Abstract
Cobalamins are vit.B12 compounds which differ for the cobalt-linked ligand: methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) are the biochemical active compounds. Vit.B12 is present in the plasma as MeCbl, 5′deoxyAdoCbl, and hydroxoCbl.
The actions of vit.B12 are several, some still unknown. HydroxoCbl has clear scavenging properties against nitric oxide (NO) (1). Such scavenging properties led Van der Kuy and coworkers to embark on an open trial of hydroxoCbl in the prevention of migraine (2). HydroxoCbl administered intranasally in 19 patients with migraine gave a reduction of at least half of the migraine attacks in 53% of the patients. No serious adverse effects were observed and compliance was controlled by monitoring Cbl serum levels. The study had limitations, the most obvious being that it was not controlled, the next being the short duration of the run-in and treatment periods. However, the magnitude of the effect was such as to suggest that it could not be due to placebo and to warrant a full double-blind vs. placebo study. Of course we must accept the Authors' words of caution and wait for a fully controlled study: migraine and neuropathic pain are indeed conditions marked by striking placebo effects, and the placebo effect, which is not absence of medication and is now being elucidated by functional neuroimaging (3), implicates brain regions hypothesized to be involved in the migraine attack cascade (4). Placebo might alone explain the effects encountered in this study. Remarkably however, vit.B12 is another vitamin proposed in migraine prophylaxis: vit.B2 (riboflavin) was found effective both in a pilot (5) and in a double-blind placebo-controlled trial (6), and coenzyme Q10 showed efficacy in an open label trial (7). Use of the latter compounds was based on the hypothesis that a decreased energy state characterizes the migraineur's brain (8), while hydroxoCbl was adopted because of its scavenging properties against NO. There is apparently no common ground to these two mechanistic hypotheses. However, there are intriguing links between the actions of riboflavin, which markedly improves ATP production through the mitochondrial chain (9), and NO scavengers such as hydroxoCbl. NO at nanomolar concentrations rapidly inhibits the mitochondrial respiration by binding to complex III and cytochrome c oxidase, in particular at low O2 tensions (10, 11). In brain nerve terminals, this results in rapid glutamate release. NO donors also inhibit complex I and catalase, stimulating the production of NO derivative peroxynitrite, which in turn inhibits complexes I, II and V and causes opening of the mitochondrial permeability transition pore, release of cytochrome c and apoptosis (12). NO produced by astrocytes may cause permanent damage to neuronal complex IV (13) and neuronal cell death (14, 15). On the other hand, NO radicals are produced by intact mitochondria and mitochondria intervene in the rapid regulation of nitric oxide synthesis by the inducible NO synthase (16, 17). It appears therefore that mitochondrial respiration and NO synthesis are closely linked and reciprocally regulated systems. Explicatory hypotheses are even more complicated if we consider that riboflavin may act as a precursor in the biosynthesis of vit.B12 (18) and that B vitamins – including riboflavin and cyanocobalamin – exert antinoceptive effects in some animal models of pain (19).
All things considered, we must wait for controlled studies of vit.B12, but, if confirmed, these trials bear testimony to the ingenuity of the clinical researchers involved. Migraine prophylaxis will be enriched with the use of natural compounds, probably at a low cost and practically devoid of adverse effects. Children with migraine could represent the category of patients likely to gain the most. Besides representing a useful and much needed adjunct to the therapeutic armamentarium, these studies remain heuristically significant for the pathogenesis of migraine, to be incorporated into any explicatory frame of migraine causation.