How Can We Cure NO/ONOO- Cycle Diseases

The NO/ONOOcycle is a biochemical vicious cycle that is thought to cause such diseases as chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), multiple chemical sensitivity (MCS), fibromyalgia (FM) and possibly a large number of other chronic inflammatory diseases. The chemistry/biochemistry of the cycle predicts that the primary mechanism is local such the depending on where it is localized in the body, it may cause a variety of different diseases. Previous studies have shown that agents that lower such cycle elements as oxidative stress, nitric oxide, inflammatory responses, mitochondrial dysfunction, tetrahydrobiopterin (BH4) depletion and NMDA activity produce clinical improvements in CFS/ME and FM patients, consistent with the predictions of the cycle mechanism. Multiagent protocols lowering several aspects of the cycle appear to be the most promising approaches to therapy. These include an entirely over-the-counter nutritional support protocol developed by the author in conjunction with the Allergy Research Group. However such mulitagent protocols to date, have not produced any substantial numbers of cures of these presumed NO/ONOOcycle disease. Why is that? This paper argues that what is called the central couplet of the cycle, the reciprocal relation between peroxynitrite elevation and BH4 depletion, is not being adequately down-regulated by these multiagent protocols. Ten agents/classes of agents are available, each of which down-regulates one or the other end of this central couplet. It is suggested, then, that treatments that simultaneously effectively down regulate both ends to the central couplet, when used along with multiagent protocols lowering other aspects of the cycle and avoidance of stressors that otherwise up-regulate the cycle, will lead to substantial numbers of cures of these chronic diseases. The basic concept of the NO/ONOOvicious cycle mechanism is simple. It is that various short term stressors can initiate this cycle which, like all vicious cycles, propagates itself over time. The cycle then, depending on where it is located in the body, causes various chronic diseases. But in order to treat chronic diseases caused by the NO/ONOOcycle and hopefully cure them, one needs to understand the details of the cycle mechanism. And that is where things becomes much more complex. The NO/ONOOcycle is a primarily local biochemical vicious cycle that appears to be the central cause of such multisystem diseases as chronic fatigue syndrome/myalgic * The NO/ONOOcycle is named for two of its many elements, nitric oxide (NO) and peroxynitrite (ONOO-) and is pronounced no, oh no. encephalomyelitis (CFS/ME), multiple chemical sensitivity (MCS), fibromyalgia (FM) and post-traumatic stress disorder (PTSD) (1-7). Cases of all four of these share many symptoms and signs and are each highly variable from one patient to another (1-4). These diseases often occur together in specific patients, that is they are comorbid (1-4,6,7). The variations among different patients is explained by the primarily local nature of the cycle, such that the different tissue localization of the NO/ONOOcycle from one case to another produces different tissue impact and therefore different symptoms and often different diagnoses (1-3). The NO/ONOOcycle is diagrammed in Fig. 1. Each of the arrows shown in Fig. 1 represents one or more mechanisms by which one element of the cycle raises the levels of another cycle element. There are now a total of 30 specific mechanisms involved here, most of which are well documented, well accepted biochemistry and physiology (1-3). The three mechanisms that were least documented at the time my book was published (1) are now substantially better documented (2). Consequently, there is very little that is truly original about the NO/ONOOcycle mechanism, except that when taken together, the individual mechanisms act to produce multiple, interacting vicious cycles which explain the chronic nature of these diseases, the challenges in treating them and many other important features (1-7). Central to the cycle is the reaction of two free radicals in the body, nitric oxide with superoxide to form peroxynitrite (abbreviated PRN in Fig. 1). Peroxynitrite, a potent oxidant, produces oxidative stress (lower center, Fig. 1). On the right side of Fig. 1 are a number of inflammatory responses, including elevation of the transcription factor NF-kappa B, increased production of inflammatory cytokines (upper right box) and also induction of the inducible nitric oxide synthase (iNOS). These predict that much of the inflammatory cascade will be at least modestly elevated in NO/ONOOcycle diseases. Nitric oxide synthase activity may be elevated not only from iNOS induction but also from the calcium-dependent elevation of the other two nitric oxide synthases, nNOS and eNOS (upper center). Multiple mechanisms lead to increases in superoxide (center TRP rec NMDA Ca