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

Abstract

BackgroundSystemic 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.MethodsTo 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.ResultsIncreased 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1186-5) contains supplementary material, which is available to authorized users.

<p>Selenium Nanoparticles Pre-Treatment Reverse Behavioral, Oxidative Damage, Neuronal Loss and Neurochemical Alterations in Pentylenetetrazole-Induced Epileptic Seizures in Mice</p>

“…Previous reports have demonstrated the development of inflammatory response in epileptic model. 7 , 62 The authors attributed this effect to the disturbance in the oxidative status and the overproduction of ROS which activates nuclear factor kappa B (NF-κB) resulting in the elevation in pro-inflammatory cytokines. Meanwhile, the SeNPs administration suppressed the inflammation in the hippocampal tissue.…”

Effects of Prolonged Dietary Curcumin Exposure on Skeletal Muscle Biochemical and Functional Responses of Aged Male Rats

“…The membranes were treated with chemiluminescent reagents (Bio-Rad) and imaged using a ChemiDoc XRS+ System and Image Lab Software (Bio-Rad). Protein is expressed relative to a loading control protein, glyceraldehyde 3-phosphate dehydrogenase ( GAPDH) (Cell Signaling Technology Danvers, MA, USA; RRID:AB_561053) [ 88 , 89 ] or β-actin (Santa Cruz Biotechnology; RRID:AB_626632) [ 90 , 91 ].…”

Reactive oxygen species in status epilepticus

“…Vasogenic oedema formation during status epilepticus has also been linked to endothelin B (ETB) receptor-mediated astrocytic ROS production through NADPH oxidase activation [43]. NADPH oxidase has also been identified as a pharmacological target for increased seizure susceptibility after systemic inflammation [44] and NADPH oxidase inhibition with apocynin has been shown to lead to ameliorate seizure-induced reduction of adult hippocampal neurogenesis [45]. However, the precise roles of different NOX isoforms subtypes in hyperexcitability, seizures and epilepsy are still unclear and await further studies using genetic ablation or isoform specific inhibitors.…”