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U.S.A."],"published-print":{"date-parts":[[2023,4,4]]},"abstract":"<jats:p>Previous studies revealed a latitudinal gradient of multiple sclerosis (MS) prevalence, increasing by moving from the equator to the poles. The duration and quality of an individual\u2019s exposure to sunlight vary with latitude. Skin exposure to sunlight activates vitamin D synthesis, while light absence, as perceived by the eyes, activates melatonin synthesis in the pineal gland. Vitamin D or melatonin deficiency\/insufficiency or overdose can occur at any latitude due to specific lifestyles and diets. Moving away from the equator, especially beyond 37\u00b0, decreases vitamin D while raising melatonin. Furthermore, melatonin synthesis increases in cold habitats like northern countries. Since melatonin's beneficial role was shown in MS, it is expected that northern countries whose individuals have higher endogenous melatonin should show a lower MS prevalence; however, these are ranked with the highest scores. In addition, countries like the United States and Canada have uncontrolled over-the-counter usage. In high latitudes, vitamin D deficiency and a higher MS prevalence persist even though vitamin D is typically compensated for by supplementation and not sunlight. Recently, we found that prolonged darkness increased MS melatonin levels, mimicking the long-term increase in northern countries. This caused a reduction in cortisol and increased infiltration, inflammation, and demyelination, which were all rescued by constant light therapy. In this review, we explain melatonin and vitamin D's possible roles in MS prevalence. The possible causes in northern countries are then discussed. Finally, we suggest strategies to treat MS by manipulating vitamin D and melatonin, preferably with sunlight or darkness, not supplements.<\/jats:p>","DOI":"10.1073\/pnas.2219334120","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T15:21:56Z","timestamp":1679930516000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":25,"title":["Melatonin and vitamin D, two sides of the same coin, better to land on its edge to improve multiple sclerosis"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2344-3640","authenticated-orcid":false,"given":"Majid","family":"Ghareghani","sequence":"first","affiliation":[{"name":"Neuroscience Laboratory, Centre Hospitalier Universitaire de Qu\u00e9bec Research Center, Department of Molecular Medicine, Faculty of Medicine, Laval University, Qu\u00e9bec City, QC G1V 4G2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9887-072X","authenticated-orcid":false,"given":"Kazem","family":"Zibara","sequence":"additional","affiliation":[{"name":"Platform for Research and Analysis in Environmental Science (PRASE) and Biology Department, Faculty of Sciences - I, Lebanese University, Beirut 1003, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Rivest","sequence":"additional","affiliation":[{"name":"Neuroscience Laboratory, Centre Hospitalier Universitaire de Qu\u00e9bec Research Center, Department of Molecular Medicine, Faculty of Medicine, Laval University, Qu\u00e9bec City, QC G1V 4G2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab104"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz088"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awq147"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2018-320189"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1177\/1352458511405562"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0317167100007587"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1177\/1352458509105579"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2018.01.009"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1177\/1352458510379614"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-65-5-823"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40101-016-0103-9"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-079X.1994.tb00079.x"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(97)00358-2"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1177\/074873049501000406"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-079X.2003.00069.x"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2004.023416"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01451040"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep39865"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules23030703"},{"key":"e_1_3_4_20_2","first-page":"266","article-title":"Role of the pineal gland and melatonin in seasonal reproductive function in mammals","volume":"8","author":"Arendt J.","year":"1986","unstructured":"J. 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