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Re: Melatonin suppression may not be a promising therapeutic option for the treatment of RA

Dear Editor,

The article, "Circadian Rhythms in RA" postulates a dynamic equilibrium between melatonin and cortisol as at least part of the etiology of rheumatoid arthritis. The authors note that the clinical symptoms of pain and stiffness seem to peak around 5:00 o'clock in the morning and that this coincides with the diurnal rhythms of melatonin and cortisol. Because melatonin enhances inflammatory cytokine and nitric oxide production, they suggest that inhibitors of melatonin or melatonin antagonists should be considered as possible therapeutic tools.[1]

Another variable that changes throughout the sleep cycle is regional cerebral blood flow. The lowest absolute cerebral blood flow values occur during REM sleep towards the end of the sleep cycle.[2] Nitric oxide release causes the depressed cerebral blood flow. It can persist for several hours.[3] Nitric oxide synthase inhibition abolishes sleep-wake differences in cerebral circulation.[4]

Nitric oxide release correlates with disease activity in patients with rheumatoid arthritis.[5] Additionally, nitric oxide synthase inhibitors are currently under consideration for the treatment of the pain associated with rheumatoid arthritis.[6]

On the other hand, melatonin and its precursors scavenge nitric oxide.[7] Thus, it would seem that any therapeutic benefit achieved by suppressing melatonin would be reduced, if not eliminated, by the loss of the nitric oxygen scavenging ability of endogenous melatonin production on the nitric oxide released during the sleep cycle.

References

1. Cutolo M, Seriolo B, Craviotto C, Pizzorni C, Sulli A. Circadian Rhythms in RA. Ann. Rheum. Dis 2003; 63:593-596.

2. Braun A, Balkin T, Wesenten N, et al. Regional cerebral blood flow throughout the sleep-wake cycle. An H2 (15) O PET study. Brain, 120:1173- 97.

3. Lauritzen M. Cerebral blood flow in migraine and cortical spreading depression. Acta Neurol Scand Suppl.1987; 113:1-40.

4. Zoccoli G, Grant D, Wild J. et al. Nitric oxide inhibition abolishes sleep-wake differences in cerebral circulation 2001. Am J Physiol Heart Circ Physiol, 280 Issue 6, H2598-2606.

5. St Clair EW, Wilkinson WE, Lang T. et al. Increased expression of blood mononuclear cell nitric oxide synthase type 2 in rheumatoid arthritis patients. J Exp Med. 1996 Sep 1; 184(3):1173-8.

6. Nakamura H, Ueki Y, Sakito S, Matsumoto K. et al. Clinical effects of actarit in rheumatoid arthritis: improvement of early disease activity mediated by reduction of serum concentrations of nitric oxide. Clin Exp Rheumatol. 2000; 18(4):445-50.