FK866 an inhibitor of the pro-inflammatory cytokine visfatin attenuates pain and inflammation in a rodent model of acute inflammation and obesity

N. Alorfi, S. Dolan. Glasgow Caledonian University, Glasgow, UNITED KINGDOM.

Introduction: Nicotinamide phosphoribosyltransferase (Nampt)-derived nicotinamide adenine dinucleotide (NAD+) promotes inflammation by sustaining immune cell viability and promoting cytokine production.1 Pharmacological inhibition of Nampt blocks activity of the pro-inflammatory cytokine visfatin, which has also been linked to inflammatory conditions such as pain and obesity.2,3,4 The aim of this study was to determine whether treatment with the visfatin inhibitor, FK866, has any anti-inflammatory and/or analgesic effects in normal and obese rats.

Method: The effect of intraperitoneal (i.p.) injection of FK866 (3, 10 mg/kg) or vehicle on carrageenan (3%)-induced thermal and mechanical hyperalgesia and paw oedema was measured in: 1) adult male Wistar rats (n = 6-8/group) fed a normal diet (2.9% of fat), and 2) adult male Wistar rats (n = 6/group) fed a high fat diet (HFD; 22% fat) for 12 weeks (an established model of obesity).

Results: Carrageenan induced significant thermal and mechanical hyperalgesia and paw oedema in the injected paw in vehicle treated animals. Pre-administration of FK866 (10 mg/kg) significantly attenuated thermal and mechanical hyperalgesia at 6 hours (P < 0.05 vs. vehicle) and reduced paw oedema (P < 0.05 vs. vehicle). Obese rats displayed potentiated mechanical and thermal hyperalgesia, and paw oedema (all P < 0.05) compared to rats fed a normal diet. Pre-administration of FK866 (10 mg/kg) to obese rats significantly attenuated mechanical hyperalgesia, and paw oedema (both P < 0.05 vs. HFD + vehicle group), restoring potentiated responses to normal levels (p > 0.05 vs. rats fed a normal diet + vehicle).

Conclusion: These data show that FK866 has powerful anti-inflammatory and analgesic properties at higher dose, suggesting that visfatin plays a crucial role in inflammatory pain. The potentiated response to pain and inflammation obsedved in obese rats fits well with the hypothesis that obesity is a chronic low-grade inflammatory disorder. The reversal of this effect by blocking visfatin indicates a key role for this cytokine in pain pathogenesis with obesity.

References:

1. Montecucco F et al. (2013). Antioxidants & redox signaling 18.6: 630-641.

2. Busso N et al. (2008). PloS one 3.5: e2267

3. Revollo JR et al. (2007). Current opinion in gastroenterology 23.2: 164-170 4. Sethi, J et al. (2005). Trends in molecular medicine, 11(8): 44-347.