Neurochemical Research

, Volume 33, Issue 3, pp 569–578 | Cite as

Thyroid Hormones affect the Level and Activity of Nitric Oxide Synthase in Rat Cerebral Cortex during Postnatal Development

  • Zoltán Serfőző
  • Péter B. Kiss
  • Zoltán Kukor
  • Beáta Lontay
  • Károly Palatka
  • Vince Varga
  • Ferenc Erdődi
  • Károly Elekes
Original paper


The effects of thyroid hormones (TH) on the enzyme level and activity of neuronal nitric oxide synthase (nNOS) were studied in the rat cerebral cortex during postnatal life. As revealed by arginine/citrulline conversion assay and Western blot analysis of the homogenate of the parietal cortex T4 significantly increased nNOS activity and nNOS protein level to 153 ± 25% and to 178 ± 20%, respectively. In contrast, 6-n-propyl-2-thyouracil (PTU) decreased nNOS activity and nNOS level to 45 ± 10% and to 19 ± 4%, respectively. The number of nNOS-immunoreactive neurons did not change after either T4 or PTU treatment, however, following T4 administration the percentage of intensively immunoreactive neurons increased to 85 ± 3% compared to control (65 ± 6%), whereas it decreased to 49 ± 2% after PTU treatment. Our findings indicate that abnormal TH levels differentially regulate the activity and the level of nNOS and suggest a cross-talk between the TH and NO signaling pathway in the developing cerebral cortex of rats.


Cerebral cortex Development Nitric oxide synthase Thyroid hormone 



The substantial contribution of Dr Ágota Lenkey (Institute of Clinical Biochemistry and Molecular Pathology, Medical and Health Science Center, University of Debrecen, Hungary) in the measurement of serum fT4 and TSH level, and Dr Mária Földvári (Veszprém Central Laboratory, Prodia Diagnostic Rt, Veszprém, Hungary) in the determination of total T4 and T3 concentration in the cortical samples is greatly appreciated. This work was supported by the Universitas Foundation 2000 from the University of Debrecen to Z.S., the Mecenatura 5/99 grant from the Medical and Health Science Center at the University of Debrecen to K.P., the Hungarian Scientific Research Fund T49090 to K.E., and ETT 244/2006 grant from the Ministry of Health to F.E.


  1. 1.
    Dussault JH, Ruel J (1987) Thyroid hormones and brain development. Annu Rev Physiol 49:321–334PubMedCrossRefGoogle Scholar
  2. 2.
    Bernal J (2005) Thyroid hormones and brain development. Vitam Horm 71:95–122PubMedGoogle Scholar
  3. 3.
    Guix FX, Uribesalgo I, Coma M et al (2005) The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol 76:126–152PubMedCrossRefGoogle Scholar
  4. 4.
    Vincent SR, Kimura H (1992) Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience 46:755–784PubMedCrossRefGoogle Scholar
  5. 5.
    Rodrigo J, Springall DR, Uttenthal O et al (1994) Localization of nitric oxide synthase in the adult rat brain. Philos Trans R Soc Lond B Biol Sci 345:175–221PubMedCrossRefGoogle Scholar
  6. 6.
    Yan XX, Garey LJ, Jen LS (1994) Development of NADPH-diaphorase activity in the rat neocortex. Brain Res Dev Brain Res 79:29–38PubMedCrossRefGoogle Scholar
  7. 7.
    Sancesario G, Morello M, Reiner A et al (2000) Nitrergic neurons make synapses on dual-input dendritic spines of neurons in the cerebral cortex and the striatum of the rat: implication for a postsynaptic action of nitric oxide. Neuroscience 99:627–642PubMedCrossRefGoogle Scholar
  8. 8.
    Brenman JE, Bredt DS (1997) Synaptic signaling by nitric oxide. Curr Opin Neurobiol 7:374–378PubMedCrossRefGoogle Scholar
  9. 9.
    Contestabile A, Ciani E (2004) Role of nitric oxide in the regulation of neuronal proliferation, survival and differentiation. Neurochem Int 45:903–914PubMedCrossRefGoogle Scholar
  10. 10.
    Keilhoff G, Seidel B, Noack H et al (1996) Patterns of nitric oxide synthase at the messenger RNA and protein levels during early rat brain development. Neuroscience 75:1193–1201PubMedCrossRefGoogle Scholar
  11. 11.
    Ueta Y, Levy A, Chowdrey HS et al (1995) Hypothalamic nitric oxide synthase gene expression is regulated by thyroid hormones. Endocrinology 136:4182–4187PubMedCrossRefGoogle Scholar
  12. 12.
    Chakrabarti N, Ray AK (2000) Rise of intrasynaptosomal Ca2+ level and activation of nitric oxide synthase in adult rat cerebral cortex pretreated with 3-5-3′-L-triiodothyronine. Neuropsychopharmacol 22:36–41CrossRefGoogle Scholar
  13. 13.
    Serfőző Z, Kiss PB, Erdődi F et al (2000) Thyroid hormone affects nitric oxide synthase content in the developing cerebral cortex and hippocampus of postnatal rats. Eur J Neurosci 12(Suppl S):282Google Scholar
  14. 14.
    Morreale de Escobar G, Pastor R, Obregon MJ et al (1985) Effects of maternal hypothyroidism on the weight and thyroid hormone content of rat embryonic tissues, before and after onset of fetal thyroid function. Endocrinology 117:1890–1900CrossRefGoogle Scholar
  15. 15.
    Kukor Z, Valent S, Tóth M (2000) Regulation of nitric oxide synthase activity by tetrahydrobiopterin in human placenta from normal and pre-eclamptic pregnancies. Placenta 21:763–772PubMedCrossRefGoogle Scholar
  16. 16.
    Galton VA (2005) The roles of the iodothyronine deiodinases in mammalian development. Thyroid 15:823–834PubMedCrossRefGoogle Scholar
  17. 17.
    Courtin F, Zrouri H, Lamirand A et al (2005) Thyroid hormone deiodinases in the central and peripheral nervous system. Thyroid 15:931–942PubMedCrossRefGoogle Scholar
  18. 18.
    Broedel O, Eravci M, Fuxius S et al (2003) Effects of hyper- and hypothyroidism on thyroid hormone concentrations in regions of the rat brain. Am J Physiol Endocrinol Metab 285:E470–E480PubMedGoogle Scholar
  19. 19.
    Kundu S, Pramanik M, Roy S (2006) Maintenance of brain thyroid hormone level during peripheral hypothyroid condition in adult rat. Life Sci 79:1450–1455PubMedCrossRefGoogle Scholar
  20. 20.
    Escobar-Morreale HF, Obregón MJ, Escobar del Rey F et al (1995) Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest 96:2828–2838PubMedCrossRefGoogle Scholar
  21. 21.
    Sasaki M, Gonzalez-Zulueta M, Huang H et al (2000) Dynamic regulation of neuronal NO synthase transcription by calcium influx through a CREB family transcription factor-dependent mechanism. Proc Natl Acad Sci USA 97:8617–8622PubMedCrossRefGoogle Scholar
  22. 22.
    Martel J, Cayrou C, Puymirat J (2002) Identification of new thyroid hormone-regulated genes in rat brain neuronal cultures. Neuroreport 13:1849–1851PubMedCrossRefGoogle Scholar
  23. 23.
    Haas MJ, Mreyoud A, Fishman M et al (2004) Microarray analysis of thyroid hormone-induced changes in mRNA expression in the adult rat brain. Neurosci Lett 365:14–18PubMedCrossRefGoogle Scholar
  24. 24.
    Dong H, Wade M, Williams A et al (2005) Molecular insight into the effects of hypothyroidism on the developing cerebellum. Biochem Biophys Res Commun 3304:1182–1193CrossRefGoogle Scholar
  25. 25.
    Davis PJ, Davis FB (1996) Nongenomic actions of thyroid hormone. Thyroid 6:497–504PubMedCrossRefGoogle Scholar
  26. 26.
    Palumbo A, d’Ischia M, Cioffi F (2000) 2-Thiouracil is a selective inhibitor of neuronal nitric oxide synthase antagonising tetrahydrobiopterin-dependent enzyme activation and dimerisation. FEBS Lett 485:109–112PubMedCrossRefGoogle Scholar
  27. 27.
    Wei G, Dawson VL, Zweier JL (1999) Role of neuronal and endothelial nitric oxide synthase in nitric oxide generation in the brain following cerebral ischemia. Biochim Biophys Acta 1455:23–34PubMedGoogle Scholar
  28. 28.
    Bidmon HJ, Wu J, Godecke A et al (1997) Nitric oxide synthase-expressing neurons are area-specifically distributed within the cerebral cortex of the rat. Neuroscience 81:321–330PubMedCrossRefGoogle Scholar
  29. 29.
    Chung YH, Kim YS, Lee WB (2004) Distribution of neuronal nitric oxide synthase-immunoreactive neurons in the cerebral cortex and hippocampus during postnatal development. J Mol Histol 35:765–770PubMedCrossRefGoogle Scholar
  30. 30.
    Seress L, Abraham H, Hajnal A et al (2005) NOS-positive local circuit neurons are exclusively axo-dendritic cells both in the neo- and archi-cortex of the rat brain. Brain Res 1056:183–190PubMedCrossRefGoogle Scholar
  31. 31.
    Judas M, Sestan N, Kostovic I (1999) Nitrinergic neurons in the developing and adult human telencephalon: transient and permanent patterns of expression in comparison to other mammals. Microsc Res Tech 45:401–419PubMedCrossRefGoogle Scholar
  32. 32.
    Terada H, Nagai T, Okada S et al (2001) Ontogenesis of neurons immunoreactive for nitric oxide synthase in rat forebrain and midbrain. Brain Res Dev Brain Res 128:121–137PubMedCrossRefGoogle Scholar
  33. 33.
    Vargas F, Moreno JM, Rodriguez-Gomez I et al (2006) Vascular and renal function in experimental thyroid disorders. Eur J Endocrinol 154:197–212PubMedCrossRefGoogle Scholar
  34. 34.
    Estrada C, DeFelipe J (1998) Nitric oxide-producing neurons in the neocortex: morphological and functional relationship with intraparenchymal microvasculature. Cereb Cortex 8:193–203PubMedCrossRefGoogle Scholar
  35. 35.
    Tong XK, Hamel E (2000) Basal forebrain nitric oxide synthase (NOS)-containing neurons project to microvessels and NOS neurons in the rat neocortex: cellular basis for cortical blood flow regulation. Eur J Neurosci 12:2769–2780PubMedCrossRefGoogle Scholar
  36. 36.
    Vaucher E, Linville D, Hamel E (1997) Cholinergic basal forebrain projections to nitric oxide synthase-containing neurons in the rat cerebral cortex. Neuroscience 79:827–836PubMedCrossRefGoogle Scholar
  37. 37.
    Raszkiewicz JL, Linville DG, Kerwin JF Jr et al (1992) Nitric oxide synthase is critical in mediating basal forebrain regulation of cortical cerebral circulation. J Neurosci Res 33:129–135PubMedCrossRefGoogle Scholar
  38. 38.
    Gould E, Butcher LL (1989) Developing cholinergic basal forebrain neurons are sensitive to thyroid hormone. J Neurosci 9:3347–3358PubMedGoogle Scholar
  39. 39.
    Oh JD, Butcher LL, Woolf NJ (1991) Thyroid hormone modulates the development of cholinergic terminal fields in the rat forebrain: relation to nerve growth factor receptor. Brain Res Dev Brain Res 59:133–142PubMedCrossRefGoogle Scholar
  40. 40.
    Hohmann CF, Berger-Sweeney J (1998) Cholinergic regulation of cortical development and plasticity. New twists to an old story. Perspect Dev Neurobiol 5:401–425PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Zoltán Serfőző
    • 1
  • Péter B. Kiss
    • 1
  • Zoltán Kukor
    • 2
  • Beáta Lontay
    • 3
  • Károly Palatka
    • 4
  • Vince Varga
    • 5
  • Ferenc Erdődi
    • 3
  • Károly Elekes
    • 1
  1. 1.Department of Experimental Zoology, Balaton Limnological Research InstituteHungarian Academy of SciencesTihanyHungary
  2. 2.Department of Medical Chemistry, Molecular Biology and PathobiochemistrySemmelweis UniversityBudapestHungary
  3. 3.Department of Medical Chemistry, Medical and Health Science CenterUniversity of DebrecenDebrecenHungary
  4. 4.Department of Gastroenterology, Medical and Health Science CenterUniversity of DebrecenDebrecenHungary
  5. 5.Department of Physiology and Brain Research CenterUniversity of TampereTampereFinland

Personalised recommendations