Inhibition of Constitutive Nitric Oxide Production Increases the Severity of Lipopolysaccharide-Induced Sickness Behaviour: A Role for TNF-α

Abstract

Administration of bacterial lipopolysaccharide (LPS) to rodents induces hypophagia, body weight loss and hypolocomotion, a constellation of symptoms collectively referred to as ‘sickness behaviour’. We examined the role of the gaseous transmitter nitric oxide (NO) in mediating LPS-induced sickness behaviour in rats. Treatment with the non-selective NO synthase (NOS) inhibitor N^G-nitro-L-arginine (L-NA) (20 mg/kg; i.p.) increased the severity of LPS-induced sickness behaviour in rats, suggesting that endogenous NO does not act as a mediator of LPS-induced sickness behaviour, but may rather have a protective role, acting in an inhibitory feedback manner to limit LPS-induced sickness. To evaluate the role of the different NOS isoforms in this response, we examined the effect of the neuronal NOS inhibitor, 7-nitroindazole (7-NI; 25 and 50 mg/kg; i.p.), and the inducible NOS inhibitor, aminoguanidine (AGN; 50 and 100 mg/kg; i.p.). Neither 7-NI nor AGN significantly altered LPS-induced sickness behaviour. Therefore, it is likely that the endothelial isoform of NOS mediates the effect of L-NA on LPS-induced sickness behaviour. As pro-inflammatory cytokines are mediators of LPS-induced sickness behaviour, we examined the effect of L-NA (20 mg/kg; i.p.) on LPS-induced interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α production. L-NA increased LPS-induced TNF-α without significantly altering IL-1β or IL-6 production. Moreover, pre-treatment with the TNF-α inhibitor pentoxyfilline (25 mg/kg; i.p.) largely reversed the augmenting effect of L-NA on LPS-induced sickness behaviour, suggesting that the ability of L-NA to increase TNF-α production underpinned its ability to increase the severity of sickness. In conclusion, L-NA increases the severity of LPS-induced sickness behaviour, most likely by blocking the tonic inhibitory action of constitutively produced NO on TNF-α production.

Propentofylline Prevents Sickness Behavior and Depressive-Like Behavior Induced by Lipopolysaccharide in Rats via Neuroinflammatory Pathway

“…DY510, Minneapolis, USA). TNF-α is considered a biomarker of sickness behavior [35, 40] and depression [11]. BDNF levels were determined using a Promega kit (cat.…”

Flavonoid-Rich Fraction of Ocimum gratissimum Attenuates Lipopolysaccharide-Induced Sickness Behavior, Inflammatory and Oxidative Stress in Mice

“…However, there are suggestions that constitutive nitric oxide does not act as mediator of LPS-induced sickness behavior but have a role in an inhibitory feedback manner to limit LPS-induced sickness behavior. It has been shown that only inhibitors of endothelial ni- tric oxide synthase (example, L-NA) increased the severity of LPS-induced sickness behavior while iNOS or nNOS inhibitors does not have the same properties [47]. Ribeiro et al, [26] provides further evidence to show that the synthesis of NO modulates changes in depressive-like and exploratory behaviors in mice.…”

Regulation of avoidant behaviors and pain by the anti-inflammatory tyrosine phosphatase SHP-1

“…This seems counter-intuitive because the behavioral effects of acute LPS treatment are mediated via type 1 pro-inflammatory cytokines (Bluthe et al, 2000a;Bluthe et al, 2000b;Connor et al, 2002). This seems counter-intuitive because the behavioral effects of acute LPS treatment are mediated via type 1 pro-inflammatory cytokines (Bluthe et al, 2000a;Bluthe et al, 2000b;Connor et al, 2002).…”