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A calcium channel blocker flunarizine attenuates the neurotoxic effects of iron

Cell Biology and Toxicology volume 22, pages 119–125 (2006)Cite this article

Abstract

Iron is a metal highly concentrated in liver and brain tissue, and known to induce neuronal hyperactivity and oxidative stress. It has been established that iron levels rise in the brain in some neurodegenerative diseases such as Parkinson's and Alzheimer's diseases (AD). A body of evidence indicates a link between neuronal death and intracellular excessive calcium accumulation. The aim of the present study was to investigate the effects of a calcium antagonist, flunarizine, on neurotoxicity induced by intracerebroventricular (i.c.v.) iron injection. For this reason rats were divided into three groups as control, iron and iron+flunarizine groups. Animals in iron and iron+flunarizine groups received i.c.v. FeCl3 injection (200 mM, 2.5 μl), while control rats received the same amount of saline into the cerebral ventricles. Rats in iron+flunarizine group also received i.c.v. flunarizine (1 μM, 2 μl) following FeCl3 injection. All animals were kept alive for ten days following the operation and animals in iron+flunarizine group received intraperitoneal (i.p.) flunarizine injections once a day (10 mg/kg/day) during this period. After ten days, rats were sacrificed. The total numbers of neurons in hippocampus of all rats were estimated with the latest, unbiased stereological techniques. Findings of the present study suggest that flunarizine may attenuate the neurotoxic effects of iron injection by inhibiting the cellular influx of excessive calcium ions.

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References

  • Aisen P, Wessling-Resnick M, Leibold EA. Iron metabolism. Curr Opin Chem Biol. 1999;3:200–6.

    Article  CAS  PubMed  Google Scholar 

  • Albers GW, Goldberg MP, Choi DW. Do NMDA antagonists prevent neuronal injury? Yes. Arch Neurol. 1992;49:418–20.

    CAS  PubMed  Google Scholar 

  • Aust SD, Morehouse LA, Thomas CE. Role of metals in oxygen radicals reactions. J Free Rad Biol Med. 1985;1:3–25.

    CAS  Google Scholar 

  • Bagirici F, Gokce FM, Demir S, Marangoz C. Calcium channel blocker flunarizine suppresses epileptiform activity induced by penicillin in rats. Neurosci Res Cummun. 2001;28:135–40.

    CAS  Google Scholar 

  • Beal MF. Aging, energy and oxidative stress in neurodegenerative disease. Ann Neurol. 1995;38:357–66.

    Article  CAS  PubMed  Google Scholar 

  • Bostanci MO, Bagirici F, Korkmaz A. The neurotoxic effect of iron on pyramidal cell number in rat hippocampus: A stereological study. Neurosci Res Cummun. 2003;32:151–9.

    CAS  Google Scholar 

  • Braughler JM, Duncan LA, Chase RL. The involvement of iron in lipid peroxidation. J Biol Chem. 1986;261:10282–9.

    CAS  PubMed  Google Scholar 

  • Carbone E, Lux HD. A low voltage activated, fully inactivating calcium channel in vertebrate sensory neurons. Nature. 1984;310:501–2.

    CAS  PubMed  Google Scholar 

  • Chakraborti T, Das S, Mondal M, Roychoudhury S, Chakraborti S. Oxidant, mitochondria and calcium: an overview. Cell Signal. 1999;11:77–85.

    Article  CAS  PubMed  Google Scholar 

  • Choi DV. Glutamate neurotoxicity and disease of the nervous system. Neuron. 1988;1:623.

    Article  CAS  PubMed  Google Scholar 

  • Dawson R, Beal MF, Bondy SC, Di Monte DA, Ison GE. Excitotoxins, aging and environmental neurotoxins: Implications for understanding human neurodegenerative diseases. Toxicol Applied Pharmacol. 1995;134:2553–62.

    Google Scholar 

  • Deibel MA, Ehmann WD, Markesbery WR. Copper, iron and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress. J Neurol Sci. 1996;143:137–42.

    Article  CAS  PubMed  Google Scholar 

  • Farber JL. The role of calcium in cell death. Life Sci. 1981;29:1289–95.

    Article  CAS  PubMed  Google Scholar 

  • Flayn CJ, Farooqui AA, Horocks LA. Ischemia and Hypoxia. In: Siegel GJ, Agranoff BW, Albers RW, Molinoff PB, eds. Basic Neurochemistry, Molecular, Cellular and Medical Aspects. New York: Raven Pres; 1989: 783.

    Google Scholar 

  • Gerlach M, Ben-Shachar D, Riederer P, Youdim MB. Altered brain metabolism of iron as a cause of neurodegenerative diseases. J Neurochem. 1994;63:793–807.

    CAS  PubMed  Google Scholar 

  • Gundersen HJ. Stereology of arbitrary particles. A review of unbiased number and size estimator and the presentation of some new ones, in memory of William R. Thompson. J Microsc 1986;143:3–45.

    Google Scholar 

  • Gundersen HJ, Bendtsen TF, Korbo L, Marcussen N, Moller A, Nielsen K, Nyengaard JR, Pakkenberg B, Sorensen FB. A some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APMIS. 1988;96:379–94.

    Google Scholar 

  • Hansen AK, Zeuthen T. Extracellular ion concentrations during spreading depression and ischemia in the rat brain cortex. Acta Physiol Scand. 1981;113:437–45.

    CAS  PubMed  Google Scholar 

  • Herbelte LG, Katz AM. Molecular model for the binding of 1,4-dhydropyridine calcium channel antagonists to their receptors in the heart: drug “imaging” in membranes in considerations for drug design. In: Venter JC, Triggle D, eds. Structure and physiology of the slow inward calcium channel. New York: Alan Rliss Inc; 1987: 89.

    Google Scholar 

  • Izumi Y, Benz AM, Clifford DB, Zorumski CF. Nitric oxide inhibitors attenuate N-methyl-D-aspartate excitotoxicity in rat hippocampal slices. Neurosci Let. 1992;135:227–30.

    Article  CAS  Google Scholar 

  • Landfield PW, Thibault O, Mazzanti ML, Porter NM, Kerr DS. Mechanism of neuronal death in brain aging and Alzheimer's disease: Role of endocrine-mediated calcium dyshomeostasis. J Neurobiol. 1992;23:1247–60.

    Article  CAS  PubMed  Google Scholar 

  • Leysen JM, Gommeron W. The Pharmacological Basis of Migraine Therapy. In: Amery WK, Van Nueten JM, Wauquier A, eds. In vitro binding profile of drugs used in migraine. London: Pitman; 1984:255–67.

    Google Scholar 

  • Meyerhoff JL, Lee JK, Rittase BW, Tsang AY, Yourick DL. Lipoic acid pretreatment attenuates ferric chloride-induced seizures in the rat. Brain Res. 2004;1016:139–44.

    Article  CAS  PubMed  Google Scholar 

  • Orrenius S, Ankarcrona M, Nicotera P. Mechanism of calcium related cell death. Adv Neurol. 1996;71:137–51.

    CAS  PubMed  Google Scholar 

  • Pellegrini-Giampietro DE, Cherici G, Alesiani M, Carla V, Moroni F. Excitatory amino acid release from rat hippocampal slices as a consequence of free radical formation. J Neurochem. 1988;51:1960–3.

    CAS  PubMed  Google Scholar 

  • Porter NA, Caldwell SE, Mills KA. Mechanisms of free radical oxidation of unsaturated lipids. Lipids. 1995;30:277–90.

    CAS  PubMed  Google Scholar 

  • Qian ZM, Wang Q, Pu Y. Brain iron and neurological disorders. Chin Med J. 1997;110:455–8.

    CAS  PubMed  Google Scholar 

  • Qian ZM, Wang Q. Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders. Brain Res Rev. 1998;27:257–67.

    Article  CAS  PubMed  Google Scholar 

  • Robb SJ, Robb-Gaspers LD, Scaduto RC, Jr Thomas AP, Connor JR. Influence of calcium and iron on cell death and mitochondrial function in oxidatively stressed astrocytes. J Neurosci Res. 1999;55:674–86.

    Article  CAS  PubMed  Google Scholar 

  • Samudralwer DL, Diprete CC, Ni B-F, Ehmann WD, Markesbery WR. Elemental imbalances in the olfactory pathway in Alzheimer's disease. J Neurol Sci. 1995;130:139–45.

    Google Scholar 

  • Sayre LM, Perry G, Smith MA. Redox metals and neurodegenerative disease. Curr Opin Chem Biol. 1999;3:220–5.

    Article  CAS  PubMed  Google Scholar 

  • Schanne FAX, Kane AB, Young EE, Farber JL. Calcium dependence of toxic cell death: A final common pathway. Science. 1979;206:700–2.

    CAS  PubMed  Google Scholar 

  • Sterio DC. The unbiased estimation of number and sizes of arbitrary particles using the dissector. J Microsc. 1984;134:127–36.

    PubMed  Google Scholar 

  • Swaiman KF. Hallervorden-Spatz and brain iron metabolism. Arch Neurol. 1991;48:1285–93.

    CAS  PubMed  Google Scholar 

  • Tytgat J, Vereecke J, Carmeliet E. Differential effects of verapamil and flunarizine on cardiac L-type and T-type Ca channels. Naunyn Schmiedebergs Arch Pharmacol. 1988;337:690–2.

    Article  CAS  PubMed  Google Scholar 

  • Uematsu D, Araki N, Greenberg JH. Alterations in cytosolic free calcium in the cat cortex during bicuculline-induced epilepsy. Brain Res Bull. 1990;24:285–8.

    Article  CAS  PubMed  Google Scholar 

  • Weiner DA. Calcium Channel Blockers. Med Clin North America. 1988;72:83–115.

    CAS  Google Scholar 

  • West MJ, Slomianka L, Gundersen HJG. Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. The Anatomical Record. 1991;231:482–97.

    Article  CAS  PubMed  Google Scholar 

  • Willmore LJ, Sypert GW, Munson JB. Recurrent seizures induced by cortical iron injection: A model of posttraumatic epilepsy. Ann Neurol. 1978;4:329–36.

    CAS  PubMed  Google Scholar 

  • Willmore LJ, Hiramatsu M, Kochi H, Mori A. Formation of superoxide radicals after FeCl3 injection into rat isocortex. Brain Res. 1983;277:393–6.

    Article  CAS  PubMed  Google Scholar 

  • Willmore LJ, Triggs WJ. Iron-induced lipid peroxidation and brain injury responses. Int J Dev Neurosci. 1991;9:175–80.

    CAS  PubMed  Google Scholar 

  • Youdim MB. Iron in the brain: Implication for Parkinson's and Alzheimer's diseases. Mt Sinai J Med. 1998;55:97–101.

    Google Scholar 

  • Zaleska MM, Floyd RA. Regional lipid peroxidation in rat brain in vitro possible role of endogenous iron. Neurochem Res. 1985;10:397–410.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, University of Ondokuz Mayis, 55139, Samsun, Turkey

    M. Ömer Bostanci & Faruk Bağirici

  2. Department of Physiology, Faculty of Medicine, University of Baskent, 06530, Ankara, Turkey

    Sinan Canan

  3. Department of Physiology, Faculty of Medicine, University of Ondokuz Mayis, 55139, Samsun, Turkey

    M. Ömer Bostanci

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  1. M. Ömer Bostanci
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  2. Faruk Bağirici
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Correspondence to M. Ömer Bostanci.

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Bostanci, M.Ö., Bağirici, F. & Canan, S. A calcium channel blocker flunarizine attenuates the neurotoxic effects of iron. Cell Biol Toxicol 22, 119–125 (2006). https://doi.org/10.1007/s10565-006-0037-9

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  • DOI: https://doi.org/10.1007/s10565-006-0037-9

Keywords

  • iron
  • hippocampus
  • cell death
  • flunarizine
  • stereology