Abstracts

Rationale: Accumulated evidence suggests that neuroinflammation leads to increased neuronal excitability dominantly arising from microglia activation in CNS. NADPH oxidase complexes (NOX2) generating superoxide anion (O2-) is essential for microglia activation. We hypothesized that NOX2-derived neuroinflamation has a major impact on seizure susceptibility. Methods: We investigated the role of NOX2-based ROS in seizure susceptibility using p47phox and gp91phox-deficient mice as well as dpi, a NADPH oxidase inhibitor. Neuroinflammation was induced by LPS (4 mg/kg) intraperitoneal (i.p.) injection into male mice. Seizure susceptibility of mice was measured by administration of pentylenetetrazole (i.p.) at day 3 after LPS. To identify features of neuroinflammation in the CNS, brain tissues of the mice were obtained for assays of the pro-inflammatory factors, gene expression, and imunohistological staining for morphological changes of microglia. Results: The gp91phox-/-, and P47 -/- mice showed less susceptibility to PTZ seizures as well as subsequent microglia and astroglia activation than septic wt mice. We demonstrated that deletion of gp91phox and p47phox subunits attenuated seizure-associated proinflammatoy gene transcripts and protein expression in hippocampus. DPI pre- and post-treatment confirmed that NOX-based ROS significantly attenuated increased seizure susceptibility to PTZ at dose of 0.1 and 1 mg/kg in a concentration dependent manner. Conclusions: We showed that NOX2 plays a critical role in the modulation of seizure susceptibility to the convulsant in mice after LPS. Microglia became activated and expressed seizure-related cytokine depending on NOX2-dependent redox state of microenvironment. Pharmacologic inhibition of NOX2 represents a promising therapeutic approach to reduce sepsis-associated neuroinflammation and subsequent seizure development. Funding: NSC104WHK2750031