Metabolic Brain Disease

, Volume 33, Issue 2, pp 481–489 | Cite as

Expression of thyroid-stimulating hormone receptors and thyroglobulin in limbic regions in the adult human brain

Original Article
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Abstract

Expression of the human thyroid-specific proteins, thyroid-stimulating hormone receptor (TSH-R) and thyroglobulin (TG) in non-thyroid tissue is well-documented. TSH-R has been identified in the heart, kidney, bone, pituitary, adipose tissue, skin and astrocyte cultures. TG has been identified in the skin, thymus and kidney. However, none of those previous studies had identified TSH-R or TG in specific human brain regions. Previously, a pilot study conducted by our group on normal adult human brain demonstrated TSH-R and TG in cortical neurons and cerebral vasculature, respectively, within various brain areas. In the present study, we extend this investigation of thyroid proteins specifically in limbic regions of normal human brain. Forensic human samples of amygdalae, cingulate gyrii, frontal cortices, hippocampii, hypothalamii, and thalamii were obtained from five individuals who had died of causes unrelated to head injury and had no evidence of brain disease or psychological abnormality. Tissues were probed with commercial polyclonal antibodies against human TSH-R and TG which resulted in the significant demonstration of neuronal TSH-R in all limbic regions examined. Other novel results demonstrated TG in vascular smooth muscle of all limbic regions and in some neurons. Finding thyroid proteins in limbic areas of the human brain is unique, and this study demonstrates that cerebro-limbic localisation of thyroid proteins may have potential roles in neuro-psycho-pharmacology.

Keywords

Thyroid-stimulating hormone receptor Thyroglobulin Thyroid gland Limbic regions Auto-immune thyroid disease Immuno-histochemistry 

Abbreviations

TSH-R

thyroid-stimulating hormone receptor

TG

thyroglobulin

AITD

auto-immune thyroid disorders

HPT

hypothalamic-pituitary-thyroid axis

BBB

blood-brain barrier

CNS

central nervous system

DAB

diaminobenzidine

ROI

region of interest

RT

room temperature

Notes

Acknowledgements

The authors thank Cathy Connelly from the Biostatistics Unit within the Department of Family Medicine and Public Health, University of KwaZulu-Natal for providing statistical assistance.

Compliance with ethical standards

Funding

This work was supported by the College of Health Sciences, University of KwaZulu-Natal and the Medical Research Council of South Africa.

Conflict of interest

The authors are unaware of any conflict of interest arising from the current project, and any, and all output therefrom, including but, not limited to journal articles, conference proceedings and scientific reports.

References

  1. Ai J, Leonardt JM, Heymann WR (2003) Autoimmune thyroid diseases: etiology, pathogenesis, and dermatologic manifestations. J Am Acad Dermatol 48:641–662CrossRefPubMedGoogle Scholar
  2. Berer K, Wekerle H, Krishnamoorthy G (2011) B cells in spontaneous autoimmune diseases of the central nervous system. Mol Immunol 48:1332–1337CrossRefPubMedGoogle Scholar
  3. Bockmann J, Winter C, Wittkowski W, Kreutz MR, Bockers TM (1997) Cloning and expression of a brain-derived TSH-receptor. Biochem Biophys Res Commun 238:173–178CrossRefPubMedGoogle Scholar
  4. Bodo E, Kromminga A, Biro T, Borbiro I, Gaspar E, Zmijewski MA, van Beek N, Langbein L, Slominski AT, Paur R (2009) Human female hair follicles are a direct, nonclassical target for thyroid-stimulating hormone. J Invest Dermatol 129:1126–1139CrossRefPubMedGoogle Scholar
  5. Bolton SJ, Anthony DC, Perry VH (1998) Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood-brain barrier breakdown in vivo. Neuroscience 86:1245–1257CrossRefPubMedGoogle Scholar
  6. Brent GA (2012) Mechanisms of thyroid hormone action. J Clin Invest 122:3035–3043CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chabaud O, Lissitzky S (1977) Thyrotropin-specfic binding to human peripheral blood monocytes and polymorphonuclear leukocytes. Mol Cell Endocrinol 7:79–87CrossRefPubMedGoogle Scholar
  8. Cianfarani F, Baldini E, Cavalli A, Marchioni E, Lembo L, Teson M, Persecjino S, Zambruno G, Ulisse S, Odorisio T, D’Armiento M (2010) TSH receptor and thyroid-specific gene expression in human skin. J Invest Dermatol 130:93–101CrossRefPubMedGoogle Scholar
  9. Clement K, Viguerie N, Diehn M, Alizadeh A, Barbe P, Thalamas C (2002) In vivo regulation of human skeletal muscle gene expression by thyroid hormone. Genome Res 12:281–291CrossRefPubMedPubMedCentralGoogle Scholar
  10. Crisanti P, Omri B, Hughes E, Meduri G, Hery C, Clauser E, Jacquemin C, Saunier B (2001) The expression of thyrotropin receptor in the brain. Endocrinology 142:812–822CrossRefPubMedGoogle Scholar
  11. Davies T, Marians R, Latif R (2002) The TSH receptor reveals itself. J Clin Invest 110:161–164CrossRefPubMedPubMedCentralGoogle Scholar
  12. Drvota V, Janson A, Norman C, Sylven C (1995) Evidence for the presence of functional thyrotropin receptor in cardiac muscle. Biochem Biophys Res Commun 211:426–431CrossRefPubMedGoogle Scholar
  13. Endo T, Ohta K, Haraguchi K, Onaya T (1995) Cloning and functional expression of a thyrotropin receptor cDNA from rat cells. J Biol Chem 270:10833–10837CrossRefPubMedGoogle Scholar
  14. Freitas BCG, Gereben B, Castillo M, Kallo I, Zeold A, Egri P et al (2010) Paracrine signalling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells. J Clin Invest 120:2206–2217CrossRefPubMedPubMedCentralGoogle Scholar
  15. Guyton AC, Hall JE (2000) Textbook of medical physiology, tenth edn. Elsevier, PhiladelphiaGoogle Scholar
  16. Inoue M, Tawata M, Yokomori N, Endo T, Onaya T (1998) Expression of thyrotropin receptor on clonal osteoblast-like rat osteosarcoma cells. Thyroid 8:1059–1064CrossRefPubMedGoogle Scholar
  17. Kumar RS, Ijiri S, Kight K, Swanson P, Dittmann A (2000) Cloning and functional expression of a thyrotropin receptor from the gonads of a vertebrate (bony fish): potential thyroid-independent role for thyrotropin in reproduction. Mol Cell Endocrinol 167:1–9CrossRefPubMedGoogle Scholar
  18. Lou J, Chofflon M, Juillard C, Donati Y, Mili N, Siegrisy CA, Grau GE (1997) Brain microvascular endothelial cells and leukocytes derived from patients with multiple sclerosis exhibit increased adhesion capacity. Neuroreport 8:629–633CrossRefPubMedGoogle Scholar
  19. Minagar A, Shapshak P, Fujimura R, Ownby R, Heyes M, Eisdorfer C (2002) The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. J Neurol Sci 202:13–23CrossRefPubMedGoogle Scholar
  20. Moodley K, Botha J, Raidoo DM, Naidoo S (2011) Immuno-localisation of anti-thyroid antibodies in adult human cerebral cortex. J Neurol Sci 302:114–117CrossRefPubMedGoogle Scholar
  21. Murakami M, Hosoi Y, Negishi T, Kamiya Y, Miyashita K, Yamada M, Iriuchijima T, Yokoo K, Yoshida I, Tsushima Y, Mori M (1996) Thymic hyperplasia in patients with graves’ disease. Identification of thyrotropin receptors in human thymus. J Clin Invest 98:2228–2234CrossRefPubMedPubMedCentralGoogle Scholar
  22. Nwoye L, Mommaerts WF, Simpson DR, Seradarian K, Marusich M (1982) Evidence for a direct action of thyroid hormone in specifying muscle properties. Am J Phys 242:R401–R408Google Scholar
  23. Ojamaa K, Klemperer JD, Klein I (1996) Acute effects of thyroid hormone on vascular smooth muscle. Thyroid 5:505–512CrossRefGoogle Scholar
  24. Pardridge WM, Buciak JL, Friden PM (1991) Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo. J Pharmacol Exp Ther 259:66–70PubMedGoogle Scholar
  25. Patel JP, Frey BN (2015) Disruption in the blood-brain barrier: the missing link between brain and body inflammation in bipolar disorder. Neural Plast 2015:1–12CrossRefGoogle Scholar
  26. Perkonen F, Weintraub BD (1978) Thyrotropin binding to cultured lymphocytes and thyroid cells. Endocrinology 103:1668–1677CrossRefGoogle Scholar
  27. Prummel MF, Brokken LJS, Meduri G, Misrahi M, Bakker O, Wiersinga WM (2000) Expression of the thyroid-stimulating hormone receptor in the folliculo-stellate cells of the human anterior pituitary. J Clin Endocrinol Metab 85:4347–4353CrossRefPubMedGoogle Scholar
  28. Raidoo DM, Ramsaroop R, Naidoo S, Bhoola KD (1996) Regional 2 distribution of tissue kallikrein in the human brain. Immunopharmacology 32:39–47CrossRefPubMedGoogle Scholar
  29. Ramsay ID (1966) Muscle dysfunction in hyperthyroidism. Lancet 2:931–934CrossRefPubMedGoogle Scholar
  30. Rojko JL, Price-Schiavi S (2008) Physiologic IgG biodistribution, transport, and clearance: implications for monoclonal antibody products. In: Cavagnaro JA (ed) Preclinical safety evaluation of biopharmaceuticals, vol Chapter 11. Wiley, Hoboken, pp 241–276CrossRefGoogle Scholar
  31. Saunders NR, Liddelow SA, Dziegielewska KM (2012) Barrier mechanism in the developing brain. Front Pharmacol 3:46CrossRefPubMedPubMedCentralGoogle Scholar
  32. Sellitti DF (2000) Renal expression of two ‘thyroid-specific’ genes: thyrotropin receptor and thyroglobulin. Exp Nephrol 8:235–243CrossRefPubMedGoogle Scholar
  33. Spitzweg C, Joba W, Heufelder AE (1999) Expression of thyroid-related genes in human thymus. Thyroid 9:133–141CrossRefPubMedGoogle Scholar
  34. St-Amour I, Pare I, Alata W, Coulombe K (2013) Brain bioavailability of human intravenous immunoglobulin and its transport through the murine blood-brain barrier. J Cereb Blood Flow Metab 33:1983–1992CrossRefPubMedPubMedCentralGoogle Scholar
  35. Szkudlinski MW, Fremont V, Ronin C, Weintraub BD (2002) Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Physiol Rev 82:473–502CrossRefPubMedGoogle Scholar
  36. Terasaki T, Ohtsuki S (2005) Brain-to-blood transporters for endogenous substrates and xenobiotics at the blood-brain barrier: an overview of biology and methodology. NeuroRx 2:63–72CrossRefPubMedPubMedCentralGoogle Scholar
  37. Udayakumar N, Rameshkumar AC, Srinivasan AV (2005) Hoffmann syndrome: presentation in hypothyroidism. J Postgrad Med 51:332–333PubMedGoogle Scholar
  38. Valyasevi RW, Erickson DZ, Harteneck DA, Dutton CM, Heufelder AE (1999) Differentiation of human orbital preadipocyte fibroblasts induces expression of functional thyrotropin receptor. J Clin Endocrinol Metab 84:2557–2562PubMedGoogle Scholar
  39. Wright JK, Botha JH, Naidoo S (2008) Influence of the kallikrein-kinin system on prostate and breast tumour angiogenesis. Tumour Biol 29:130–136CrossRefPubMedGoogle Scholar
  40. Yu F, Gothe S, Wikstrom L, Forest D, Vennstrom B, Larsson L (2000) Effects of thyroid hormone receptor gene disruption on myosin isoform expression in mouse skeletal muscles. Am J Phys Regul Integr Comp Phys 278:R1545–R1554Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Therapeutics and Medicines Management, Pharmaceutical Sciences, Nelson, R Mandela School of MedicineUniversity of KwaZulu-NatalDurbanSouth Africa

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