Influence of Orexinergic System on Survival in Septic Rats

Abstract

Background: The orexinergic (OXergic) system contributes to the defense system. It has also been reported that the degeneration of OXergic neurons occurs during sepsis. Thus, the decline of OXergic activity may contribute to impairment of the defense system in sepsis. In this study, we determined whether: (i) lipopolysaccharide (LPS) reduces the brain orexin A (OXA) content and (ii) the OXergic system contributes to survival from sepsis in rats. Methods: With approval of our protocol by our University Animal Ethics Committee, OX neuron-ablated (OX/ataxin-3 transgenic [OX/AT3 TG]) and wild-type Sprague-Dawley rats, weighing 250–350 g, were used. LPS (10 mg/kg) was administered intraperitonally to the wild-type rats (group SD, n = 26) and OX/AT3 TG rats (group TG, n = 14). Another 7 SD rats were included as a saline control (group C). Survival analysis was then performed over a period of 3 days. All surviving rats were decapitated and the brain OXA contents (from the cerebrocortex, hippocampus, hypothalamus, and pons) were quantified using ELISA kits. Results: In group SD, 61.5% rats survived, while in group TG, only 21.4% survived (p < 0.05). LPS significantly reduced OXA content (pg/mg of tissue) in group SD (2.92 ± 0.38) compared to in group C (4.10 ± 1.21) in the pons (p < 0.05). OXA content in group TG was substantially lower than in group C and group SD in all brain regions. Conclusions: LPS significantly reduced OXA contents in the pons which contains the locus coeruleus to regulate sympathetic activity in the defense system.

Plasma orexin A does not reflect severity of illness in the intensive care units patients with systemic inflammation

“…The OXergic neurons could degenerate by neuroinflammation with the decline of OXergic activity, which may partly characterize the symptoms of sepsis [ 12 ]. Indeed, we recently found that LPS significantly reduced OXA contents in the pons containing the locus coeruleus which may impair sympathetic nervous system [ 9 ]. Several reports [ 13 , 14 ] suggest that plasma OXA may reflect OXergic activity.…”

“…In addition, recent animal studies showed that inflammation degenerate orexin (OX) neurons and reduce OXergic activity [ 6 – 8 ]. Indeed, we found that lipopolysaccharide (LPS) significantly reduces OXA content in the pons and there was a good correlation between OXA content in the pons and survival rate of rats [ 9 ]. We previously suggested that plasma OXA may reflect neuronal OXergic activity because of significant increases in plasma OXA at emergence from general anesthesia.…”

Orexins as Novel Therapeutic Targets in Inflammatory and Neurodegenerative Diseases

“…Other reports indicate that LPS or TNFα (a major cytokine involved in septic shock) were also able to suppress orexin neuronal activity (159). More recently, the use of orexin-neuron ablated mouse model (OX/ataxin-3 transgenic mouse model) injected with LPS revealed a high mortality rate as compared to wild type mice (160). Moreover, the injection of LPS in wild type mice reduced OXA tissue content compared to untreated mice (160).…”

“…More recently, the use of orexin-neuron ablated mouse model (OX/ataxin-3 transgenic mouse model) injected with LPS revealed a high mortality rate as compared to wild type mice (160). Moreover, the injection of LPS in wild type mice reduced OXA tissue content compared to untreated mice (160). Yanagisawa's group had clearly shown that the subcutaneous diffusion of OXA using an osmotic pump in LPS-induced endotoxin shock mice improve the survival of these mice (77).…”