Melatonin: A Novel Target for Neuroinflammation in Multiple Sclerosis

Melatonin, a neuro-endocrine hormone, secreted by pineal gland best known for the regulating our
circadian rhythm, can act as a potent anti-inflammatory and immunomodulatory properties that may
countervail the pathogenesis of multiple sclerosis (MS). MS is an autoimmune disorder where our immune
system accidentally activates immune cells against the myelin protein residue. This activation mistakenly
attacks the protective myelin covering of nerve fibres. Experimental and clinical studies reveal that
melatonin modulates immune balance and reduce the action of pathogenic effector T cells (TH17/TH1)
toward regulatory subsets such as FoxP3⁺ Tregs and IL-10 producing Tr1 cells. Acting mainly through
MT1/MTNR1A and MT2 receptors and nuclear factors including ROR-α, melatonin activates ERK1/2
and C/EBPα to repress REV-ERBα, relieving NFIL3 and thereby suppressing ROR-γt dependent TH17
differentiation and key cytokines IL-17 and GM-CSF. In parallel, MTNR1A–ERK1/2 and ROR-α
pathways enhance Tr1 development and IL-10 production, while dendritic cell IL-27 is increased, helping
to reduce immune cells infiltration into the central nervous system through down-regulation of
chemokines CCL20/CCL19 and adhesion molecules ICAM-1. Melatonin’s antioxidant activity further
limits NF-κB driven inflammation. Preclinical experimental autoimmune encephalomyelitis models show
reduced disease severity, lower TH17 responses, and higher IL-10 across varied dosing regimens. Limited
clinical studies reveal decreased nocturnal melatonin during relapses and elevations following interferon
β or natalizumab therapy. A proposed “seasonal paradox,” characterized by spring-summer relapse peaks
despite high vitamin D, may reflect melatonin suppression by longer daylight. However, causality remains
unproven, optimal dosing and long-term safety require clarification, and interactions with vitamin D or
Epstein-Barr virus are not fully explored. Overall, melatonin represents a biologically plausible yet still
investigational target for immunomodulatory strategies in MS.