Role of thyroid hormones in normal and abnormal central nervous system myelination in humans and rodents

Pagnin, Maurice; Kondos-Devcic, Delphi; Chincarini, Ginevra; Cumberland, Angela; Richardson, Samantha J.; Tolcos, Mary

doi:10.1016/j.yfrne.2021.100901

Cited by 25 publications

(10 citation statements)

References 208 publications

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“…Thyroid hormones play an important role in myelination in normal development and in pathological conditions [ 31 , 56 ]. Free T4 levels have been found to be proportional to the WM volume, although in older people, the relationship may be inverse [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

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An in vivo accelerated developmental myelination model for testing promyelinating therapeutics

et al. 2022

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Background Therapeutic agents stimulating the process of myelination could be beneficial for the treatment of demyelinating diseases, such as multiple sclerosis. The efficient translation of compounds promoting myelination in vitro to efficacy in vivo is inherently time-consuming and expensive. Thyroid hormones accelerate the differentiation and maturation of oligodendrocytes, thereby promoting myelination. Systemic administration of the thyroid hormone thyroxine (T4) accelerates brain maturation, including myelination, during early postnatal development. The objective of this study was to validate an animal model for rapid testing of promyelinating therapeutic candidates for their effects on early postnatal development by using T4 as a reference compound. Methods Daily subcutaneous injections of T4 were given to Sprague Dawley rat pups from postnatal day (PND) 2 to PND10. Changes in white matter were determined at PND10 using diffusion tensor magnetic resonance imaging (DTI). Temporal changes in myelination from PND3 to PND11 were also assessed by quantifying myelin basic protein (MBP) expression levels in the brain using the resonance Raman spectroscopy/enzyme-linked immunosorbent assay (RRS-ELISA) and quantitative immunohistochemistry. Results DTI of white matter tracts showed significantly higher fractional anisotropy in the internal capsule of T4-treated rat pups. The distribution of total FA values in the forebrain was significantly shifted towards higher values in the T4-treated group, suggesting increased myelination. In vivo imaging data were supported by in vitro observations, as T4 administration significantly potentiated the developmental increase in MBP levels in brain lysates starting from PND8. MBP levels in the brain of animals that received treatment for 9 days correlated with the FA metric determined in the same pups in vivo a day earlier. Furthermore, accelerated developmental myelination following T4 administration was confirmed by immunohistochemical staining for MBP in coronal brain sections of treated rat pups. Conclusions T4-treated rat pups had increased MBP expression levels and higher MRI fractional anisotropy values, both indications of accelerated myelination. This simple developmental myelination model affords a rapid test of promyelinating activity in vivo within several days, which could facilitate in vivo prescreening of candidate therapeutic compounds for developmental hypomyelinating diseases. Further research will be necessary to assess the utility of this platform for screening promyelination compounds in more complex demyelination disease models, such us multiple sclerosis.

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Section: Discussionmentioning

confidence: 99%

“…The thyroid hormones triiodothyronine and its precursor thyroxine (T4) are necessary for the normal development of myelin-generating oligodendrocytes [ 30 , 31 ]. The stimulatory role of T4 on myelination is known since the 1960s [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

An in vivo accelerated developmental myelination model for testing promyelinating therapeutics

et al. 2022

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“…EGF is also a positive regulator of thyroid cell proliferation (35), and tri-iodothyronine plays a key role in the timing of OPC differentiation by stopping OPC proliferation and starting their terminal differentiation (36,37). Therefore, it is no accident that tri-iodothyronine has been successfully used to treat experimental allergic encephalomyelitis (EAE) (36), cuprizone-induced CNS demyelination, and MS (38,39).…”

Section: The Egf Role In the Genesis And Maintenance Of Cns Myelinmentioning

confidence: 99%

New Epidermal-Growth-Factor-Related Insights Into the Pathogenesis of Multiple Sclerosis: Is It Also Epistemology?

Scalabrino

2021

Front. Neurol.

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Recent findings showing that epidermal growth factor (EGF) is significantly decreased in the cerebrospinal fluid (CSF) and spinal cord (SC) of living or deceased multiple sclerosis (MS) patients, and that its repeated administration to rodents with chemically- or virally-induced demyelination of the central nervous system (CNS) or experimental allergic encephalomyelitis (EAE) prevents demyelination and inflammatory reactions in the CNS, have led to a critical reassessment of the MS pathogenesis, partly because EGF is considered to have little or no role in immunology. EGF is the only myelinotrophic factor that has been tested in the CSF and spinal cord of MS patients, and it has been shown there is a good correspondence between liquid and tissue levels. This review: (a) briefly summarises the positive EGF effects on neural stem cells, oligodendrocyte cell lineage, and astrocytes in order to explain, at least in part, the biological basis of the myelin loss and remyelination failure in MS; and (b) after a short analysis of the evolution of the principle of cause-effect in the history of Western philosophy, highlights the lack of any experimental immune-, toxin-, or virus-mediated model that precisely reproduces the histopathological features and “clinical” symptoms of MS, thus underlining the inapplicability of Claude Bernard's crucial sequence of “observation, hypothesis, and hypothesis testing.” This is followed by a discussion of most of the putative non-immunologically-linked points of MS pathogenesis (abnormalities in myelinotrophic factor CSF levels, oligodendrocytes (ODCs), astrocytes, extracellular matrix, and epigenetics) on the basis of Popper's falsification principle, and the suggestion that autoimmunity and phologosis reactions (surely the most devasting consequences of the disease) are probably the last links in a chain of events that trigger the reactions. As it is likely that there is a lack of other myelinotrophic growth factors because myelinogenesis is controlled by various CNS and extra-CNS growth factors and other molecules within and outside ODCs, further studies are needed to investigate the role of non-immunological molecules at the time of the onset of the disease. In the words of Galilei, the human mind should be prepared to understand what nature has created.

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“…Girls are more likely to be affected than boys (female to male ratios are 2:1) [1][2][3]. Early diagnosis methods for CH are still necessary to establish more efficient treatments of CH, which is an important public health issue worldwide, including developed countries [4].…”

Section: Introductionmentioning

confidence: 99%

Mutational and bioinformatics analysis of the NKX2.1 gene in a cohort of Iranian pediatric patients with congenital hypothyroidism (CH)

Heidari

Manshadi

Eshghi

et al. 2022

PhysInt

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Congenital hypothyroidism (CH) occurs with a relatively alarming prevalence in infants, and if not diagnosed and treated in time, it can have devastating consequences for the development of the nervous system. CH is associated with genetic changes in several genes that encode transcription factors responsible for thyroid development, including mutations in the NK2 homeobox 1 (NKX2.1) gene, which encodes the thyroid transcription factor-1 (TTF-1). Although CH is frequently observed in pediatric populations, there is still a limited understanding of the genetic factors and molecular mechanisms contributing to this disease. The sequence of the NKX2.1 gene was investigated in 75 pediatric patients with CH by polymerase chain reaction (PCR), single-stranded conformation polymorphism (SSCP), and direct DNA sequencing. Four missense heterozygous variations were identified in exon 3 of the NKX2.1 gene, including three novel missense variations, namely c.708A>G, p.Gln202Arg; c.713T>G, p.Tyr204Asp; c.833T>G, p.Tyr244Asp, and a previously reported variant rs781133468 (c.772C>G, p.His223Gln). Importantly, these variations occur in highly conserved residues of the TTF-1 DNA-binding domain and were predicted by bioinformatics analysis to alter the protein structure, with a probable alteration in the protein function. These results indicate that nucleotide changes in the NKX2.1 gene may contribute to CH pathogenesis.

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Role of thyroid hormones in normal and abnormal central nervous system myelination in humans and rodents

Cited by 25 publications

References 208 publications

An in vivo accelerated developmental myelination model for testing promyelinating therapeutics

An in vivo accelerated developmental myelination model for testing promyelinating therapeutics

New Epidermal-Growth-Factor-Related Insights Into the Pathogenesis of Multiple Sclerosis: Is It Also Epistemology?

Mutational and bioinformatics analysis of the NKX2.1 gene in a cohort of Iranian pediatric patients with congenital hypothyroidism (CH)

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