The Histamine and Multiple Sclerosis Alliance: Pleiotropic Actions and Functional Validation

Multiple sclerosis (MS) is a disease with a resilient inflammatory component caused by accumulation into the CNS of inflammatory infiltrates and macrophage/microglia contributing to severe demyelination and neurodegeneration. While the causes are still in part unclear, key pathogenic mechanisms are the direct loss of myelin-producing cells and/or their impairment caused by the immune system. Proposed etiology includes genetic and environmental factors triggered by viral infections. Although several diagnostic methods and new treatments are under development, there is no curative but only palliative care against the relapsing-remitting or progressive forms of MS. In recent times, there has been a boost of awareness on the role of histamine signaling in physiological and pathological functions of the nervous system. Particularly in MS, evidence is raising that histamine might be directly implicated in the disease by acting at different cellular and molecular levels. For instance, constitutively active histamine regulates the differentiation of oligodendrocyte precursors, thus playing a central role in the remyelination process; histamine reduces the ability of myelin-autoreactive T cells to adhere to inflamed brain vessels, a crucial step in the development of MS; histamine levels are found increased in the cerebrospinal fluid of MS patients. The aim of the present work is to present further proofs about the alliance of histamine with MS and to introduce the most recent and innovative histamine paradigms for therapy. We will report on how a long-standing molecule with previously recognized immunomodulatory and neuroprotective functions, histamine, might still provide a renewed and far-reaching role in MS.