Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system characterized by multifocal demyelinated lesions dispersed throughout the brain. Although white matter lesions have been the most extensively studied, cortical demyelination lesions are also detected in the MS brain. Cuprizone-induced demyelination (CPZ) in rodents has been widely used as a model for MS. Administration of the CPZ neurotoxin to mice also produces cortical demyelination, similar to the lesions found in MS patients. In rats Wistar induces demyelination in cortical areas of the forebrain. Ultrastructurally, demyelination is observed in the cortex before a detectable loss of myelin in the subcortical white matter. The loss of oligodendroglia in CPZ-intoxicated rats correlates with an increased number of astrocytes (reactive gliosis), which seek to repair the damage.
The regrowth of oligodendrocytes for the reconstruction of myelin is physiologically under the control of various hormones. Among these are the thyroid hormones, T3 and T4, which through their nuclear receptors induce the direct and indirect expression of proteins constituting the myelin sheath. Early in development, thyroid hormone acts as an instructive agent, triggering cell cycle exit to direct the cell towards specialization. In terminal oligodendrocytes, it enhances their morphological and functional maturation by stimulating the expression of various genes, such as myelin-oligodendrocyte glycoprotein (MOG), MBP and glutamine synthetase. Myelination is effectively delayed in hypothyroid animals and accelerated in hyperthyroid animals. Administration of thyroid hormones significantly enhances this process, as indicated by the increased expression of markers for different stages of oligodendrocyte differentiation and maturation, i.e. O4, MBP, A2B5 and PDGFR-alpha, and this corresponds to in vitro studies.
It is known that under physiological conditions the thyroid hormone regulates the endogenous synthesis of NGF and a single injection of T4 is able to increase the NGF content in the brain. There is also data indicating that T3 or T4 potentiate the activity of the PDGFR-alpha receptor, a growth factor receptor that induces cell proliferation and regeneration. Furthermore, thyroid hormones could also act on neural stem cells, promoting the production of more oligodendrocytes. Finally, they also influence the survival of developing oligodendrocytes, also overcoming the lethal effects mediated by inflammatory cytokines responsible for the course of MS, such as TNF-alpha and IL-1. As previously reported, treatment with thyroid hormones also accelerates the rate of remyelination in the cortex, compared to rats expecting spontaneous remyelination. A 2002 study reported that their administration increases the re-synthesis of myelin and growth factor NGF in the spinal cord of the EAE experimental model.
The effects of intranasal thyroid hormone on the progression of cortical lesions were tested in 2012 in CPZ rats. The results suggested that manipulating T3/T4 levels could be considered a strategy to promote the remyelination process in the cortex and prevent irreversible neuronal damage in MS patients. However, therapy with T3 or T4 has not been pursued clinically, as their high chronic systemic exposure (hyperthyroidism) adversely affects the heart, bone, and skeletal muscle, thereby limiting their therapeutic potential. Thyroid agonists, or thyromimetics, are a class of compounds that mimic the binding of T3 to the thyroid receptor (TR-alpha). Sobetirome is an investigational thyromimetic, devoid of the adverse effects associated with hyperthyroidism, and unique among thyromimetics in its ability to cross the blood-brain barrier and distribute to the central nervous system from a systemic dose.
Sobetirome has been shown to stimulate shooting-like actions during brain development and to alter brain lipid biomarkers in a model of X-linked adrenoleukodystrophy. The increased margin of safety for sobetirome over T3 results from a combination of differential tissue distribution and specificity for the TR-beta versus TR-alpha receptor. In experimental animals with gliotoxin-induced MS, the scientists found that chronic administration of T3 was not tolerated in this model and inhibited the proliferation of oligo precursors, underscoring the need for selective thyromimetic action. Thus, sobetirome appears to have the necessary properties and therapeutic index to stimulate myelin repair through a T3-like mechanism of action. Studies published in 2019 and 2021 seem to indicate that sobetirome is quite safe in long-term treatments. A chemically improved version of this drug has been developed.
Sob-AM2 is a new prodrug of sobetirome which, when dosed systemically, leads to increased central nervous system distribution and reduced peripheral exposure. In the last few years, other analogs of sobetirome and Sob-AM2 have been developed, which will be tested in pre-clinical and clinical studies to ascertain the feasibility of a regenerative hormone-like therapy for MS.
- By Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific publications
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– Degree in Medicine and Surgery in 1998 (MD Degree in 1998) – Specialist in Clinical Biochemistry in 2002 (Clinical Biochemistry residency in 2002) – Doctorate in Neurobiology in 2006 (Neurobiology PhD in 2006) – Stayed in the United States, Baltimore (MD ) as a researcher employed by the National Institute on Drug Abuse (NIDA/NIH) and then at Johns Hopkins University, from 2004 to 2008. – Since 2009 he has been involved in Personalized Medicine. – Emergency medical care in private structures since 2010 – Holder of two patents on the preparation of gluten-free products starting from regular enzymatically neutralized wheat flour (owner of patents concerning the production of gluten-free bakery products, starting from regular wheat flour). – Head of the Research and Development department for CoFood srl (Leader of the R&D for the partnership CoFood srl) – Author of articles on medical and health information on the website www.medicomunicare.it (Medical/health information on website) – Author of ECM FAD courses advertised on the website www.salutesicilia.it