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Effects of Inducible Nitric Oxide Production on the LPS-Induced Reduction in Wheel-Running Behavior in Mice

Yano, Hiromi1; Yoon, Patrick J.2; Lowder, Thomas W.2; Shiva, Daisuke1; Woods, Jeffrey A. FACSM2

Medicine & Science in Sports & Exercise: May 2004 - Volume 36 - Issue 5 - p S228–S229
Annual Meeting Abstracts: E-51 – Free Communication/Slide: Exercise Immunology II

1Department of Health and Sports Sciences, Kawasaki University of Medical Welfare, Kurashiki, Japan.

2Department of Kinesiology, University of Illinois at Urbana-Champaign, Urbana, IL.



One characteristic of sickness behavior is lethargy, in rodents this is demonstrated by a reduction in voluntary wheel running activity during infection. Evidence suggests that proinflammatory cytokines (e.g. IL-1, TNF-a), induced as a consequence of infection, may be responsible for this effect by acting on the brain. Lipopolysaccharide (LPS) is a component of gram-negative bacteria that induces sickness behavior and increases proinflammatory cytokines, however, LPS also activates macrophages to produce nitric oxide (NO), which plays an important role in inflammation and host-defense. NO's influence on sickness behavior has not been well characterized. PURPOSE: To determine whether LPS-induced NO production, mediated through toll-like receptor (TLR) 4 signaling, is responsible for reduced spontaneous physical activity. METHODS: We measured LPS-induced changes in voluntary wheel-running activity in both C3H/HeOuJ (LPS responsive) and C3H/HeJ (LPS unresponsive due to a mutation in the tlr4 gene) mice. Mice were also injected with the inducible nitric oxide synthase (iNOS) inhibitor L-canavanine (L-CN; 30mg/kg, i.v.), the macrophage inhibitor gadolinium chloride (GdCl3; 10mg/kg, i.v.), or saline, before and after LPS (1mg/kg, i.p.). RESULTS: Wheel-running activity in C3H/HeJ mice was maintained in spite of LPS injection, but activity in C3H/HeOuJ mice was significantly reduced from ∼5,800 m/day (prior to LPS) to 30 m/day and 1,700 m/day on the 2 days following LPS. Running wheel activity was fully recovered by Day 3. L-CN partially, but significantly attenuated the LPS-induced reduction in wheel running activity in C3H/HeOuJ mice (∼9–12%, p<0.01). Furthermore, GdCl3 treated C3H/HeOuJ mice also demonstrated a significant (∼9%, p<0.01) attenuation in the LPS-induced reduction in running activity. In vitro experiments revealed that peritoneal macrophage NO production was lower in C3H/HeJ when compared to C3H/HeOuJ mice (p<0.01). L-CN and GdCl3 treatment significantly inhibited LPS-induced peritoneal macrophage NO production in C3H/HeOuJ mice. CONCLUSIONS: Our results suggest that the transient reduction in physical activity after LPS injection is partially mediated by LPS-induced macrophage NO production, but other factors appear to play a major role. Supported by NIH AG-13928 to J.A. Woods

©2004The American College of Sports Medicine