Recovery from Chronic Demyelination by Thyroid Hormone Therapy: Myelinogenesis Induction and Assessment by Diffusion Tensor Magnetic Resonance Imaging

The failure of the remyelination processes in multiple sclerosis contributes to the formation of chronic demyelinated plaques that lead to severe neurological deficits. Long-term cuprizone treatment of C57BL/6 mice resulted in pronounced white matter pathology characterized by oligodendrocyte depletion, irreversible demyelination and persistent functional deficits after cuprizone withdrawal. The use of a combination of in vivo diffusion tensor magnetic resonance imaging (DT-MRI) and histological analyses allowed for an accurate longitudinal assessment of demyelination. Injection of triiodothyronine (T3) hormone over a 3 week interval after cuprizone withdrawal progressively restored the normal DT-MRI phenotype accompanied by an improvement of clinical signs and remyelination. The effects of T3 were not restricted to the later stages of remyelination but increased the expression of sonic hedgehog and the numbers of Olig2+ and PSA-NCAM+ precursors and proliferative cells. Our findings establish a role for T3 as an inducer of oligodendrocyte progenitor cells in adult mouse brain following chronic demyelination.

[1]  Jun Yoshino,et al.  Demyelination increases radial diffusivity in corpus callosum of mouse brain , 2005, NeuroImage.

[2]  M. Raff,et al.  Role of thyroid hormone receptors in timing oligodendrocyte differentiation. , 2001, Developmental biology.

[3]  Hsiao-Fang Liang,et al.  Noninvasive detection of cuprizone induced axonal damage and demyelination in the mouse corpus callosum , 2006, Magnetic resonance in medicine.

[4]  L. Calzà,et al.  Thyroid hormone activates oligodendrocyte precursors and increases a myelin-forming protein and NGF content in the spinal cord during experimental allergic encephalomyelitis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[5]  P. Grenier,et al.  MR imaging of intravoxel incoherent motions: application to diffusion and perfusion in neurologic disorders. , 1986, Radiology.

[6]  Jens Frahm,et al.  Multicontrast MRI of remyelination in the central nervous system , 2005, NMR in biomedicine.

[7]  J. M. McKenzie,et al.  Zinc deficiency and brain development in the rat. , 1975, Federation proceedings.

[8]  B D Trapp,et al.  Axonal pathology in multiple sclerosis: relationship to neurologic disability. , 1999, Current opinion in neurology.

[9]  R. Miller,et al.  Local sonic hedgehog signaling regulates oligodendrocyte precursor appearance in multiple ventricular zone domains in the chick metencephalon. , 2001, Developmental biology.

[10]  Ueli Suter,et al.  Quantifying the Early Stages of Remyelination Following Cuprizone‐induced Demyelination , 2003, Brain pathology.

[11]  H. Lassmann,et al.  Neuropathology of multiple sclerosis—new concepts , 2003, Brain Research Bulletin.

[12]  Susumu Mori,et al.  High resolution diffusion tensor imaging of axonal damage in focal inflammatory and demyelinating lesions in rat spinal cord. , 2007, Brain : a journal of neurology.

[13]  G J Barker,et al.  Investigation of MS normal-appearing brain using diffusion tensor MRI with clinical correlations , 2001, Neurology.

[14]  D. A. Howard,et al.  Iodine deficiency and brain development in the rat. , 1981, Australian Journal of Biological Sciences.

[15]  J. Puymirat,et al.  Oligodendrocyte maturation and progenitor cell proliferation are independently regulated by thyroid hormone , 1997, Glia.

[16]  L. Schomburg,et al.  Hepatic deiodinase activity is dispensable for the maintenance of normal circulating thyroid hormone levels in mice. , 2005, Biochemical and biophysical research communications.

[17]  Ludwin Sk.  Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. , 1978 .

[18]  G Venturini,et al.  ENZYMIC ACTIVITIES AND SODIUM, POTASSIUM AND COPPER CONCENTRATIONS IN MOUSE BRAIN AND LIVER AFTER CUPRIZONE TREATMENT IN VIVO , 1973, Journal of neurochemistry.

[19]  L. Sarliève,et al.  Expression of Thyroid Hormone Receptor Isoforms in the Oligodendrocyte Lineage , 2004, Neurochemical Research.

[20]  R. Franklin,et al.  To what extent is oligodendrocyte progenitor migration a limiting factor in the remyelination of multiple sclerosis lesions? , 1997, Multiple sclerosis.

[21]  T. Ben-Hur,et al.  From Neural Stem Cells to Myelinating Oligodendrocytes , 1999, Molecular and Cellular Neuroscience.

[22]  L. Calzà,et al.  Thyroid hormone administration enhances remyelination in chronic demyelinating inflammatory disease. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Denis Le Bihan,et al.  Looking into the functional architecture of the brain with diffusion MRI , 2003, Nature Reviews Neuroscience.

[24]  M. Rovaris,et al.  Secondary progressive multiple sclerosis: current knowledge and future challenges , 2006, The Lancet Neurology.

[25]  Blakemore Wf.  The response of oligodendrocytes to chemical injury. , 1984 .

[26]  Myung Soo Cho,et al.  Efficient Induction of Oligodendrocytes from Human Embryonic Stem Cells , 2007, Stem cells.

[27]  G. Martino,et al.  Cell-based remyelinating therapies in multiple sclerosis: evidence from experimental studies , 2004, Current opinion in neurology.

[28]  R. Miller,et al.  The origin of spinal cord oligodendrocytes is dependent on local influences from the notochord. , 1996, Developmental biology.

[29]  Shu-Wei Sun,et al.  Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia , 2003, NeuroImage.

[30]  Robin J. M. Franklin,et al.  Why does remyelination fail in multiple sclerosis? , 2002, Nature Reviews Neuroscience.

[31]  J. Oppenheimer,et al.  Molecular basis of thyroid hormone-dependent brain development. , 1997, Endocrine reviews.

[32]  Olivier Yu,et al.  Remyelination assessment by MRI texture analysis in a cuprizone mouse model. , 2004, Magnetic resonance imaging.

[33]  S. Mori,et al.  Principles of Diffusion Tensor Imaging and Its Applications to Basic Neuroscience Research , 2006, Neuron.

[34]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[35]  J. Goldman,et al.  Oligodendrocytes and progenitors become progressively depleted within chronically demyelinated lesions. , 2004, The American journal of pathology.

[36]  P. Morell,et al.  The Neurotoxicant, Cuprizone, as a Model to Study Demyelination and Remyelination in the Central Nervous System , 2001, Brain pathology.

[37]  L. Calzà,et al.  Thyroid hormone and remyelination in adult central nervous system: a lesson from an inflammatory-demyelinating disease , 2005, Brain Research Reviews.

[38]  G. Comi,et al.  Quantification of cervical cord pathology in primary progressive MS using diffusion tensor MRI , 2005, Neurology.

[39]  Patrick Poulet,et al.  Astrocytic hypertrophy in dysmyelination influences the diffusion anisotropy of white matter , 2007, Journal of neuroscience research.

[40]  Oppenheimer Jh.  Citation for the 1997 Edwin B. Astwood Lecture Award of The Endocrine Society to John D. Baxter. , 1997 .

[41]  S. Ludwin.  Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. , 1978, Laboratory investigation; a journal of technical methods and pathology.

[42]  W. Blakemore.  The response of oligodendrocytes to chemical injury. , 1984, Acta neurologica Scandinavica. Supplementum.

[43]  M. Ghandour,et al.  Proliferation and Death of Oligodendrocytes and Myelin Proteins Are Differentially Regulated in Male and Female Rodents , 2006, The Journal of Neuroscience.

[44]  C. Mariash,et al.  Triiodothyronine is a survival factor for developing oligodendrocytes , 2003, Molecular and Cellular Endocrinology.

[45]  C. Mariash,et al.  Thyroid hormone regulates oligodendrocyte accumulation in developing rat brain white matter tracts. , 2004, Endocrinology.

[46]  P. Poulet,et al.  Brain dysmyelination and recovery assessment by noninvasive in vivo diffusion tensor magnetic resonance imaging , 2006, Journal of neuroscience research.

[47]  S. Komoly.  Experimental demyelination caused by primary oligodendrocyte dystrophy. Regional distribution of the lesions in the nervous system of mice [corrected]. , 2005, Ideggyogyaszati szemle.

[48]  M. Ghandour,et al.  New Insights on Neuronal Alterations in Jimpy Mutant Brain , 2004, Neurochemical Research.

[49]  P. Basser,et al.  Estimation of the effective self-diffusion tensor from the NMR spin echo. , 1994, Journal of magnetic resonance. Series B.

[50]  M. Ghandour,et al.  Coexpression of thyroid hormone receptor isoforms in mouse oligodendrocytes , 2002, Journal of neuroscience research.

[51]  M. Ghandour,et al.  Recovery of Myelin after Induction of Oligodendrocyte Cell Death in Postnatal Brain , 2005, The Journal of Neuroscience.

[52]  W. Cammer,et al.  Expression of carbonic anhydrase II mRNA and protein in oligodendrocytes during toxic demyelination in the young adult mouse , 1996, Neurochemical Research.