA in TNF-α Ko mice. Taken together, our findings showed that deficiency of TNF-α worsens KA-induced neurotoxicity. These results highlighted the protective effects of TNF-α in KA-induced neurotoxicity and suggested that these neuroprotective effects may be through the regulation of microglial activation, induction of antioxidant defensive mechanisms and regulation of the NFκB signaling pathway.