Abstract
It is well recognized that variation in the geographical distribution of prevalence of multiple sclerosis (MS) exists: increasing the latitude its prevalence increases as well, but the underlying causes of such dissimilarity still remained elusive as of today. Currently, the most accredited hypothesis is that the closer to the equator the more pronounced is the amount of sunlight which, in turn, increases the production of vitamin D. Cholecalciferol is indeed deficient in MS patients, but this factor does not explain by itself the etiopathogenesis of the disease. In the present study, to search for a pattern and provide a model of the disease’s etiology consistent with this regional factor, as well with its changing ethnic, sex-ratio, lifestyle variations and the other unexplained aspects of MS, an extensive analysis of peer-reviewed literature and data was conducted. The arisen hypothesis was that, increasing the latitude, the factor that varies and can have the stronger effect on the human organism, is the continuous and ever-increasing diversity of the natural light–dark cycle. The consequent effort of the suprachiasmatic nucleus to entrain the organism’s circadian rhythm affects the hypothalamic–pituitary–adrenal axis resulting in desynchronizing the central and peripheral circadian clocks and pathologizing the immunitary system. To verify such hypothesis, a theoretical framework of the etiopathogenesis, coherent with the gathered literature, was conceived and a demonstration to corroborate it was eventually devised and performed. The results underscored that people living in countries subjected to a further circadian disruptive factor, as daylight saving time, have a 6.35 times higher prevalence of MS than States placed on their same latitude that do not observe it, thus strongly supporting the hypothesis. As further reinforcement of the conclusions, it is worth mentioning that the levels of polyamines rise abruptly in autoimmune diseases. Moreover, among their numerous roles, these polycations participate to the regulation of the circadian clock so their sudden variation might disrupt it. Following these interesting findings, new perspectives in therapies are, therefore, proposed.
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Abbreviations
- MS:
-
Multiple sclerosis
- HPA axis:
-
Hypothalamic–pituitary–adrenal axis
- DST:
-
Daylight saving time
- LD:
-
Light–dark
- SCN:
-
Suprachiasmatic nucleus
- SWS:
-
Summer winter solstice
- PD:
-
Parkinson’s disease
- NKs:
-
Natural killer
- GID:
-
Gender identity disorders
- CNS:
-
Central nervous system
- ST:
-
Standard time
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Acknowledgements
The authors thank Anna Petrova for the helpful and fruitful suggestions and discussion as well as for the daily insights provided and Arch. Roberto Mezzaroma for having continuously encouraged the writing out of the manuscript and the drawing up of the project. Our gratitude is also due to the “International Polyamines Foundation—ONLUS” for the availability to look up in the Polyamines documentation.
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This study was also supported by resources provided by SAPIENZA University of Rome, Italy (EA).
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FG and EA conceived this investigation and coordinated the collaboration among the authors. All the authors wrote the manuscript and all the authors have read and approved the final manuscript.
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Gasperoni, F., Turini, P. & Agostinelli, E. A novel comprehensive paradigm for the etiopathogenesis of multiple sclerosis: therapeutic approaches and future perspectives on its treatment. Amino Acids 51, 745–759 (2019). https://doi.org/10.1007/s00726-019-02718-1
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DOI: https://doi.org/10.1007/s00726-019-02718-1