| Summary: | 博士 === 國立中山大學 === 生物科學系研究所 === 103 === Epilepsy is a common neurological disorder. Neuroinflammation is involved in the pathophysiology of epilepsy. Tissue oxidative stress is another confounding factor in epilepsy. While both neuroinflammation and brain oxidative stress are involved, relationship between these two factors in epileptogenesis, however, is not fully understood. In this study, I investigated the relationship and the underlying molecular mechanism.
In aim 1, I established a rodent model of chronic neuroinflammation via peripheral inflammation induced by continuous infusion of E. coli lipopolysaccharide (LPS; 2.5 mg/kg/day) in the peritoneum for 7 or 14 days. Results showed an increased proinflammatory cytokines level, including IL-1β, IL-6 and TNF-α in plasma and various areas of brain (frontal lobe, temporal lobe, hippocampus, striatum, rostral ventrolateral medulla (RVLM), nucleus tractus solitarii (NTS)), increased number of the activated microglia in brain and sensitivity to induction of seizure by KA (KA, 10 mg/kg) injection. Based on these findings, I focused my study on the hippocampus, which is associated with temporal lobe epilepsy, a common form of epilepsy in human. Pharmacological agents were delivered via intracerebroventricular infusion with an osmotic minipump in chronic neuroinflammation model for 7 days.
In aim 2, a cycloxygenase-2 inhibitor, NS398 (5 μg/μl/h), was used to study the relationship between neuroinflammation and tissue oxidative stress in seizure susceptibility after the LPS-induced peripheral inflammation. The results showed that NS398 significantly blunted the increase in microglia activation, production of proinflammatory cytokines, and tissue oxidative stress (upregulations of the NADPH oxidase subunits) in the hippocampus. The same treatment also ameliorated the increase in seizure susceptibility in the KA-induced seizure model.
In aim 3, a reactive oxygen species scavenger, tempol (2.5 μg/μl/h), was used to study the relationship between neuroinflammation and oxidative stress in the increase in seizure susceptibility under peripheral inflammation. The results showed that tempol did not blunt the increase in activated microglia, production of proinflammatory cytokines, but significantly blunted tissue oxidative stress (upregulations of the NADPH oxidase subunits) in the hippocampus and ameliorated the increase in seizure susceptibility in the KA-induced seizure model.
These results indicated that peripheral inflammation evoked neuroinflammation and the subsequent oxidative stress in the hippocampus, resulting in the increase seizure susceptibility. Moreover, protection from neuroinflammation and oxidative stress in the hippocampus exerted beneficial effect on seizure susceptibility following peripheral inflammation.
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