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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

NADPH oxidases as potential pharmacological targets against increased seizure susceptibility after systemic inflammation

Authors: Wan-Yu Huang, Shankung Lin, Hsuan-Ying Chen, Ya-Ping Chen, Ting-Yu Chen, Kuei-Sen Hsu, Hung-Ming Wu

Published in: Journal of Neuroinflammation | Issue 1/2018

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Abstract

Background

Systemic inflammation associated with sepsis can induce neuronal hyperexcitability, leading to enhanced seizure predisposition and occurrence. Brain microglia are rapidly activated in response to systemic inflammation and, in this activated state, release multiple cytokines and signaling factors that amplify the inflammatory response and increase neuronal excitability. NADPH oxidase (NOX) enzymes promote microglial activation through the generation of reactive oxygen species (ROS), such as superoxide anion. We hypothesized that NOX isoforms, particularly NOX2, are potential targets for prevention of sepsis-associated seizures.

Methods

To reduce NADPH oxidase 2-derived ROS production, mice with deficits of NOX regulatory subunit/NOX2 organizer p47phox (p47phox−/−) or NOX2 major subunit gp91phox (gp91phox−/−) were used or the NOX2-selective inhibitor diphenyleneiodonium (DPI) was used to treat wild-type (WT) mice. Systemic inflammation was induced by intraperitoneal injection of lipopolysaccharide (LPS). Seizure susceptibility was compared among mouse groups in response to intraperitoneal injection of pentylenetetrazole (PTZ). Brain tissues were assayed for proinflammatory gene and protein expression, and immunofluorescence staining was used to estimate the proportion of activated microglia.

Results

Increased susceptibility to PTZ-induced seizures following sepsis was significantly attenuated in gp91phox−/− and p47phox−/− mice compared with WT mice. Both gp91phox−/− and p47phox−/− mice exhibited reduced microglia activation and lower brain induction of multiple proconvulsive cytokines, including TNFα, IL-1β, IL-6, and CCL2, compared with WT mice. Administration of DPI following LPS injection significantly attenuated the increased susceptibility to PTZ-induced seizures and reduced both microglia activation and brain proconvulsive cytokine concentrations compared with vehicle-treated controls. DPI also inhibited the upregulation of gp91phox transcripts following LPS injection.

Conclusions

Our results indicate that NADPH oxidases contribute to the development of increased seizure susceptibility in mice after sepsis. Pharmacologic inhibition of NOX may be a promising therapeutic approach to reducing sepsis-associated neuroinflammation, neuronal hyperexcitability, and seizures.
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Metadata
Title
NADPH oxidases as potential pharmacological targets against increased seizure susceptibility after systemic inflammation
Authors
Wan-Yu Huang
Shankung Lin
Hsuan-Ying Chen
Ya-Ping Chen
Ting-Yu Chen
Kuei-Sen Hsu
Hung-Ming Wu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1186-5

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