Neurol Sci (2014) 35 (Suppl 1):S141–S144 DOI 10.1007/s10072-014-1755-z

SESSION IV UNCONVENTIONAL TREATMENTS

Riboflavin and migraine: the bridge over troubled mitochondria Bruno Colombo • Lorenzo Saraceno Giancarlo Comi



Ó Springer-Verlag Italia 2014

Abstract Brain energy metabolism has been found to be disturbed in migraine. A mitochondrial defect may reduce the threshold for migraine attacks both increasing neuronal excitability and leading migrainous brain to a hyperresponsiveness to triggering stimuli. Riboflavin, a major co-factor in oxidative metabolism, may overcome this impairment. RCT studies in adult confirmed that riboflavin is safe and probably effective in migraine prophylaxis, based on level B evidence. Improving brain energy metabolism may reduce the susceptibility to migraine when brain energy demand increases due to both physiological and biopsychological factors. Keywords

Migraine  Mitochondria  Riboflavin

Introduction Although pathophysiology of migraine is still uncertain, brain energy metabolism in migraine has been found to be disturbed. There are evidences that in migraine, neuronal dysfunction is present and that brain of migraineurs is hyperexcitable. These data are suggestive for a possible abnormal brain energy activity, both during and between migraine attacks [1]. This fascinating theory is supported by a large line of evidence (Table 1). In example, migraine patients show a lack of habituation (unchanged or increased response to repetitive

B. Colombo (&)  L. Saraceno  G. Comi Headache Unit, Department of Neurology, San Raffaele Hospital, University Vita-Salute, Via Olgettina 48, 20132 Milan, Italy e-mail: [email protected]

stimulation), possibly due to an increased cortical excitability or a reduced intracortical inhibition [2]. It is conceivable that the continuous interaction between excitatory and inhibitory neurons determines the ‘‘cortex excitability threshold’’ leading to a sort of oscillation between the two excitability poles [3]. This mechanism is possibly related to mitochondrial activity. Mitochondria are bacterium-size organelles found in all mammalian cell, functioning both to produce adenosine tri-phosphate (ATP) via the electron transport chain and reactive oxygen species (ROS). They also regulate calcium homeostasis and apoptosis [4]. In case of brain mitochondrial dysfunction, impaired oxidative metabolism could lead to a diminished energy production, leading to a disturbance in cortex excitability [5]. In fact, brain is highly dependent on oxidative metabolism. This altered mitochondrial metabolism could affect migraine susceptibility lowering the threshold for propagation of migraine attack (i.e., cortical spreading depression) (Table 2). This could be explained by mitochondrial activity disregulation leading to impaired cellular ion homeostasis (particularly of calcium), membrane instability with raising neuronal transmembrane potential and more easily depolarizable neurons in case of adequate triggering stimuli. Several mechanisms may be involved (Table 3).

Mitochondria and migraine: an intriguing evidence A great number of biochemical and phosphorus magnetic resonance spectroscopy studies have shown that functionality of mitochondria in migraine patients is impaired with specific patterns of metabolic abnormalities. The biochemical evidence of impairment in NADH dehydrogenase and cytochrome-c oxidase in patients affected by migraine

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S142 Table 1 Brain hyperexcitability in migraine Interictal brain abnormal information processing CO2 hyper-reactivity Enhanced photic driving and enhanced visual stimulation Lower threshold for generation of phosphenes on Transcranial Magnetic Stimulation (TMS) Abnormal habituation on auditory evoked potentials

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or are consequences of primary mitochondrial disregulation is still unsolved. In other words, the cause of impaired energy metabolism is debatable: is it primary or secondary to causative factors such as ion channel disorders or reduced magnesium concentration? Anyway, the predilection of maternal inheritance of migraine makes a mitochondrial etiology particularly reliable. Genetic studies on full mitochondrial DNA are suggested to detect a possible role of mitochondrial-related gene in migraine.

Table 2 The link between impaired mitochondrial activity and migraine Mitochondrial dysfunction (abnormality of oxidative metabolism) ? decreased ATP production and energy metabolism ? imbalance in calcium ions ? increase of neuronal excitability ? disturbance of neuronal information processing ? decreased migraine threshold ? triggering of cortical spreading depression

Table 3 How can a primary brain mitochondrial defect possibly reduce the threshold for migraine? Reduction of mitochondrial energy reserve may lead to a local rise in lactate concentration. This mechanism may be enhanced by the coexistence of habituation defect in sensory processing. The imbalance of brain metabolic homeostasis might trigger the trigeminovascular system The sensitivity of meningeal blood vessels to exogenous stimuli (dietary or nitric oxide) may be due to mitochondrial abnormalities in the wall of meningeal blood vessels A functional mitochondrial defect (primary or secondary) confined in several brain areas (heteroplasmic defect) may enhance neuronal excitability if restricted in brainstem structures or trigeminal nerve nucleus

was detected, as well as the lower platelet levels of superoxide dismutase in patients affected by migraine with aura [6, 7]. These data are suggestive for a vulnerability to oxidative stress. In other studies, energy failure was associated to decarboxylase enzymes shift and increasing levels of neuromodulators tyramine, octopamine and synephrine [8]. With phosphorus magnetic resonance spectroscopy (a technique used to evaluate brain energy metabolism in vivo) it is possible to detect the intracellular concentration of phosphocreatine (PCr), adenosine diphosphate (ADP) and inorganic phosphate (Pi). In migraine patients, low PCr–Pi ratios (a measurement of intracellular energy status and mitochondrial functionality) and high levels of ADP (showing a lower energy reserve in neurons) were demonstrated, confirming a low availability of free energy and an unstable metabolic state in the brain of migraineurs [9, 10]. This could lead to a diminished ability to cope with increased energy demand. The intriguing question whether these abnormalities are an effect of brain hyperexcitability

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Riboflavin: the possible connection Riboflavin, or Vitamin B2, is a water-soluble precursor to coenzymes, flavin mononucleotide (FMN) and flavin– adenosine–dinucleotide (FAD), both of which are of pivotal importance for electron transport in mitochondrial complex I and II. These so-called ‘‘yellow enzymes’’ have the role to transport hydrogen and are fundamental not only in the degradation of a great number of substrates such as amino acids, fatty acids and purines but also particularly in the oxido-reduction reactions of the mitochondrial respiratory chain. Riboflavin is considered a vital component of mitochondrial energy production. It is particularly important to normal production of ATP, leading to membrane stability and sustaining adequate energy-related cellular functions. The evidence that riboflavin is able to improve both biochemical and clinical abnormalities and reduce the frequency of migraine attacks in a subgroup of patient with MELAS, and other mitochondrial diseases provided a theoretical basis to utilize Vitamin B2 as a compound able to replete mitochondrial energy stores in migraineurs, enhancing mitochondrial function and efficiency [11, 12]. In fact, riboflavin directly influences the activity of mitochondria respiratory chain flavin-dependent respiratory enzymes affecting mitochondrial phosphorylation. The maximal dose of riboflavin absorbable from a single dose is 27 mg with saturation of absorption reached at 30–50 mg. Half-life of riboflavin is about 1 h [13]. First report (open-label study) concerning the successful use of riboflavin in migraine prophylaxis was published in 1946 [14]. Years later, in 1994, another open-label study confirmed the improvement of migraine severity in 68.2 % of patients treated with riboflavin 400 mg daily both alone and in association with Aspirin 75 mg [15]. This result was replicated in another open-label study [16]. Most recently, in a third open-label trial, 62.5 % of a sample of adult patients affected by migraine were responsive to riboflavin (400 mg daily for 4 months), particularly if not carrying mitochondrial DNA H haplotype (an haplogroup particularly found in the European population). The presence of aura was not associated with riboflavin effectiveness.

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These results suggested that response to riboflavin might be influenced by mitochondrial DNA haplogroups [17]. Two small RCTs in adult patients have valuated the efficacy of riboflavin for the prophylaxis of migraine. First well-designed RCT compared placebo to riboflavin (duration 4 months), showing the superiority of riboflavin in reducing the frequency of attacks (50 % reduction in 59 % of patients compared to 15 % for placebo, number needed to treat of 2.8). Minor adverse events (polyuria and diarrhea) were reported in the treatment group. A common side effect is a bright yellow discolouration of the urine [18]. In the second study, a combination of riboflavin (400 mg), magnesium and feverfew was compared with low-dose riboflavin (25 mg daily). Results showed no difference between groups in the outcomes measures [19]. Based on these literature data (although classified of low quality), the American Academy of Neurology Guideline concludes that riboflavin is probably effective in the prophylaxis of migraine in adults, based on level B evidence [20]. The Canadian Headache Society strongly recommends the use of riboflavin in adults affected by migraine based on very low side effects profile and promising clinical results [21]. An RCT study in pediatric patients affected by migraine (4 months of treatment) compared high-dose riboflavin (at least 200 mg/day) to placebo in migraine prevention. Results showed no statistically significant difference in the responder rates, although the placebo rate was particularly high (66.6 %) [22]. This negative result could be explained by methodological issues. Admittedly, this study was not powered to detect a small or moderate statistical difference between active and placebo groups (possible bias in sample size calculations). An open-label study in pediatric patients (in this group severely affected patients were represented) suggested that high-dose riboflavin (200 or 400 mg on a daily basis for 3–6 months) may be effective in migraine, particularly in boys. The results showed that 68.4 % of the included patients had a reduction of 50 % or more in the frequency of attacks with same response rates of two dosages [23]. A subsequent RCT cross-over study addressed the effectiveness of a 50 mg/day dose of riboflavin (4 months of treatment) in the prevention of migraine in a small group (42 subjects) of pediatric patients (age 6–13 years) [24]. The results were not statistically significant (no difference in migraine duration, frequency and severity between the two groups), possibly due to the suboptimal low dose of riboflavin if compared with other studies. Based on these study results, riboflavin is not recommended for the prophylaxis of pediatric migraine. To understand this failure in pediatric population, we have to consider that the once daily dosing used in the literature could be possibly not sufficient to achieve and maintain adequate steady-state levels of riboflavin (the half-life is

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about one hour) in order to sustain a definite preventive activity for migraine. Further studies with multiple daily dosing and correct administration (the absorption of riboflavin is diminished if taken on an empty stomach) are to be planned to investigate why the effect of riboflavin is defined in adults, but not achieved in pediatric population.

Conclusion Migraine attacks may be sustained by an impaired oxidative metabolism, leading to the ‘‘threshold character’’ of migraine pathology. Mitochondria have a pivotal role in this energetic imbalance, by influencing neuronal processing and excitability, making the migrainous brain hyper-responsive to several different stimuli. High-dose riboflavin might be helpful in reducing this impairment, overcoming the mitochondrial disturbance. Results in RCT studies are encouraging in adults affected by migraine, suggesting this well-tolerated treatment as a favorable option. More studies with adequate methodologies are needed to investigate the efficacy of riboflavin in children affected by migraine. Approaching independent mechanisms of migraine pathophysiology with a rational polytherapy addressing the multiple aspects of the disease might be a successful option. Riboflavin could be considered for future combination in migraine treatments, socalled pharmacological synergy, considering the abundant scientific evidence supporting the theory of a mitochondrial disturbance enhancing migraine disorder. Conflict of interest I certify that there is no actual or potential conflict of interest in relation to this article.

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S144 9. Welch KM, Levine SR, D’Andrea G et al (1989) Preliminary observations on brain energy metabolism in migraine studied by in vivo phosphorus 31 NMR spectroscopy. Neurology 39:538–541 10. Montagna P, Cortelli P, Barbiroli B et al (1994) Magnetic resonance spectroscopy studies in migraine. Cephalalgia 14:184–193 11. Antozzi C, Garavaglia B, Mora M et al (1994) Late-onset riboflavin-responsive myopathy with combined multiple acyl coenzyme A dehydrogenase and respiratory chain deficiency. Neurology 44:2153–2158 12. Scholte HR, Busch HF, Bakker HD et al (1995) Riboflavinresponsive complex I deficiency. Biochim Biophys Acta 1271: 75–83 13. Taylor FR (2011) Nutraceuticals and headache: the biological basis. Headache 2011(51):484–501 14. Smith C (1946) Riboflavin in migraine. CMAJ 54:589–591 15. Schoenen J, Lenaerts M, Bastings E (1994) High-dose riboflavin as a prophylactic treatment of migraine: results of an open pilot study. Cephalalgia 14:328–329 16. Boehnke C, Reuter U, Flach U et al (2004) High-dose riboflavin treatment is efficacious in migraine prophylaxis: an open study in a tertiary care centre. Eur J Neurol 11:475–477 17. Di Lorenzo C, Pierelli F, Coppola G (2009) Mitochondrial DNA haplogroups influence the therapeutic response to riboflavin in migraineurs. Neurology 72:1588–1594 18. Schoenen J, Jacquy J, Lenaerts M (1998) Effectiveness of highdose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology 50(2):466–470

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Neurol Sci (2014) 35 (Suppl 1):S141–S144 19. Maizels M, Blumenfeld A, Burchette R (2004) A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial. Headache 44:885–890 20. Holland S, Silberstein SD, Freitag F et al (2012) Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 78:1346–1353 21. Pringsheim T, Davenport W, Mackie G et al (2012) Canadian Headache Society guideline for migraine prophylaxis. Can J Neurol Sci 39(2 Suppl 2):S1–S59 22. MacLennan SC, Wade FM, Forrest KM et al (2008) High-dose riboflavin for migraine prophylaxis in children: a double-blind, randomized, placebo-controlled trial. J Child Neurol 23(11): 1300–1304 23. Condo` M, Posar A, Arbizzani A et al (2009) Riboflavin prophylaxis in pediatric and adolescent migraine. J Headache Pain 10(5):361–365 24. Bruijn J, Duivenvoorden H, Passchier J et al (2010) Medium-dose riboflavin as a prophylactic agent in children with migraine: a preliminary placebo-controlled, randomised, double-blind, crossover trial. Cephalalgia 30(12):1426–1434

Riboflavin and migraine: the bridge over troubled mitochondria.

Brain energy metabolism has been found to be disturbed in migraine. A mitochondrial defect may reduce the threshold for migraine attacks both increasi...
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