Highlights •Melatonin levels negatively correlate with multiple sclerosis relapses in humans •Melatonin treatment ameliorates pathology in a mouse model of multiple sclerosis •Melatonin blocks ROR-γt expression and Th17 differentiation •Melatonin boosts Tr1 development via Erk1/2 and ROR-α
Researchers have found an explanation that could lead to a deeper understanding of multiple sclerosis and more targeted treatment options for patients. By first looking broadly at possible environmental factors and then deeply at preclinical models of MS, the research team found that melatonin – a hormone involved in regulating a person’s sleep-wake cycle – may influence MS disease activity.
Why do symptoms of multiple sclerosis (MS) seem to get better in the winter and worse in the summer? The team found that during the fall and winter, the group of 139 relapsing remitting MS patients they studied experienced a significant improvement in symptoms (a phenomenon that’s been observed in previous studies). The team then explored a variety of environmental factors including vitamin D levels, UV incidence and upper respiratory tract infections. But the factor that was consistently associated with severity of MS symptoms was melatonin. Melatonin levels are known to correlate with day length – during the longer days of the spring and summer, levels are lower and during the shorter days of the fall and winter, levels are higher.
The team tested this lead in the lab, studying the role that melatonin may play on a cellular level. Using both a mouse model and human cells, they investigated the effects of melatonin on certain types of cells, known to play a role in the immune response that leads to MS symptoms. Melatonin affected the roles of 2 cell types important in MS disease progression: pathogenic T cells that directly attack and destroy tissue and regulatory T cells, which are supposed to keep pathogenic T cells in check.
ie Melatonin induces expression of repressor transcription factor Nfil3, blocking the differentiation of pathogenic Th17 cells and boosts the generation of protective Tr1 cells via Erk1/2 and the transactivation of the IL-10 promoter by ROR-α. Melatonin is thus another example of how environmental-driven cues can impact T cell differentiation and have implications for autoimmune disorders. “We found that melatonin has a protective effect,” said Quintana. “It dampens the immune response and helps keep the bad guys – or pathogenic T cells — at bay.”
Although melatonin is available over the counter, it has significant drawbacks, including causing unwanted drowsiness. The team’s goal is to tease apart the molecular mechanisms that underlie melatonin’s role in order to develop targeted, non-toxic drugs that are safe and effective with minimal side effects. The team is currently working to establish a pilot clinical trial to study the effects of targeting melatonin signaling in MS patients and identify additional mechanisms of action. http://www.eurekalert.org/pub_releases/2015-09/bawh-mam090315.php
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