Multiple sclerosis (MS) is a complex neurological condition. Genetic, behavioural and environmental factors are implicated in the aetiology and clinical course of the disease. Worldwide the prevalence of MS is increasing, exceeding 2.3 million people. In Australia, the incidence of MS increased by 9% between 2010 and 2017, with women representing three quarters of the 25,600 people diagnosed.
Demyelination of axons in the central nervous system (CNS) is a primary feature of MS. Myelin is necessary to ensheathe and isolate axons, allowing for appropriate nerve impulse transmission. Remyelination of axons may be more efficient during the acute focal stage of MS and, if this occurs, early lesions (fresh plaques) may be repaired and functionality restored.[2,3]
To form and regenerate myelin, oligodendrocyte progenitor cells (OPCs) must differentiate into mature oligodendrocytes, which then extend and wrap processes around nerve cell axons. The presence of OPCs in demyelinating lesions highlight an impairment of cell maturation. This is regarded as the foremost cause of remyelination failure in MS and supports the hypothesis that remyelination relies on ensuring successful OPC differentiation.[2,3]
A number of growth factors have been shown to promote endogenous oligodendrocyte differentiation in vitro, with triiodothyronine (T3) proving most effective. T3 is not only critical for CNS myelination during development, as highlighted by cretinism, but it is integral for the expression of oligodendrocyte specific genes and white matter turnover in adulthood.[3-5]
T3 has proven to enhance myelin repair in numerous in vivo demyelination models, yet has limited potential as a remyelination therapy. To promote oligodendrocyte differentiation, T3 doses would cause serum concentrations likely to induce hyperthyroidism and result in serious side-effects such as muscle weakness, anxiety, heart palpitations and thyrotoxic crisis. It is also indicated that chronic hyperthyroidism may inhibit genesis of OPCs and oligodendrocytes.[2,4]
All thyroid hormone receptor (THR) isoforms are expressed throughout the CNS, but THR-alpha predominates in the heart, bone and brain, while THR-beta predominates in the liver and pituitary. Thyromimetic medications selective for THR-beta have been shown to mediate specific TH functions including myelination, while avoiding serious side-effects related to the heart.[3,5-7]
Discovery of a natural thyromimetic with beta receptor specificity may show promise for remyelination in MS. Practitioners should also be mindful of monitoring thyroid function in MS patients due to the association between thyroid disorders, particularly hypothyroidism, and MS.[6,8]
- Campbell JA, Simpson S, Ahmad H, et al. Change in multiple sclerosis prevalence over time in Australia 2010-2017 utilising disease-modifying therapy prescription data. Mult Schler 2019 [Ahead of print] [Abstract].
- Hartley M, Banerji T, Tagge I, et al. Myelin repair stimulated by CNS-selective thyroid hormone action. JCI Insight 2019;4(8):e126329. [Full text]
- Calzà L, Fernández M, Giardino L. Role of the thyroid system in myelination and neural connectivity. Compr Physiol 2015;5(3):1405-1421. [Abstract]
- Baxi EG, Schott JT, Fairchild AN, et al. A selective thyroid hormone β receptor agonist enhances human and rodent oligodendrocyte differentiation. Glia 2014;62(9):1513-1529. [Full text]
- Shultz R, Wang Z, Nong J, et al. Local delivery of thyroid hormone enhances oligodendrogenesis and myelination after spinal cord injury. J Neural Eng 2017;14(3):036014. [Abstract]
- Lima S, Merrigan T, Rodrigues ED. Synthetic and plant derived thyroid hormone analogs. In: Ward L (Ed). Thyroid and Parathyroid Diseases - New Insights into Some Old and Some New Issues. London: IntechOpen, 2012.
- Grover G, Kelly J, Malm J. Thyroid hormone receptor subtype-β- selective agonists as potential treatments for metabolic syndrome. Future Lipidology 2007;2(6):641-649. [Full text]
- Karni A, Abramsky O. Association of MS with thyroid disorders. Neurology 1999;53(4):883-885. [Abstract]