Lipopolysaccharide-induced radical formation in the striatum is abolished in Nox2 gp91phox-deficient mice

Abstract

Encephalopathy associated with septic shock as well as psychiatric disorders can be caused by the central nervous formation of reactive oxygen species (ROS) associated with inflammation. The systemic application of lipopolysaccharide (LPS, 100 mug/kg i.p.) also serves as a model for major depression and results in enhanced inflammatory processes. which are characterized by the stimulation of microglia or macrophages that then impair normal brain function. The aim of the present study was to analyze the effect of peripherally applied LPS on the central nervous formation of ROS and IL-6 in wild-type mice and in mice lacking the NADPH oxidase Nox2 subunit gp91phox. Microdialysis was performed in the striatum of the mice. Central nervous ROS were detected by electron spin resonance spectroscopy using 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (CMH) as reactant, which was infused via a microdialysis probe. IL-6 was measured in microdialysis samples by an immunoassay. Finally, blood samples were taken by heart puncture to detect IL-6 in plasma. In the wild-type mice, LPS significantly increased the ROS formation in the striatum of wild-type mice and resulted in a significantly enhanced IL-6 production. In the mice lacking the NADPH oxidase Nox2 subunit gp91phox, LPS did not enhance ROS formation, while central IL-6 was significantly increased. IL-6 plasma values were enhanced in both types of mice. In conclusion, the gp91phox-containing NADPH oxidase complex is involved in the central nervous ROS formation after peripheral LPS stimulation and might be a pharmacological target in patients with septic shock.

Redox regulation of NF‐κB p50 and M1 polarization in microglia

“…Peripheral injection of LPS (5 mg/kg, IP) in NF-κB p50 +/+ and NF-κB p50 −/− adult mice was employed to determine how loss of NF-κB p50 function impacts the peripheral circulating cytokine response, the transfer of inflammation from the periphery to the brain, and the degree of M1 activation in the brain. Peripheral LPS administration rapidly stimulates circulating cytokine production, where cytokines cross the blood brain barrier, activate microglia in the substantia nigra pars compacta (SNpc) in the midbrain (Qin et al 2007), and elevate ROS production in the striatum (Clement et al 2010). As such, serum and midbrain measures of pro-inflammatory factors in the current study were assessed at 3 h after treatment.…”

The Use of Microdialysis in the Study of Encephalopathies

“…In the mice lacking NADPH oxidase Nox2 subunit gp91phox, LPS did not enhance ROS formation, whereas IL-6 increased. They conclude that gp91phox-containing NADPH oxidase complex was involved in the central nervous ROS formation after peripheral LPS stimulation and these results suggest that ROS determination could be a pharmacological target in patients with this pathological condition (Clement et al, 2010).…”

“…Clement et al (2010) analyzed the effect of peripherally applied lipopolysaccharide (LPS, 100 mug/kg i.p.) that is used as a model for major depression and results in enhanced inflammatory processes, on the central nervous formation of ROS and interleukin-6 (IL-6) in wild-type mice and in mice lacking NADPH oxidase Nox2 subunit gp91phox using microdialysis paradigm.…”

Alternative Intronic Polyadenylation Generates the Interleukin-6 Trans-signaling Inhibitor sgp130-E10

“…Construction of Expression Plasmids-To create expression plasmids for sgp130-E10, we amplified the corresponding cDNA with specific primers from the plasmid pcDNADEST40_gp130-EYFP (17). The novel C terminus of sgp130-E10 was introduced via the reverse primer.…”