( Medical Hypotheses ‘%&dimlHypolhaLs(199L) 34.69-72 0 Lmummn Cimu~ UK Lid 1991
Multiple Sclerosis Track?
Is Research on the Wrong
M. LINDSTEDT Vallmoviigen
7, S - 240
10 Dalby, Sweden
Abstract - The search for a MS virus, specific or otherwise, seems to be futile and I therefore contend that the activation mechanism of MS deserves much more attention than it has received. Could it be located in the pineal that transmits information by altering the secretion rate of melatonin, a hormone with noradrenaline or serotonin as precursor? The human pineal - and its major hormone, melatonin - is very likely to prove that it has a number of physiological roles involving the brain and perhaps other organs. There is also the possibility that a mycotoxin, ergotamine or a related alkaloid e.g. could be the triggering factor for the manifestation of MS. It is noteworthy that the geographical distribution of ergot corresponds to such an extent with the geographical distribution of MS as is shown in the present paper.
Introduction
Discussion
There is much evidence of a correlation between light and MS, but the predominant opinion amonst leading MS researchers, at least in Sweden, would appear to be that the etiology of MS involves a virus, specific or otherwise (l), and they unfortunately tend to ignore other proposals. As a result of this blinkered approach, many research projects for exploring other avenues are ruled out or delayed. What I question is not the virus hypothesis as such but the search for a specific MS virus (1). If it is the case that a virus or viruses are involved in the inception or induction of MS, then I am convinced that the activation mechanism involves factors in the internal and/or external environment.
Might MS be caused or triggered by a hormonal or enzymatic disturbance induced by light? The hormone that comes to mind is melatonin, which is produced in the pineal body and plays a part in daily rhythms in man, and perhaps even more so its precursor serotonin. Having been formed by the enzymatic transformation of an amino acid (tryptophan), serotonin is converted in a similar process into N-acetyl-serotonin, which is then used for the synthesis of melatonin (2). Instead of being a gland in the traditional sense, the pineal appears to be one of four neuroendocrine transducers, i.e. a junction where an input of neural information is converted into a hormonal
Date received 20 February 1990 Date accepted 28 March 1!390 69
70 or endocrine output for distribution in the blood. The neural input of the pineal is noradrenaline or serotonin, released from postganglionic sympathetic nerves, and its hormonal output is melatonin. The pineal transmits information by altering the rate at which it secretes melatonin, which appears to be synthesized only in this organ (2, 3). In mammals, melatonin is secreted at night time and it seems that the circulating level is influenced by, but not dependent on, light (5); the level is low in the daytime and rises during the night (6). There are various routes by which information about external lighting could be transmitted to the pineal: retinal stimulation could reach the pineal via nerve pathways, light could act indirectly by influencing other circulating hormones that in turn affect enzyme activity, or light could impinge directly on the pineal (3). Although the skulls of mammals do admit significant amounts of light, it appears that the pineal responds only if the light activates the retina of the eye (2). Apparently, then, light stimulates the retina and information about the light is transmitted to the pineal via sympathetic nerves.
MEDICAL HYPOTHESES
duction of) the enzyme (hydroxyindole-O-methyltransferase, HIOMT) that regulates the synthesis of melatonin (2). The fact that light affects both the weight of the pineal and at least two enzyme systems in this organ suggests that it may regulate many other, as yet undiscovered biochemical phenomena in the pineal via the sympathetic nervous system (2). Experiments performed in rats to determine the effect on the pineal of normal lighting rhythms showed that in the five hours from the onset of darkness to midnight, the formation of melatonin increased between two and three times. The weight of the pineal also changed significantly in this period, again indicating that light may affect many more compounds in the pineal than the single enzyme that was being studied (2).
I
I
Fig. 2
Fig. 1 Source: Kurtzke, J.F. Geographic distribution of multiple sclerosis: An update with special reference to Europe and the Mediterranean region. Acta Neurol. Scandinav. 1980, 62, 65 - 80.
The sympathetic nervous system is involved in adaptation to rapid internal and external changes (2). Sympathetic nerves to the pineal release neurohormones (noradrenaline or serotonin) that act on the pineal cells to induce (or block the in-
Thus, the pineal rhythm in HIOMT activity appears to be truly exogenous and wholly dependent on changes in the environmental lighting (2). The serotonin rhythm in the pineal is endogenous and environmental light functions only as an external synchronizer. The regulating mechanism appears to reside in the central nervous system. The pineal organ accordingly contains at least two distinct biological clocks, one entirely dependent on environmental lighting and the other originating in the brain but susceptible to changes in lighting (2). Given the melatonin is released from the pineal into the circulation and acts as a hormone on distant organs, the relationship between light and pineal HIOMT activity may represent a new kind of neuroendocrine regulatory mechanism: light
MULTIPLE SCLEROSIS -
IS RESEARCH ON THE WRONG TRACK?
71
controls the supply of a hormone by regulating the activity of an enzyme needed for its synthesis (3). The identification of melatonin over 30 years ago was followed by the discovery that the pineal organ, in cattle as well as in man, has a comparatively high content of serotonin, a hormone with a molecular structure similar to that of melatonin and a function in nervous tissue that is sti!l largely unknown (2). Leading American pineal researchers are fairly confident that the human pineal - and its major hormone, melatonin - will prove to have a number of physiological roles involving the brain and perhaps other organs and that melatonin may also participate in a number of diseases and in mediating effects of drugs (4). The pineal therefore appears to function as an intricate and sensitive biological clock that converts cyclic nervous activity, generated by light, into endocrine information (2).
The cerebral turnover of serotonin is influenced by ergotamine and the firing rate of central serotonergic neurons is known to be depressed by several ergot alkaloids. The evidence that central serotonergic circuits are involved in circulatory regulation is an indication that the primary site of action of ergotamine might be central rather than peripheral (10). The occurrence of ergot is largely determined by climatic conditions - the fungus is known to thrive in cold, wet seasons with little sunshine. Ideal conditions for its development and dissemination are provided by high humidity and cool weather; under such circumstances the disease can quickly become epidemic (11). As to the geographical distribution of ergot, Claviceps purpurea, I find it noteworthy, to say the least, that it corresponds to such an extent with the geographical distribution of MS, Figures 1 and 2 (12, 13).
Might MS be caused or triggered by mycotoxins?
Conclusion
I am thinking primarily of ergotamine (Secale cornutum), the principal component of ergot (Claviceps purpurea). Ergot poisoning produces symptoms similar in many respects to those of MS. The ergot fungus is associated with grasses, in particular with rye, which is grown mainly in northern latitudes (7). Symptoms of iatrogenic as well as natural ergotism appear to result from local ischemia caused by ergot-induced vasospasm (8). Natural ergotism seems to have been studied more thoroughly in livestock (horses, e.g.) than in man, perhaps understandably, but the symptoms do seem to be similar in many respects. Tolerance to ergot varies greatly between individuals. It has long been known that some patients are quite sensitive, while others develop no symptoms for years on doses considered to be in the toxic range. It still remains to be explained why some patients suddenly develop symptoms of ergot intoxication after tolerating large doses for years (8). Besides inducing the constriction of distended extracranial arteries, ergotamine may affect serotonergic neurons in the CNS (9). The capacity for vasomotor regulation has been located in the CNS, via serotonergic neural circuits, which is consistent with the hypothesis that the modulation of serotonin - centrally as well as peripherally - is of pathogenic importance (10).
Considering that the unavailing search for a specific MS virus seems to be futile, researchers should pay much more attention to the underlying cause of MS or its activation mechanism, such as e.g. an abnormality in melatonin secretion, or a mycotoxin, such as e.g. ergotamine or a related alkaloid, acting as the triggering factor for the manifestation of MS. References 1. Mims C. Multiple Sclerosis - the case against viruses, New Scientist 1983. 98. 938 - 40. 2. Wurtman RJ, Axklrod J. The pineal gland. Scientific American 1965, 213, 50-60. 3. Wurtman RJ, Axelrod J, Phillips LS. Melatonin synthesis in the pineal gland: control by light. Science 1963, 142, 1071-73.7. 4. Wurtman RJ. Introduction: Melatonin in Humans. In: Melatonin in Humans. (Eds. R.J. Wurtman and F. Waldhauser). International Conference on Melatonin in Humans, Vienna, Austria, November 7-9, 1985. J. Neural Transm. 1986, Suppl. 21, 1 - 8.7. Wurtman RJ. Summary and Forecast. Idem, 475 - 477. Boyce PH, Kennaway DJ. Effects of light on melatonin production. Biol. Psychiatry 1987, 22, 473 - 8. FAO production yearbook, 1986, 40, table 21, p. 81, FAO, Rome. Merhoff CC, Porter JM. Ergot intoxication: historical review and description of unusual clinical manifestations. Ann. Surg. November 1974, 180. 773 - 779. 9. Tfelt-Hansen, P. The effect of ergotamine on the arterial system in man. Acta Pharmacol. et Toxicol. 1986, 59, Suppl, III, 3 - 29. 10. Raskin NH. Pharmacology of migraine. Ann. Rev. Pharmacol. Toxicol. 1981, 21, 463 -478.
72 11. Bradley-Jones J. Ergot and ergotism. NAAS Quarterly Review 1964, 157- 164. 12. Kurtzke JF. Geographical distribution of multiple sclerosis: an update with special reference to Europe and the
MEDICAL HYPOTHESES
Mediterranean region. Acta Neural Scandinav. 1980, 62, 65 - 80. 13. Commonwealth Mycological Institute. Distribution Maps of Plant Diseases, Map No. 10, 1966.
Multiple Sclerosis Track?
Is Research on the Wrong
M. LINDSTEDT Vallmoviigen
7, S - 240
10 Dalby, Sweden
Abstract - The search for a MS virus, specific or otherwise, seems to be futile and I therefore contend that the activation mechanism of MS deserves much more attention than it has received. Could it be located in the pineal that transmits information by altering the secretion rate of melatonin, a hormone with noradrenaline or serotonin as precursor? The human pineal - and its major hormone, melatonin - is very likely to prove that it has a number of physiological roles involving the brain and perhaps other organs. There is also the possibility that a mycotoxin, ergotamine or a related alkaloid e.g. could be the triggering factor for the manifestation of MS. It is noteworthy that the geographical distribution of ergot corresponds to such an extent with the geographical distribution of MS as is shown in the present paper.
Introduction
Discussion
There is much evidence of a correlation between light and MS, but the predominant opinion amonst leading MS researchers, at least in Sweden, would appear to be that the etiology of MS involves a virus, specific or otherwise (l), and they unfortunately tend to ignore other proposals. As a result of this blinkered approach, many research projects for exploring other avenues are ruled out or delayed. What I question is not the virus hypothesis as such but the search for a specific MS virus (1). If it is the case that a virus or viruses are involved in the inception or induction of MS, then I am convinced that the activation mechanism involves factors in the internal and/or external environment.
Might MS be caused or triggered by a hormonal or enzymatic disturbance induced by light? The hormone that comes to mind is melatonin, which is produced in the pineal body and plays a part in daily rhythms in man, and perhaps even more so its precursor serotonin. Having been formed by the enzymatic transformation of an amino acid (tryptophan), serotonin is converted in a similar process into N-acetyl-serotonin, which is then used for the synthesis of melatonin (2). Instead of being a gland in the traditional sense, the pineal appears to be one of four neuroendocrine transducers, i.e. a junction where an input of neural information is converted into a hormonal
Date received 20 February 1990 Date accepted 28 March 1!390 69
70 or endocrine output for distribution in the blood. The neural input of the pineal is noradrenaline or serotonin, released from postganglionic sympathetic nerves, and its hormonal output is melatonin. The pineal transmits information by altering the rate at which it secretes melatonin, which appears to be synthesized only in this organ (2, 3). In mammals, melatonin is secreted at night time and it seems that the circulating level is influenced by, but not dependent on, light (5); the level is low in the daytime and rises during the night (6). There are various routes by which information about external lighting could be transmitted to the pineal: retinal stimulation could reach the pineal via nerve pathways, light could act indirectly by influencing other circulating hormones that in turn affect enzyme activity, or light could impinge directly on the pineal (3). Although the skulls of mammals do admit significant amounts of light, it appears that the pineal responds only if the light activates the retina of the eye (2). Apparently, then, light stimulates the retina and information about the light is transmitted to the pineal via sympathetic nerves.
MEDICAL HYPOTHESES
duction of) the enzyme (hydroxyindole-O-methyltransferase, HIOMT) that regulates the synthesis of melatonin (2). The fact that light affects both the weight of the pineal and at least two enzyme systems in this organ suggests that it may regulate many other, as yet undiscovered biochemical phenomena in the pineal via the sympathetic nervous system (2). Experiments performed in rats to determine the effect on the pineal of normal lighting rhythms showed that in the five hours from the onset of darkness to midnight, the formation of melatonin increased between two and three times. The weight of the pineal also changed significantly in this period, again indicating that light may affect many more compounds in the pineal than the single enzyme that was being studied (2).
I
I
Fig. 2
Fig. 1 Source: Kurtzke, J.F. Geographic distribution of multiple sclerosis: An update with special reference to Europe and the Mediterranean region. Acta Neurol. Scandinav. 1980, 62, 65 - 80.
The sympathetic nervous system is involved in adaptation to rapid internal and external changes (2). Sympathetic nerves to the pineal release neurohormones (noradrenaline or serotonin) that act on the pineal cells to induce (or block the in-
Thus, the pineal rhythm in HIOMT activity appears to be truly exogenous and wholly dependent on changes in the environmental lighting (2). The serotonin rhythm in the pineal is endogenous and environmental light functions only as an external synchronizer. The regulating mechanism appears to reside in the central nervous system. The pineal organ accordingly contains at least two distinct biological clocks, one entirely dependent on environmental lighting and the other originating in the brain but susceptible to changes in lighting (2). Given the melatonin is released from the pineal into the circulation and acts as a hormone on distant organs, the relationship between light and pineal HIOMT activity may represent a new kind of neuroendocrine regulatory mechanism: light
MULTIPLE SCLEROSIS -
IS RESEARCH ON THE WRONG TRACK?
71
controls the supply of a hormone by regulating the activity of an enzyme needed for its synthesis (3). The identification of melatonin over 30 years ago was followed by the discovery that the pineal organ, in cattle as well as in man, has a comparatively high content of serotonin, a hormone with a molecular structure similar to that of melatonin and a function in nervous tissue that is sti!l largely unknown (2). Leading American pineal researchers are fairly confident that the human pineal - and its major hormone, melatonin - will prove to have a number of physiological roles involving the brain and perhaps other organs and that melatonin may also participate in a number of diseases and in mediating effects of drugs (4). The pineal therefore appears to function as an intricate and sensitive biological clock that converts cyclic nervous activity, generated by light, into endocrine information (2).
The cerebral turnover of serotonin is influenced by ergotamine and the firing rate of central serotonergic neurons is known to be depressed by several ergot alkaloids. The evidence that central serotonergic circuits are involved in circulatory regulation is an indication that the primary site of action of ergotamine might be central rather than peripheral (10). The occurrence of ergot is largely determined by climatic conditions - the fungus is known to thrive in cold, wet seasons with little sunshine. Ideal conditions for its development and dissemination are provided by high humidity and cool weather; under such circumstances the disease can quickly become epidemic (11). As to the geographical distribution of ergot, Claviceps purpurea, I find it noteworthy, to say the least, that it corresponds to such an extent with the geographical distribution of MS, Figures 1 and 2 (12, 13).
Might MS be caused or triggered by mycotoxins?
Conclusion
I am thinking primarily of ergotamine (Secale cornutum), the principal component of ergot (Claviceps purpurea). Ergot poisoning produces symptoms similar in many respects to those of MS. The ergot fungus is associated with grasses, in particular with rye, which is grown mainly in northern latitudes (7). Symptoms of iatrogenic as well as natural ergotism appear to result from local ischemia caused by ergot-induced vasospasm (8). Natural ergotism seems to have been studied more thoroughly in livestock (horses, e.g.) than in man, perhaps understandably, but the symptoms do seem to be similar in many respects. Tolerance to ergot varies greatly between individuals. It has long been known that some patients are quite sensitive, while others develop no symptoms for years on doses considered to be in the toxic range. It still remains to be explained why some patients suddenly develop symptoms of ergot intoxication after tolerating large doses for years (8). Besides inducing the constriction of distended extracranial arteries, ergotamine may affect serotonergic neurons in the CNS (9). The capacity for vasomotor regulation has been located in the CNS, via serotonergic neural circuits, which is consistent with the hypothesis that the modulation of serotonin - centrally as well as peripherally - is of pathogenic importance (10).
Considering that the unavailing search for a specific MS virus seems to be futile, researchers should pay much more attention to the underlying cause of MS or its activation mechanism, such as e.g. an abnormality in melatonin secretion, or a mycotoxin, such as e.g. ergotamine or a related alkaloid, acting as the triggering factor for the manifestation of MS. References 1. Mims C. Multiple Sclerosis - the case against viruses, New Scientist 1983. 98. 938 - 40. 2. Wurtman RJ, Axklrod J. The pineal gland. Scientific American 1965, 213, 50-60. 3. Wurtman RJ, Axelrod J, Phillips LS. Melatonin synthesis in the pineal gland: control by light. Science 1963, 142, 1071-73.7. 4. Wurtman RJ. Introduction: Melatonin in Humans. In: Melatonin in Humans. (Eds. R.J. Wurtman and F. Waldhauser). International Conference on Melatonin in Humans, Vienna, Austria, November 7-9, 1985. J. Neural Transm. 1986, Suppl. 21, 1 - 8.7. Wurtman RJ. Summary and Forecast. Idem, 475 - 477. Boyce PH, Kennaway DJ. Effects of light on melatonin production. Biol. Psychiatry 1987, 22, 473 - 8. FAO production yearbook, 1986, 40, table 21, p. 81, FAO, Rome. Merhoff CC, Porter JM. Ergot intoxication: historical review and description of unusual clinical manifestations. Ann. Surg. November 1974, 180. 773 - 779. 9. Tfelt-Hansen, P. The effect of ergotamine on the arterial system in man. Acta Pharmacol. et Toxicol. 1986, 59, Suppl, III, 3 - 29. 10. Raskin NH. Pharmacology of migraine. Ann. Rev. Pharmacol. Toxicol. 1981, 21, 463 -478.
72 11. Bradley-Jones J. Ergot and ergotism. NAAS Quarterly Review 1964, 157- 164. 12. Kurtzke JF. Geographical distribution of multiple sclerosis: an update with special reference to Europe and the
MEDICAL HYPOTHESES
Mediterranean region. Acta Neural Scandinav. 1980, 62, 65 - 80. 13. Commonwealth Mycological Institute. Distribution Maps of Plant Diseases, Map No. 10, 1966.
