Transitory Platelet Monoamine Oxidase Deficit In Migraine: Some Reflections Merton Sandler, M.D., F.R.C.P., F.R.C.Path. Bernhard Baron Memorial Research Laboratories and Institute of Obstetrics and Gynaecology, Queen Charlotte's Maternity Hospital, Goldhawk Road, London, W6 OXG, Great Britain (Prof. Mesandler). Reprint requests to: Bernhard Baron Memorial Research Laboratories, Queen Charlotte's Maternity Hospital, Goldhawk Road, London, W6 OXG, Great Britain (Prof. Sandler). Presented in part at the 19th Annual Meeting of the American Association for the Study of Headache, June 18, 19, 1977, San Francisco, Calif. Accepted for publication: 3/25/77 SYNOPSIS A transitory but highly significant decrease in platelet monoamine oxidase activity was found during headache attacks in migrainous subjects and reverted to normal during attack-free periods. This is not the result of drugs used for the treatment of migraine. It is possible that decreased platelet monoamine oxidase and 5-hydroxytryptamine occur in response to release of an unidentified substance into the circulation during headache and, perhaps, is responsible for it. Attention is drawn to the biochemical relationship of migraine and depressive illness. (Headache 17:153-158, 1977) The causative agent in schizophrenia, manic-depressive illness, and migraine has not been identified; therefore, the definition of each must be clinical. While it is believed that these illnesses have a physical basis, strenuous effort has failed to identify the etiologic agent. Migraine, like other members of the group, is encumbered by an unwieldy, muddled and contradictory literature inversely proportional in size to the objective findings of the disease. Even so, certain facts are clear about migraine1: it is associated with a characteristic progression of cranial vascular changes2 and often responds to certain drugs (ergotamine or methysergide). However, two and a half thousand years of experience3 has taught us that, with migraine, one can take nothing for granted! Thus, even if vasospasm is followed by vasodilatation, and aura and headache occur successively, one cannot assume cause and effect. It may be that the agent producing pain is responsible for secondary changes in the cranial vasculature unrelated to pain. Similarly, it is unsafe to assume that drugs of proven effectiveness have a single, specific action. Because we know that methysergide is a 5-hydroxytryptamine (5-HT) -receptor blocking drug, it is tempting to interpret its therapeutic action in terms of this property;4 invariably, supposedly specific drugs have a multiple action. This does not imply that 5-HT does not play a part in the pathogenesis of headache although its precise role is not known. 5-HT injected intravenously in man does not initiate headache, but may even benefit an established attack.5 To some extent then, all drugs are "dirty" and methysergide and ergotamine may be agonists for, or antagonists of, an undefined receptor system. We concentrate on 5-HT or the catecholamines and their associated receptors because they are easier to measure6 than "trace amines", e.g. epinephrine, phenylethylamine, octopamine, and others the role of which is only vaguely apparent;7 and if an ever-increasing range of peptides and prostaglandins are included, we are left with a puzzling picture which can be interpreted in many ways. Although the clinical situation is complex, certain physicochemical differences between migrainous and normal subjects have emerged and seem worthy of further study. Even though the theoretic basis of 5-HT contribution to migraine is shaky,8 there is good, if empiric, information which suggests that changes in 5-HT occur during migraine episodes. Perhaps the most important evidence concerns the transitory decrease in platelet 5-HT.9-12 I propose that 5-HT release is not primary but secondary to release of another agent into the circulation. A parallel
physicochemical change takes place in another platelet constituent, monoamine oxidase (MAO), which may also be secondary to the release of a substance into the blood stream. The unknown humoral agent might be responsible for the headache attack. The release of this compound could be triggered by a variety of dietary, environmental or emotional factors which are alleged to be causative in this illness. Observations on triggering factors in dietary migraine13 have led to other studies in this area. Although disputed in some quarters,14,15 the claim that tyramine ingestion leads to headache in susceptible patients was a milestone in the attempt to identify an underlying biochemical lesion in migraine. Possessing evidence to incriminate dietary tyramine13 and later, phenylethylamine16 as attack initiators, it was suggested that affected subjects might have a MAO deficit. I suggest that this enzyme deficit, like 5-HT release, is a secondary manifestation of platelet damage rather than a direct contributor to the headache. Evidence pointing to a disturbance in platelet MAO activity has come from separate investigations. The first, a pilot study17 pointed to a decrease in activity during an attack. The second18 showed that enzyme activity is lower and more variable in migrainous patients than in controls, both during and between attacks. The third study,16 recorded a significant decrease between attacks compared with controls. Results of our work in this area are described in detail elsewhere.19 Briefly we examined platelet samples from subjects attending a migraine clinic both during and between attacks and determined whether the changes might stem from prior use of anti-migrainous drugs. Platelet MAO activity was also monitored in children presenting with recurrent abdominal pain, a condition which may be associated with increased risk of migraine in adult life20 and which has been designated "migraine-equivalent" by Sachs.21 The results in 83 adult migraine patients were unequivocal. Mean platelet MAO activity in the migraine group was significantly lower than that of 38 controls. Migraineurs examined during attacks showed lower activity than controls while activity in attack free periods, although lower, was not significantly so. Values were significantly lower during an attack than in the same patient outside an attack. There was no difference in activity between patients with dietary and non-dietary migraine during attack-free intervals. In agreement with the findings of others,22 platelet MAO activity was higher in women than men, whether migrainous or control. A separate group of patients was tested both during an attack and outside an attack. Platelet activity was significantly lower during the headache episode. Although fewer patients were tested during the attack than in an attack-free period, a significant decrease was noted only in men. Presumably fluctuations in platelet MAO associated with the menstrual cycle23 make the pattern more complicated in women. Platelet MAO activity was not significantly different in children with recurrent abdominal pain and controls, although when patients and controls were considered together, girls showed significantly higher values than boys, reflecting the adult pattern. Patients were examined for the effects of drugs commonly used in migraine. Platelet MAO activity was not affected by diazepam, ergotamine, clonidine or aspirin. Although most assays were performed with tyramine alone as substrate, many of the adult sample measurements were repeated with phenyIethylamine and tryptamine, when high correlation coefficients between all three were found. This applied to material from patients obtained both during and outside an attack and showed widely differing specific activities. A classification of MAO into A and B forms,24 based on their response to selective inhibitors, is now widely employed, although there are many exceptions and discrepancies.25-28 The enzyme variants are not distributed in constant proportion throughout MAO-bearing tissues but vary among cell-types. Although human platelets have been used extensively as an index of MAO activity in general, they appear to contain solely the B form.29 Thus they will oxidize tyramine and tryptamine, substrates of both enzyme forms, or phenylethylamine which is degraded by MAOB only in most tissues, but have little activity towards MAOA substrates such as 5-HT. The phenylethyIamine-oxidizing deficit in migraine patients,16 therefore reflects the overall decrease in platelet MAO activity we have confirmed here. This study reinforces previous findings that platelet MAO is reduced in migrainous patients compared with controls. However, most migrainous patients investigated had platelet MAO activity
within the control range when examined outside an attack, as did children with recurrent abdominal pain.20 We, therefore, have no reason to raise the question of genetic variation of platelet enzyme for the group as a whole, although a subgroup could be hidden within the larger group. A tendency to increased psychiatric morbidity in subjects with low platelet MAO activity has been reported.30 Although merely a pointer, it is of interest that 3 of 83 migrainous subjects had particularly low platelet MAO activity although this was not observed in the control group of 38 subjects. There are many different ways of looking at our results, but one fact stands clear: most migrainous patients had lower platelet MAO activity during their attacks than outside them and this was not caused by drugs. Many questions remain unanswered. The cause of the temporary decrease in platelet MAO activity during an attack is unknown. Whether the decrease contributes to the attack, results from it, or is caused independently by some other factor, e.g. an associated hormonal imbalance, has not been decided. Because of decreased platelet 5-HT during migrainous episodes,9-12 it is conceivable that a nonspecific circulating platelet-damaging agent appears transiently in the circulation during an attack; indeed, some have even cast certain fatty acids in this role.31 Examination of platelet systems other than those involved in 5-HT storage and MAO economy might well warrant careful scrutiny. Although the changes recorded were unequivocal, there was less than two-fold reduction in platelet MAO activity. Whether a deficit of this degree provides an explanation of migraine in terms of increased available monoamines such as tyramine13 or phenylethylamine16 is uncertain, even if change of platelet enzymes reflected alterations in MAO activity elsewhere in the body. Because the platelet changes involve MAOB activity only, we are now investigating MAO A-containing tissues during and outside a migraine attack. If a generalized MAO abnormality were present rather than one limited to platelets, the changes might be a compensatory response: evidence suggests that intractable migraine attacks are helped by MAO inhibitor therapy.32 Whatever the eventual explanation, the transitory decrease of platelet MAO activity in migraine, as opposed to the permanently low activity found in paranoid schizophrenia33 and bipolar depression,34 is one of the few biochemical disturbances identified in the disease, and therefore deserves careful attention. Perhaps we should stop viewing platelet MAO activity as constant. It has been shown35,36 that epinephrine injections cause increased platelet MAO activity although the mechanism of this response is obscure. One possible explanation is that a new population of platelets is released, perhaps from the spleen, by this stimulus. It is more probably, however, that the amine brings about a direct change in the MAO molecule. It has been shown that vigorous exercise results in an increase in platelet MAO activity of about 40%37 and the mechanism might be similar to that of epinephrine administration. Apart from being a pure MAOB enzyme, platelet MAO is atypical in other ways: it was previously thought that dopamine is predominantly oxidized by MAOA, judging from results from the rat.38,39 However, it has been shown that in human platelets and brain, dopamine is predominantly oxidized by MAOB.15 In human gut mucosa, dopamine is predominantly oxidized by MAOA.40 Although these observations are potentially of clinical importance in the treatment of parkinsonism with the MAOB inhibitor, deprenyl,41,42 they do not have immediate relevance for treatment of migraine. The dopamine-oxidizing MAOA is the sole form of the enzyme in human gut mucosa. MAOB activity is low or absent and, consequently, phenylethylamine oxidation is almost non-existent. Thus, the body must rely on the liver, if large amount of this amine, generated in the gut by action of its flora on phenylalanine43 are not to get through to the pulmonary vascular bed and beyond. Whether phenylethylamine has a bearing on the onset of migrainous headache16 is still an open question. Certainly, in the rat, this amine seems to have little direct effect on the cerebral vasculature.44 The hypothesis45 suggesting that migraine might be a pulmonary disease, may still have much to recommend it. It was based on the observation45 that the introduction of monoamines such as 5-HT or tryptamine into the afferent pulmonary circulation, caused the release of vasoactive agents into the systemic circulation.46 These included the prostaglandins and "rabbit aorta contracting substance (RCS)" now known to belong to the potent thromboxanes.47 Prostaglandin E1 can provoke a headache almost indistinguishable from migraine when injected intravenously,48 even though most of it is removed from the circulation on first pass through the lungs and liver.49 Apart from their powerful platelet-clumping action, little is known of the in vivo effects of the thromboxanes47 which are
difficult to study, possessing a half-life of seconds only. If compounds of this type are liberated into the circulation from the lungs and bring about migraine-associated symptoms by acting on the cerebral vasculature then they should be detectable in arterial blood. Practical aspects of measuring the relatively unstable prostaglandins may present unsuspected pitfalls. Some of these compounds may actually be generated in blood after it has been drawn if a prostaglandin synthesis inhibitor is not present in the collection tube.48 In order to detect the short-lived vasoactive compounds such as prostaglandin endoperoxides47 or thromboxanes, it may be that a completely novel assay approach is needed. We hope to dialyse arterial blood from volunteers during migraine episodes and perfuse the dialysate over a bank of tissues, by the technique of Vane.51 It is possible that the situation is even more complex. There is evidence that the prostaglandins sensitize pain receptors to other noxious agents52 rather than producing pain by direct receptor stimulation. Such an action might explain the time lag observed between challenge by tyramine13 or phenylethylamine16 and the onset of the headache. Another important aspect of the migraine problem to which reference should be made is the decreased output of conjugated tyramine after an oral tyramine load in patients with dietary migraine compared to control subjects.53 A similar deficit was also found in patients with depressive illness.54 The original explanation of this in terms of a possible increase of in vivo MAO activity was shown to be untenable by the finding of decreased rather than increased p-hydroxyphenylacetic acid, the major metabolite of tyramine, in patients with severe depressive illness.55 Perhaps the most dramatic and far-reaching result emerging from studies on this group was observed after modified leucotomy. In six patients with dramatic clinical improvement, the original conjugation deficit was still present. Thus fundamental metabolic error may be present which is also common to migrainous subjects. Although an overlap between depressive and migrainous patients has been noted previously56 the basic process and common pathology are not apparent. A common denominator explanation for these findings might be impeded membrane transport which could characterize both depressive illness and migraine. Why one group of patients with a generalized transport deficit develops depression while others present acutely with headache is not understood. It is of interest that certain drugs with a therapeutic effect in depression may also be helpful in the treatment of migraine, i.e. MAO inhibitors,32 tricyclic anti-depressants57 and lithium.58 Perhaps we are poised for a major breakthrough in the study of this group of diseases. REFERENCES 1.
World Federation of Neurology Research Group on Migraine and Headache, Meeting 1969: Definition of migraine. Cochrane AL (ed), In "Background to Migraine. Third Migraine Symposium", London, Heinemann, 1970, p. 181.
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Graham JR, Wolff HG: Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiat 39:737-763, 1938.
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Critchley M: Migraine from Cappadocia to Queen Square, Smith R (ed) In "Background to Migraine. First Migraine Symposium", London, Heinemann, 1967, p 28.
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Sicuteri F: Prophylactic and therapeutic properties of 1-methyl-lysergic-acid butanolamide. Int Arch Allergy Appl Immunol 15:300-307, 1959.
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Kimball RW, Friedman AP, Vallejo E: Effect of serotonin in migraine patients. Neurology 10:107-111, 1960.
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Sandler M: Closing remarks. Usdin E, Snyder SH (eds), In "Frontiers in Catecholamine Research. New York, Pergamon, 1973, p 1187.
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Sandler M: Monoamines and migraine: a path through the wood? Diamond S, Dalessio DJ, Graham JR, Medina JL, In "Vasoactive Substances Relevant to Migraine", Springfield, Thomas, 1975, p 3.
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Anthony M, Hinterberger H, Lance JW: Plasma serotonin in migraine and stress. Arch Neurol 16:544-552, 1967.
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Dalsgaard-Nielsen T, Genefke IK: Serotonin release and uptake in platelets from healthy persons and migraine patients in attack-free intervals. Headache 14:26-32, 1974.
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Hilton BP, Cumings JN: 5-hydroxytryptamine levels and platelet aggregation responses in subjects with acute migraine. J Neurol Neurosurg Psychiat 5:505-509, 1972.
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Dvilansky A, Rishpon S, Nathan I, Zolotow Z, Korczyn AD: Release of platelet 5-hydroxytryptamine by plasma taken from platelets during and between migraine attacks. Pain 2:315, 1976.
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Hanington E: Preliminary report on tyramine headache. Brit Med J 2:550-551, 1967.
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Moffett A, Swash M, Scott DF: Effect of tyramine in migraine: a double-blind study. J Neurol Neurosurg Psychiat 35:496-499, 1972.
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Ryan RE Jr: A clinical study of tyramine as an etiological factor in migraine. Headache 14:43-48, 1974.
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Sandler M, Youdim MBH, Hanington E: A phenylethylamine-oxidising defect in migraine. Nature, Lond 250:335-337, 1974.
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Sandler M, Youdim MBH, Southgate J, Hanington E: The role of tyramine in migraine: some possible biochemical
mechanisms. Cochrane AL (ed) In "Background to Migraine. Third Migraine Symposium", London, Heinemann, 1970, p 103. 18.
Sicuteri F, Buffoni F, Anselmi B, Delbianco PL: An enzyme (MAO) defect on the platelets in migraine. Res Clin Stud Headache 3:245-251, 1972.
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Glover V, Sandler M, Grant E, Rose FC, Orton D, Wilkinson M, Stevens D: Transitory decrease in platelet monoamine oxidase activity during migraine attacks. Lancet 1:391-393, 1977.
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Apley J: The Child with Abdominal Pain. 2nd Ed. Philadelphia, Lippincott, 1975.
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Sachs O: Migraine. The Evolution of a Common Disorder. London, Faber, 1971.
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Robinson DS, Davis JM, Nies A, Ravaris CL, Sylvester D: Relation of sex and aging to monoamine oxidase activity of human brain, plasma and platelets. Arch Gen Psychiat 24:536-539, 1971.
23.
Belmaker RH, Murphy DL, Wyatt RJ, Loriaux DL: Human platelet monoamine oxidase changes during the menstrual cycle. Arch Gen Psychiat 31:553-556, 1974.
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Johnston JP: Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmac 17:1285-1297, 1968.
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Williams D, Gascoigne JE, Williams ED: A specific form of rat brain monoamine oxidase in circumventricular structures. Brain Res 100:231-235, 1975.
26.
Lyles GA, Callingham BA: Evidence for a clorgyline-resistant monoamine oxidase in circumventricular structures. Brain Res 100:231, 1975.
27.
Mantle TJ, Houslay MD, Garrett MD, Tipton KF: 5-Hydroxytryptamine as a substrate for both species of monoamine oxidase in beef heart mitochondria. J Pharm Pharmac 28:667-671, 1976.
28.
Glover V, Sandler M, Owen F, Riley GJ: Dopamine is a monoamine oxidase B substrate in man. Nature, Lond 265:80-81, 1977.
29.
Murphy DL, Donnelly CH: Monoamine oxidase in man: enzyme characteristics in platelets, plasma and other human tissues. Usdin E (ed) In: Neuro psychopharmacology of Monoamines and their Regulatory Enzymes. New York, Raven, 1974, p 71.
30.
Buchsbaum MS, Coursey RD, Murphy DL: The biochemical high-risk paradigm: behavioral and familial correlates of low platelet monoamine oxidase activity. Science 194:339-341, 1976.
31.
Anthony M: Plasma free fatty acis and prostaglandin E1 in migraine and stress, Headache 16:58-63, 1976.
32.
Anthony M, Lance JW: Monoamine oxidase inhibition in the treatment of migraine. Arch Neurol 21:263-268, 1969.
33.
Schildkraut JJ, Herzog JM, Orsulak PJ, Edelman SE, Shein HM, Frazier SH: Reduced platelet monoamine oxidase activity in a subgroup of schizophrenic patients. Amer J Psychiat 133:438-443, 1976.
34.
Murphy DL, Weiss R: Reduced monoamine oxidase activity in blood platelets from bipolar depressed patients. Amer J Psychiat 128:1351-1357, 1972.
35.
Gentil V, Greenwood MH, Lader MH: The effect of adrenaline on human platelet MAO activity. Psychopharmacologia 44: 187-190, 1975.
36.
Gentil V, McCurdy RL, Alevizos B, Lader MH: The effects of adrenaline injections on human platelet monoamine oxidase and related measures. Psychopharmacologia 50: 187-192, 1976.
37.
Gawel M, Glover V, Park D, Rose RC, Sandler M: The effect of exercise upon platelet MAOB activity. Clin Sci Mol Med, 52:32 p, 1977.
38.
Waldmeier PC, Delini-Stula A, Maítre L: Preferential deamination of dopamine by an A type monoamine oxidase in rat brain. Naunyn-Schmiedeberg's Arch Pharmac 292:9-14, 1976.
39.
Braestrup C, Andersen H, Randrup A: The monoamine oxidase B inhibitor deprenyl potentiates phenylethylamine behaviour in rats without inhibition of catecholamine metabolite formation. Eur J Pharmac 34: 181-187, 1975.
40.
Glover V, Sandler M, Kumar P: Unpublished.
41.
Birkmayer W, Riederer P, Youdim MBH, Linauer W: The potentiation of the anti-akinetic effect after L-dopa treatment by an inhibitor of MAO-B. J Neur Transmiss 36:303-326, 1975.
42.
Ambrozi L, Birkmayer W, Riederer P, Youdim MBH: L-Dopa and (-)-deprenil in the treatment of Parkinson's disease: a long-term study. Brit J Pharmac 58:423P, 1976.
43.
Sandler M, Bonham Carter S, Goodwin BL, Ruthven CRJ: Trace amine metabolism in man. Usdin E, Sandler M (eds), In: Trace Amines and the Brain. New York, Dekker, 1976, p 233.
44.
Sandler M, Youdim MBH, Hanington E, Corne SJ, Stephens RJ: Phenylethylamine-oxidizing defect in migraine: circulatory implications. Clin Exp Pharmac Physiol Suppl 2:79, 1975.
45.
Sandler M: Migraine: a pulmonary disease? Lancet 1:618-619, 1972.
46.
Alabaster VA, Bakhle YS: Release of smooth muscle-contracting substances from isolated perfused lungs. Eur J Pharmac 35:349-350, 1976.
47.
Samuelsson B, Paoletti R (eds): Advances in Prostaglandin and Thromboxane Research. New York, Raven, 1976.
48.
Bennett A, Sjaastad O, Sandler M: unpublished.
49.
Carlson LA: Metabolic and cardiovascular effects in vivo of prostaglandins. Bergström S, Samuelsson B (eds) In: Prostaglandins. Nobel Symposium 2. New York, Interscience, 1967, p 123.
50.
Ferreira SH, Vane JR: Prostaglandins: their disappearance from and release into the circulation. Nature, Lond 216:868-873, 1967.
51.
Vane JR: The use of isolated organs for detecting active substances in the circulating blood. Brit J Pharmac 23:360-373, 1964.
52.
Moncada S, Ferreira SH, Vane JR: Sensitization of pain receptors of the dog knee joint by prostaglandins. Vane JR, Robinson H. (eds). In: Prostaglandin Synthetase Inhibitors. New York, Raven, 1974, p 189.
53.
Youdim MBH, Bonham Carter S, Sandler M, Hanington E, Wilkinson M: Conjugation defect in tyramine-sensitive migraine. Nature, Lond 230: 127-128, 1971.
54.
Sandler M, Bonham Carter S, Cuthbert MF, Pare CMB: Is there an increase in monoamine-oxidase activity in depressive illness? Lancet 1:1045-1046, 1975.
55.
Bonham Carter S, Sandler M, Bridges P. Sepping P: unpublished.
56.
Couch JR, Ziegler DK, Hassanein R: Evaluation of the relationship between migraine headache and depression. Headache 15:41-50, 1975.
57.
Couch JR, Ziegler DK, Hassanein R: Amitriptyline in the prophylaxis of migraine. Effectiveness and relationship of antimigraine and antidepressant effects. Neurology 26:121-127, 1976.
58.
Kudrow L: Comparative results of prednisone, methysergide and lithium therapy in cluster headache. Paper presented at the Migraine Trust International Symposium, London, 1976.
physicochemical change takes place in another platelet constituent, monoamine oxidase (MAO), which may also be secondary to the release of a substance into the blood stream. The unknown humoral agent might be responsible for the headache attack. The release of this compound could be triggered by a variety of dietary, environmental or emotional factors which are alleged to be causative in this illness. Observations on triggering factors in dietary migraine13 have led to other studies in this area. Although disputed in some quarters,14,15 the claim that tyramine ingestion leads to headache in susceptible patients was a milestone in the attempt to identify an underlying biochemical lesion in migraine. Possessing evidence to incriminate dietary tyramine13 and later, phenylethylamine16 as attack initiators, it was suggested that affected subjects might have a MAO deficit. I suggest that this enzyme deficit, like 5-HT release, is a secondary manifestation of platelet damage rather than a direct contributor to the headache. Evidence pointing to a disturbance in platelet MAO activity has come from separate investigations. The first, a pilot study17 pointed to a decrease in activity during an attack. The second18 showed that enzyme activity is lower and more variable in migrainous patients than in controls, both during and between attacks. The third study,16 recorded a significant decrease between attacks compared with controls. Results of our work in this area are described in detail elsewhere.19 Briefly we examined platelet samples from subjects attending a migraine clinic both during and between attacks and determined whether the changes might stem from prior use of anti-migrainous drugs. Platelet MAO activity was also monitored in children presenting with recurrent abdominal pain, a condition which may be associated with increased risk of migraine in adult life20 and which has been designated "migraine-equivalent" by Sachs.21 The results in 83 adult migraine patients were unequivocal. Mean platelet MAO activity in the migraine group was significantly lower than that of 38 controls. Migraineurs examined during attacks showed lower activity than controls while activity in attack free periods, although lower, was not significantly so. Values were significantly lower during an attack than in the same patient outside an attack. There was no difference in activity between patients with dietary and non-dietary migraine during attack-free intervals. In agreement with the findings of others,22 platelet MAO activity was higher in women than men, whether migrainous or control. A separate group of patients was tested both during an attack and outside an attack. Platelet activity was significantly lower during the headache episode. Although fewer patients were tested during the attack than in an attack-free period, a significant decrease was noted only in men. Presumably fluctuations in platelet MAO associated with the menstrual cycle23 make the pattern more complicated in women. Platelet MAO activity was not significantly different in children with recurrent abdominal pain and controls, although when patients and controls were considered together, girls showed significantly higher values than boys, reflecting the adult pattern. Patients were examined for the effects of drugs commonly used in migraine. Platelet MAO activity was not affected by diazepam, ergotamine, clonidine or aspirin. Although most assays were performed with tyramine alone as substrate, many of the adult sample measurements were repeated with phenyIethylamine and tryptamine, when high correlation coefficients between all three were found. This applied to material from patients obtained both during and outside an attack and showed widely differing specific activities. A classification of MAO into A and B forms,24 based on their response to selective inhibitors, is now widely employed, although there are many exceptions and discrepancies.25-28 The enzyme variants are not distributed in constant proportion throughout MAO-bearing tissues but vary among cell-types. Although human platelets have been used extensively as an index of MAO activity in general, they appear to contain solely the B form.29 Thus they will oxidize tyramine and tryptamine, substrates of both enzyme forms, or phenylethylamine which is degraded by MAOB only in most tissues, but have little activity towards MAOA substrates such as 5-HT. The phenylethyIamine-oxidizing deficit in migraine patients,16 therefore reflects the overall decrease in platelet MAO activity we have confirmed here. This study reinforces previous findings that platelet MAO is reduced in migrainous patients compared with controls. However, most migrainous patients investigated had platelet MAO activity
within the control range when examined outside an attack, as did children with recurrent abdominal pain.20 We, therefore, have no reason to raise the question of genetic variation of platelet enzyme for the group as a whole, although a subgroup could be hidden within the larger group. A tendency to increased psychiatric morbidity in subjects with low platelet MAO activity has been reported.30 Although merely a pointer, it is of interest that 3 of 83 migrainous subjects had particularly low platelet MAO activity although this was not observed in the control group of 38 subjects. There are many different ways of looking at our results, but one fact stands clear: most migrainous patients had lower platelet MAO activity during their attacks than outside them and this was not caused by drugs. Many questions remain unanswered. The cause of the temporary decrease in platelet MAO activity during an attack is unknown. Whether the decrease contributes to the attack, results from it, or is caused independently by some other factor, e.g. an associated hormonal imbalance, has not been decided. Because of decreased platelet 5-HT during migrainous episodes,9-12 it is conceivable that a nonspecific circulating platelet-damaging agent appears transiently in the circulation during an attack; indeed, some have even cast certain fatty acids in this role.31 Examination of platelet systems other than those involved in 5-HT storage and MAO economy might well warrant careful scrutiny. Although the changes recorded were unequivocal, there was less than two-fold reduction in platelet MAO activity. Whether a deficit of this degree provides an explanation of migraine in terms of increased available monoamines such as tyramine13 or phenylethylamine16 is uncertain, even if change of platelet enzymes reflected alterations in MAO activity elsewhere in the body. Because the platelet changes involve MAOB activity only, we are now investigating MAO A-containing tissues during and outside a migraine attack. If a generalized MAO abnormality were present rather than one limited to platelets, the changes might be a compensatory response: evidence suggests that intractable migraine attacks are helped by MAO inhibitor therapy.32 Whatever the eventual explanation, the transitory decrease of platelet MAO activity in migraine, as opposed to the permanently low activity found in paranoid schizophrenia33 and bipolar depression,34 is one of the few biochemical disturbances identified in the disease, and therefore deserves careful attention. Perhaps we should stop viewing platelet MAO activity as constant. It has been shown35,36 that epinephrine injections cause increased platelet MAO activity although the mechanism of this response is obscure. One possible explanation is that a new population of platelets is released, perhaps from the spleen, by this stimulus. It is more probably, however, that the amine brings about a direct change in the MAO molecule. It has been shown that vigorous exercise results in an increase in platelet MAO activity of about 40%37 and the mechanism might be similar to that of epinephrine administration. Apart from being a pure MAOB enzyme, platelet MAO is atypical in other ways: it was previously thought that dopamine is predominantly oxidized by MAOA, judging from results from the rat.38,39 However, it has been shown that in human platelets and brain, dopamine is predominantly oxidized by MAOB.15 In human gut mucosa, dopamine is predominantly oxidized by MAOA.40 Although these observations are potentially of clinical importance in the treatment of parkinsonism with the MAOB inhibitor, deprenyl,41,42 they do not have immediate relevance for treatment of migraine. The dopamine-oxidizing MAOA is the sole form of the enzyme in human gut mucosa. MAOB activity is low or absent and, consequently, phenylethylamine oxidation is almost non-existent. Thus, the body must rely on the liver, if large amount of this amine, generated in the gut by action of its flora on phenylalanine43 are not to get through to the pulmonary vascular bed and beyond. Whether phenylethylamine has a bearing on the onset of migrainous headache16 is still an open question. Certainly, in the rat, this amine seems to have little direct effect on the cerebral vasculature.44 The hypothesis45 suggesting that migraine might be a pulmonary disease, may still have much to recommend it. It was based on the observation45 that the introduction of monoamines such as 5-HT or tryptamine into the afferent pulmonary circulation, caused the release of vasoactive agents into the systemic circulation.46 These included the prostaglandins and "rabbit aorta contracting substance (RCS)" now known to belong to the potent thromboxanes.47 Prostaglandin E1 can provoke a headache almost indistinguishable from migraine when injected intravenously,48 even though most of it is removed from the circulation on first pass through the lungs and liver.49 Apart from their powerful platelet-clumping action, little is known of the in vivo effects of the thromboxanes47 which are
difficult to study, possessing a half-life of seconds only. If compounds of this type are liberated into the circulation from the lungs and bring about migraine-associated symptoms by acting on the cerebral vasculature then they should be detectable in arterial blood. Practical aspects of measuring the relatively unstable prostaglandins may present unsuspected pitfalls. Some of these compounds may actually be generated in blood after it has been drawn if a prostaglandin synthesis inhibitor is not present in the collection tube.48 In order to detect the short-lived vasoactive compounds such as prostaglandin endoperoxides47 or thromboxanes, it may be that a completely novel assay approach is needed. We hope to dialyse arterial blood from volunteers during migraine episodes and perfuse the dialysate over a bank of tissues, by the technique of Vane.51 It is possible that the situation is even more complex. There is evidence that the prostaglandins sensitize pain receptors to other noxious agents52 rather than producing pain by direct receptor stimulation. Such an action might explain the time lag observed between challenge by tyramine13 or phenylethylamine16 and the onset of the headache. Another important aspect of the migraine problem to which reference should be made is the decreased output of conjugated tyramine after an oral tyramine load in patients with dietary migraine compared to control subjects.53 A similar deficit was also found in patients with depressive illness.54 The original explanation of this in terms of a possible increase of in vivo MAO activity was shown to be untenable by the finding of decreased rather than increased p-hydroxyphenylacetic acid, the major metabolite of tyramine, in patients with severe depressive illness.55 Perhaps the most dramatic and far-reaching result emerging from studies on this group was observed after modified leucotomy. In six patients with dramatic clinical improvement, the original conjugation deficit was still present. Thus fundamental metabolic error may be present which is also common to migrainous subjects. Although an overlap between depressive and migrainous patients has been noted previously56 the basic process and common pathology are not apparent. A common denominator explanation for these findings might be impeded membrane transport which could characterize both depressive illness and migraine. Why one group of patients with a generalized transport deficit develops depression while others present acutely with headache is not understood. It is of interest that certain drugs with a therapeutic effect in depression may also be helpful in the treatment of migraine, i.e. MAO inhibitors,32 tricyclic anti-depressants57 and lithium.58 Perhaps we are poised for a major breakthrough in the study of this group of diseases. REFERENCES 1.
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