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Modulatory Effects of Melatonin on Cadmium-Induced Changes in Biogenic Amines in Rat Hypothalamus

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Abstract

This study was undertaken to examine whether cadmium oral exposure modifies biogenic amine concentration at hypothalamic level in adult male rats, and to investigate the possible modulatory effects of melatonin against cadmium-induced changes on these neurotransmitters. For this purpose, rats were exposed to cadmium (25 mg/l of CdCl2 in the drinking water) with or without melatonin (30 μg/rat/day intraperitoneally) for 30 days. Norepinephrine (NE), dopamine (DA), serotonin (5-HT), 3,4-dihydroxyphenyl acetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) were quantified by high performance liquid chromatography (HPLC). Oral cadmium administration led to decrease of NE, DA, and 5-HT content and DA turnover within the three hypothalamic regions examined, and therefore an inhibition of 5-HT turnover at posterior hypothalamus. Sensitivity to melatonin was specific to the hypothalamic region evaluated. Thus, the anterior hypothalamus was not nearly sensitive to exogenously administered melatonin, whereas the neurohormone decreased the content of these amines in the mediobasal hypothalamus, and melatonin increased it in the posterior hypothalamic region. Melatonin effectively prevented some cadmium-induced alterations on hypothalamic amine concentration. This is the case of DA in the anterior and posterior hypothalamus, and 5-HT metabolism in the posterior hypothalamic region. In conclusion, the obtained results indicate that melatonin treatment may be effective modulating some neurotoxic effects induced by cadmium exposure, and, more to the point, a possible role of this indolamine as a preventive agent for environmental or occupational cadmium contamination.

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References

  • Acuna-Castroviejo D, Escames G, Macias M, Munoz Hoyos A, Molina Carballo A, Arauzo M, Montes R (1995) Cell protective role of melatonin in the brain. J Pineal Res 19:57–63

    Article  PubMed  CAS  Google Scholar 

  • Antolin I, Mayo JC, Sainz RM, del Brio Mde L, Herrera F, Martin V, Rodriguez C (2002) Protective effect of melatonin in a chronic experimental model of Parkinson’s disease. Brain Res 943:163–173

    Article  PubMed  CAS  Google Scholar 

  • Bagchi D, Vuchetich PJ, Bagchi M, Hassoun EA, Tran MX, Tang L, Stohs SJ (1997) Induction of oxidative stress by chronic administration of sodium dichromate [chromium VI] and cadmium chloride [cadmium II] to rats. Free Radic Biol Med 22:471–478

    Article  PubMed  CAS  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  • Calabrese V, Bates TE, Stella AM (2000) NO synthase and NO-dependent signal pathways in brain aging and neurodegenerative disorders: the role of oxidant/antioxidant balance. Neurochem Res 25:1315–1341

    Article  PubMed  CAS  Google Scholar 

  • Cano P, Poliandri AH, Jimenez V, Cardinali DP, Esquifino AI (2007) Cadmium-induced changes in Per 1 and Per 2 gene expression in rat hypothalamus and anterior pituitary: effect of melatonin. Toxicol Lett 172:131–136

    Article  PubMed  CAS  Google Scholar 

  • Cardinali DP, Vacas MI, Boyer EE (1979) Specific binding of melatonin in bovine brain. Endocrinology 105:437–441

    Article  PubMed  CAS  Google Scholar 

  • Caride A, Fernandez-Perez B, Cabaleiro T, Bernardez G, Lafuente A (2010) Cadmium chloride exposure modifies amino acid daily pattern in the mediobasal hypothalamus in adult male rat. J Appl Toxicol 30:84–90

    Article  PubMed  CAS  Google Scholar 

  • Carretero M, Escames G, Lopez LC, Venegas C, Dayoub JC, Garcia L, Acuna-Castroviejo D (2009) Long-term melatonin administration protects brain mitochondria from aging. J Pineal Res 47:192–200

    Article  PubMed  CAS  Google Scholar 

  • Casalino E, Calzaretti G, Sblano C, Landriscina C (2002) Molecular inhibitory mechanisms of antioxidant enzymes in rat liver and kidney by cadmium. Toxicology 179:37–50

    Article  PubMed  CAS  Google Scholar 

  • Chwelatiuk E, Wlostowski T, Krasowska A, Bonda E (2006) The effect of orally administered melatonin on tissue accumulation and toxicity of cadmium in mice. J Trace Elem Med Biol 19:259–265

    Article  PubMed  CAS  Google Scholar 

  • Cory-Slechta DA, Weiss B (1981) Aversiveness of cadmium in solution. Neurotoxicology 2:711–724

    PubMed  CAS  Google Scholar 

  • Council Directive (1986/609/EC) of November 24, 1986 on the approximation of laws, regulation and administrative provisions of the Member States regarding the protection of animals used for experimental and other scientific purposes. The Commission of the European Communities. DOCE L 358, 18 December 1986, pp 1–28

  • Das KP, Das PC, Dasgupta S, Dey CD (1993) Serotonergic–cholinergic neurotransmitters’ function in brain during cadmium exposure in protein restricted rat. Biol Trace Elem Res 36:119–127

    Article  PubMed  CAS  Google Scholar 

  • Dawson R Jr, Baker D, Eppler B, Tang E, Shih D, Hern H, Hu M (2000) Taurine inhibition of metal-stimulated catecholamine oxidation. Neurotox Res 2:1–15

    Article  PubMed  CAS  Google Scholar 

  • El-Missiry MA, Shalaby F (2000) Role of beta-carotene in ameliorating the cadmium-induced oxidative stress in rat brain and testis. J Biochem Mol Toxicol 14:238–243

    Article  PubMed  CAS  Google Scholar 

  • El-Sokkary GH, Nafady AA, Shabash EH (2010) Melatonin administration ameliorates cadmium-induced oxidative stress and morphological changes in the liver of rat. Ecotoxicol Environ Saf 73:456–463

    Article  PubMed  CAS  Google Scholar 

  • Esquifino AI, Villanua MA, Agrasal C, Tresguerres JA (1989) Possible prolactin-mediated effects of melatonin on gonadotropin secretion in the rat. Pharmacol Biochem Behav 32:157–162

    Article  PubMed  CAS  Google Scholar 

  • Esquifino AI, Seara R, Fernandez-Rey E, Lafuente A (2001) Alternate cadmium exposure differentially affects the content of gamma-aminobutyric acid (GABA) and taurine within the hypothalamus, median eminence, striatum and prefrontal cortex of male rats. Arch Toxicol 75:127–133

    Article  PubMed  CAS  Google Scholar 

  • Eybl V, Kotyzova D, Koutensky J (2006) Comparative study of natural antioxidants—curcumin, resveratrol and melatonin—in cadmium-induced oxidative damage in mice. Toxicology 225:150–156

    Article  PubMed  CAS  Google Scholar 

  • Goering PL, Waalkes MP, Klaassen CD (1995) Toxicology of cadmium. In: Goyer RA, Cherian MG (eds) Toxicology of metals: biochemical aspects, vol 115. Springer, New York

    Google Scholar 

  • González-Carracedo A (2005) Envejecimiento y cronotoxicidad neuroendocrina inducida por la exposición al cadmio. Doctoral thesis, University of Vigo

  • Gupta A, Shukla GS (1995) Development of brain free radical scavenging system and lipid peroxidation under the influence of gestational and lactational cadmium exposure. Hum Exp Toxicol 14:428–433

    Article  PubMed  CAS  Google Scholar 

  • Hill JM, Switzer RC III (1984) The regional distribution and cellular localization of iron in the rat brain. Neuroscience 11:595–603

    Article  PubMed  CAS  Google Scholar 

  • Hirata H, Asanuma M, Cadet JL (1998) Melatonin attenuates methamphetamine-induced toxic effects on dopamine and serotonin terminals in mouse brain. Synapse 30:150–155

    Article  PubMed  CAS  Google Scholar 

  • Jimenez-Ortega V, Cano P, Cardinali DP, Esquifino AI (2009) 24-Hour variation in gene expression of redox pathway enzymes in rat hypothalamus: effect of melatonin treatment. Redox Rep 14:132–138

    Article  PubMed  CAS  Google Scholar 

  • Jimenez-Ortega V, Cardinali DP, Fernandez-Mateos MP, Rios-Lugo MJ, Scacchi PA, Esquifino AI (2010) Effect of cadmium on 24-hour pattern in expression of redox enzyme and clock genes in rat medial basal hypothalamus. Biometals 23:327–337

    Article  PubMed  CAS  Google Scholar 

  • Johnson MD, Kenney N, Stoica A, Hilakivi-Clarke L, Singh B, Chepko G, Clarke R, Sholler PF, Lirio AA, Foss C, Reiter R, Trock B, Paik S, Martin MB (2003) Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland. Nat Med 9:1081–1084

    Article  PubMed  CAS  Google Scholar 

  • Kara H, Cevik A, Konar V, Dayangac A, Yilmaz M (2007) Protective effects of antioxidants against cadmium-induced oxidative damage in rat testes. Biol Trace Elem Res 120:205–211

    Article  PubMed  CAS  Google Scholar 

  • Karbownik M, Gitto E, Lewinski A, Reiter RJ (2001) Induction of lipid peroxidation in hamster organs by the carcinogen cadmium: melioration by melatonin. Cell Biol Toxicol 17:33–40

    Article  PubMed  CAS  Google Scholar 

  • Kasprzak KS, Nakabeppu Y, Kakuma T, Sakai Y, Tsuruya K, Sekiguchi M, Ward JM, Diwan BA, Nagashima K, Kasprzak BH (2001) Intracellular distribution of the antimutagenic enzyme MTH1 in the liver, kidney and testis of F344 rats and its modulation by cadmium. Exp Toxicol Pathol 53:325–335

    Article  PubMed  CAS  Google Scholar 

  • Kumar R, Agarwal AK, Seth PK (1996) Oxidative stress-mediated neurotoxicity of cadmium. Toxicol Lett 89:65–69

    Article  PubMed  CAS  Google Scholar 

  • Lafuente A, Marquez N, Pazo D, Esquifino AI (2001) Cadmium effects on dopamine turnover and plasma levels of prolactin, GH and ACTH. J Physiol Biochem 57:231–236

    Article  PubMed  CAS  Google Scholar 

  • Lafuente A, Gonzalez-Carracedo A, Romero A, Esquifino AI (2003) Effect of cadmium on 24-h variations in hypothalamic dopamine and serotonin metabolism in adult male rats. Exp Brain Res 149:200–206

    PubMed  CAS  Google Scholar 

  • Lafuente A, Gonzalez-Carracedo A, Romero A, Cano P, Esquifino AI (2004) Cadmium exposure differentially modifies the circadian patterns of norepinephrine at the median eminence and plasma LH, FSH and testosterone levels. Toxicol Lett 146:175–182

    Article  PubMed  CAS  Google Scholar 

  • Lafuente A, Gonzalez-Carracedo A, Romero A, Cabaleiro T, Esquifino AI (2005a) Toxic effects of cadmium on the regulatory mechanism of dopamine and serotonin on prolactin secretion in adult male rats. Toxicol Lett 155:87–96

    Article  PubMed  CAS  Google Scholar 

  • Lafuente A, Gonzalez-Carracedo A, Cabaleiro T, Romero A, Esquifino AI (2005b) Toxic effects of cadmium on GABA and taurine content in different brain areas of adult male rats. J Physiol Biochem 61:439–446

    Article  PubMed  CAS  Google Scholar 

  • Limson J, Nyokong T, Daya S (1998) The interaction of melatonin and its precursors with aluminium, cadmium, copper, iron, lead, and zinc: an adsorptive voltammetric study. J Pineal Res 24:15–21

    Article  PubMed  CAS  Google Scholar 

  • Lin CH, Huang JY, Ching CH, Chuang JI (2008) Melatonin reduces the neuronal loss, downregulation of dopamine transporter, and upregulation of D2 receptor in rotenone-induced parkinsonian rats. J Pineal Res 44:205–213

    Article  PubMed  CAS  Google Scholar 

  • Liu J, Kadiiska MB, Corton JC, Qu W, Waalkes MP, Mason RP, Liu Y, Klaassen CD (2002) Acute cadmium exposure induces stress-related gene expression in wild-type and metallothionein-I/II-null mice. Free Radic Biol Med 32:525–535

    Article  PubMed  CAS  Google Scholar 

  • Lopez E, Arce C, Oset-Gasque MJ, Canadas S, Gonzalez MP (2006) Cadmium induces reactive oxygen species generation and lipid peroxidation in cortical neurons in culture. Free Radic Biol Med 40:940–951

    Article  PubMed  CAS  Google Scholar 

  • Mazzoccoli G, De Cata A, Carughi S, Greco A, Inglese M, Perfetto F, Tarquini R (2010) A possible mechanism for altered immune response in the elderly. In Vivo 24:471–487

    PubMed  CAS  Google Scholar 

  • Mendez-Armenta M, Villeda-Hernandez J, Barroso-Moguel R, Nava-Ruiz C, Jimenez-Capdeville ME, Rios C (2003) Brain regional lipid peroxidation and metallothionein levels of developing rats exposed to cadmium and dexamethasone. Toxicol Lett 144:151–157

    Article  PubMed  CAS  Google Scholar 

  • Micevych P, Bondar G, Kuo J (2010) Estrogen actions on neuroendocrine glia. Neuroendocrinology 91:211–222

    Article  PubMed  CAS  Google Scholar 

  • Miguez JM, Martin FJ, Lema M, Aldegunde M (1996) Changes in serotonin level and turnover in discrete hypothalamic nuclei after pinealectomy and melatonin administration to rats. Neurochem Int 29:651–658

    Article  PubMed  CAS  Google Scholar 

  • Millan-Plano S, Garcia JJ, Martinez-Ballarin E, Reiter RJ, Ortega-Gutierrez S, Lazaro RM, Escanero JF (2003) Melatonin and pinoline prevent aluminium-induced lipid peroxidation in rat synaptosomes. J Trace Elem Med Biol 17:39–44

    Article  PubMed  CAS  Google Scholar 

  • Minami A, Takeda A, Nishibaba D, Takefuta S, Oku N (2001) Cadmium toxicity in synaptic neurotransmission in the brain. Brain Res 894:336–339

    Article  PubMed  CAS  Google Scholar 

  • Ortega-Gutierrez S, Garcia JJ, Martinez-Ballarin E, Reiter RJ, Millan-Plano S, Robinson M, Acuna-Castroviejo D (2002) Melatonin improves deferoxamine antioxidant activity in protecting against lipid peroxidation caused by hydrogen peroxide in rat brain homogenates. Neurosci Lett 323:55–59

    Article  PubMed  CAS  Google Scholar 

  • Pari L, Murugavel P (2007) Diallyl tetrasulfide improves cadmium induced alterations of acetylcholinesterase, ATPases and oxidative stress in brain of rats. Toxicology 234:44–50

    Article  PubMed  CAS  Google Scholar 

  • Parmar P, Limson J, Nyokong T, Daya S (2002) Melatonin protects against copper-mediated free radical damage. J Pineal Res 32:237–242

    Article  PubMed  CAS  Google Scholar 

  • Pillai A, Priya L, Gupta S (2003) Effects of combined exposure to lead and cadmium on the hypothalamic–pituitary axis function in proestrous rats. Food Chem Toxicol 41:379–384

    Article  PubMed  CAS  Google Scholar 

  • Poliandri AH, Machiavelli LI, Quinteros AF, Cabilla JP, Duvilanski BH (2006a) Nitric oxide protects the mitochondria of anterior pituitary cells and prevents cadmium-induced cell death by reducing oxidative stress. Free Radic Biol Med 40:679–688

    Article  PubMed  CAS  Google Scholar 

  • Poliandri AH, Esquifino AI, Cano P, Jimenez V, Lafuente A, Cardinali DP, Duvilanski BH (2006b) In vivo protective effect of melatonin on cadmium-induced changes in redox balance and gene expression in rat hypothalamus and anterior pituitary. J Pineal Res 41:238–246

    Article  PubMed  CAS  Google Scholar 

  • Real Ordinance 1201/2005 of October 10, 2005 sobre protección de los animales utilizados para experimentación y otros fines científicos. BOE 252, 21 October 2005, pp 34367–34391

  • Reiter RJ (1991) Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev 12:151–180

    Article  PubMed  CAS  Google Scholar 

  • Reiter RJ, Tan DX, Osuna C, Gitto E (2000) Actions of melatonin in the reduction of oxidative stress. A review. J Biomed Sci 7:444–458

    Article  PubMed  CAS  Google Scholar 

  • Sanchez-Barcelo EJ, Cos S, Mediavilla D, Martinez-Campa C, Gonzalez A, Alonso-Gonzalez C (2005) Melatonin–estrogen interactions in breast cancer. J Pineal Res 38:217–222

    Article  PubMed  CAS  Google Scholar 

  • Satarug S, Baker JR, Urbenjapol S, Haswell-Elkins M, Reilly PE, Williams DJ, Moore MR (2003) A global perspective on cadmium pollution and toxicity in non-occupationally exposed population. Toxicol Lett 137:65–83

    Article  PubMed  CAS  Google Scholar 

  • Sugawara C, Sugawara N, Miyake H (1981) Decrease of plasma vitamin A, albumin and zinc in cadmium-treated rats. Toxicol Lett 8:323–329

    Article  PubMed  CAS  Google Scholar 

  • Sugita M, Tsuchiya K (1995) Estimation of variation among individuals of biological half-time of cadmium calculated from accumulation data. Environ Res 68:31–37

    Article  PubMed  CAS  Google Scholar 

  • Swaab DF (2003) The Human Hypothalamus: Basic and clinical aspects, Part 1. In: Aminoff MF, Boller F, Swaab DF (eds) Handbook of clinical neurology 79 (3rd Series), vol. 1. Elsevier, Amsterdam

  • Tominaga K, Shibata S, Ueki S, Watanabe S (1992) Effects of inhibitory and excitatory drugs on the metabolic rhythm of the hamster suprachiasmatic nucleus in vitro. Eur J Pharmacol 217:79–84

    Article  PubMed  CAS  Google Scholar 

  • Ugriumov MV (2009) Endocrine functions of the brain in adult and developing mammals. Ontogenez 40:19–29

    PubMed  CAS  Google Scholar 

  • Villanua MA, Agrasal C, Tresguerres JA, Vaughan MK, Esquifino AI (1989) Melatonin effects on prolactin secretion in pituitary-grafted male rats. J Pineal Res 6:33–41

    Article  PubMed  CAS  Google Scholar 

  • Von Bohlen und Halbach O, Dermietzel R (2002) Neurotransmitters and neuromodulators. Handbook of receptors and biological effects. Wiley-VCH, Weinheim

    Book  Google Scholar 

  • Waalkes MP (2003) Cadmium carcinogenesis. Mutat Res 533:107–120

    PubMed  CAS  Google Scholar 

  • World Health Organization (1995) Inorganic constituents and physical parameters. In: Guidelines for drinking water quality: health criteria and other supporting information. World Health Organization, Geneva

  • World Health Organization (2000) Evaluation of certain food additives and contaminants. In: 55th Report of the joint FAO/WHO expert committee on food additives, Geneva, Switzerland

  • Yoshioka K, Xie F, Gitzen JF, Kissinger CB, Kissinger PT (2000) Preliminary study of the effect of melatonin administration on the release of endogenous 5-HT and its metabolite in rat SCN. Curr Sepn 18:117–122

    CAS  Google Scholar 

  • Yu CX, Wu GC, Xu SF, Chen CH (2001) Effect of melatonin on release of beta-endorphin, norepinephrine and 5-hydroxytryptamine in rat brain. Yao Xue Xue Bao 36:5–9

    PubMed  CAS  Google Scholar 

  • Zisapel N, Laudon M (1983) Inhibition by melatonin of dopamine release from rat hypothalamus: regulation of calcium entry. Brain Res 272:378–381

    Article  PubMed  CAS  Google Scholar 

  • Zisapel N, Egozi Y, Laudon M (1982) Inhibition of dopamine release by melatonin: regional distribution in the rat brain. Brain Res 246:161–163

    Article  PubMed  CAS  Google Scholar 

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This work was supported by grants from the Xunta de Galicia (PGIDT99PX138301B).

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Romero, A., Caride, A., Pereiro, N. et al. Modulatory Effects of Melatonin on Cadmium-Induced Changes in Biogenic Amines in Rat Hypothalamus. Neurotox Res 20, 240–249 (2011). https://doi.org/10.1007/s12640-010-9237-4

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  • DOI: https://doi.org/10.1007/s12640-010-9237-4

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