In vivo protection against strychnine toxicity in mice by the glycine receptor agonist ivermectin
Loading...
Date
2014
Journal Title
Journal ISSN
Volume Title
Type
Article
Publisher
Hindawi
Series Info
BioMed research international;
Scientific Journal Rankings
Abstract
The inhibitory glycine receptor, a ligand-gated ion channel that mediates fast synaptic inhibition in mammalian spinal cord and
brainstem, is potently and selectively inhibited by the alkaloid strychnine. The anthelminthic and anticonvulsant ivermectin is a
strychnine-independent agonist of spinal glycine receptors. Here we show that ivermectin is an effective antidote of strychnine
toxicity in vivo and determine time course and extent of ivermectin protection. Mice received doses of 1 mg/kg and 5 mg/kg
ivermectin orally or intraperitoneally, followed by an intraperitoneal strychnine challenge (2 mg/kg). Ivermectin, through both
routes of application, protected mice against strychnine toxicity. Maximum protection was observed 14 hours after ivermectin
administration. Combining intraperitoneal and oral dosage of ivermectin further improved protection, resulting in survival rates of
up to 80% of animals and a significant delay of strychnine effects in up to 100% of tested animals. Strychnine action developed within
minutes, much faster than ivermectin, which acted on a time scale of hours. The data agree with a two-compartment distribution
of ivermectin, with fat deposits acting as storage compartment. The data demonstrate that toxic effects of strychnine in mice can
be prevented if a basal level of glycinergic signalling is maintained through receptor activation by ivermectin.
Description
MSA Google Scholar
Keywords
University of Toxicity; Glycine Receptor
Citation
[1] H. Betz and B. Laube, “Glycine receptors: recent insights into their structural organization and functional diversity,” Journal of Neurochemistry, vol. 97, no. 6, pp. 1600–1610, 2006. [2] H. G. Breitinger and C. M. Becker, “The inhibitory glycine receptor-simple views of a complicated channel,” ChemBioChem, vol. 3, pp. 1042–1052, 2002. [3] G. Grenningloh, A. Rienitz, B. Schmitt et al., “The strychninebinding subunit of the glycine receptor shows homology with nicotinic acetylcholine receptors,” Nature, vol. 328, no. 6127, pp. 215–220, 1987. [4] D. Langosch, C. M. Becker, and H. Betz, “The inhibitory glycine receptor: a ligand-gated chloride channel of the central nervous system,” European Journal of Biochemistry, vol. 194, no. 1, pp. 1– 8, 1990. [5] J. W. Lynch, “Molecular structure and function of the glycine receptor chloride channel,” Physiological Reviews, vol. 84, no. 4, pp. 1051–1095, 2004. [6] J. W. Lynch, “Native glycine receptor subtypes and their physiological roles,” Neuropharmacology, vol. 56, no. 1, pp. 303–309, 2009. [7] H. G. Breitinger and C. M. Becker, “The inhibitory glycine receptor: prospects for a therapeutic orphan?” Current Pharmaceutical Design, vol. 4, no. 4, pp. 315–334, 1998. [8] B. Laube, J. Kuhse, N. Rundstrom, J. Kirsch, V. Schmieden, and H. Betz, “Modulation by zinc ions of native rat and recombinant human inhibitory glycine receptors,” Journal of Physiology, vol. 483, no. 3, pp. 613–619, 1995. [9] S. Levi, C. Vannier, and A. Triller, “Strychnine-sensitive stabi- ´ lization of postsynaptic glycine receptor clusters,” Journal of Cell Science, vol. 111, part 3, pp. 335–345, 1998. [10] J. C. G. Marvizon, J. Vazquez, M. Garcia Calvo et al., “The glycine receptor: pharmacological studies and mathematical modeling of the allosteric interaction between the glycine- and strychnine-binding sites,” Molecular Pharmacology, vol. 30, no. 6, pp. 590–597, 1986. [11] B. Laube, D. Langosch, H. Betz, and V. Schmieden, “Hyperekplexia mutations of the glycine receptor unmask the inhibitory subsite for 𝛽-amino-acids,” NeuroReport, vol. 6, no. 6, pp. 897– 900, 1995. [12] R. J. Vandenberg, C. R. French, P. H. Barry, J. Shine, and P. R. Schofield, “Antagonism of ligand-gated ion channel receptors: two domains of the glycine receptor 𝛼 subunit form the strychnine-binding site,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 5, pp. 1765– 1769, 1992. [13] K. Raafat, U. Breitinger, L. Mahran, N. Ayoub, and H.-G. Breitinger, “Mechanism-based identification of distinct inhibitory sites for flavonoids and strychnine on recombinant 𝛼1 glycine receptors,” Toxicological Sciences, vol. 118, pp. 171–182, 2010. [14] W. C. Campbell, “Ivermectin as an antiparasitic agent for use in humans,” Annual Review of Microbiology, vol. 45, pp. 445–474, 1991. [15] W. C. Campbell, “Ivermectin, an antiparasitic agent,” Medicinal Research Reviews, vol. 13, no. 1, pp. 61–79, 1993. [16] A. G. Canga, A. M. S. Prieto, M. J. D. Liebana, N. F. Mart ´ ´ınez, M. S. Vega, and J. J. G. Vieitez, “The pharmacokinetics and metabolism of ivermectin in domestic animal species,” The Veterinary Journal, vol. 179, no. 1, pp. 25–37, 2009. [17] S. I. Hassan, N. G. Nessim, S. S. Mahmoud, and M. M. Nosseir, “Effect of a broad spectrum antiparasitic drug “ivermectin” in acute and chronic experimental giardiasis using different dose regimens.,” Journal of the Egyptian Society of Parasitology, vol. 31, no. 2, pp. 419–428, 2001. [18] V. Kumaraswami, E. A. Ottesen, V. Vijayasekaran et al., “Ivermectin for the treatment of Wuchereria bancrofti filariasis. Efficacy and adverse reactions,” The Journal of the American Medical Association, vol. 259, no. 21, pp. 3150–3153, 1988. [19] E. A. Ottesen and W. C. Campbell, “Ivermectin in human medicine,” Journal of Antimicrobial Chemotherapy, vol. 34, no. 2, pp. 195–203, 1994. [20] E. A. Ottesen, V. Vijayasekaran, V. Kumaraswami et al., “A controlled trial of ivermectin and diethylcarbamazine in lymphatic filariasis,” New England Journal of Medicine, vol. 322, no. 16, pp. 1113–1117, 1990. [21] N. S. Kane, B. Hirschberg, S. Qian et al., “Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 25, pp. 13949–13954, 2000. [22] T. Lynagh and J. W. Lynch, “Molecular mechanisms of Cys-loop ion channel receptor modulation by ivermectin,” Frontiers in Molecular Neuroscience, vol. 7, article 5, p. 60, 2012. [23] T. Lynagh, T. I. Webb, C. L. Dixon, B. A. Cromers, and J. W. Lynch, “Molecular determinants of ivermectin sensitivity at the glycine receptor chloride channel,” The Journal of Biological Chemistry, vol. 286, no. 51, pp. 43913–43924, 2011. [24] Q. Shan, J. L. Haddrill, and J. W. Lynch, “Ivermectin, an unconventional agonist of the glycine receptor chloride channel,” The Journal of Biological Chemistry, vol. 276, no. 16, pp. 12556–12564, 2001. [25] S. M. Trailovic and V. M. Varagi ´ c, “The effect of ivermectin ´ on convulsions in rats produced by lidocaine and strychnine,” Veterinary Research Communications, vol. 31, no. 7, pp. 863–872, 2007. [26] D. M. Lambert, J. H. Poupaert, J. M. Maloteaux, and P. Dumont, “Anticonvulsant activities of N-benzyloxycarbonylglycine after parenteral administration,” NeuroReport, vol. 5, no. 7, pp. 777– 780, 1994. BioMed Research International 9 [27] E. C. Crichlow, P. R. Mishra, and R. D. Crawford, “Anticonvulsant effects of ivermectin in genetically-epileptic chickens,” Neuropharmacology, vol. 25, no. 10, pp. 1085–1088, 1986. [28] G. R. Dawson, K. A. Wafford, A. Smith et al., “Anticonvulsant and adverse effects of avermectin analogs in mice are mediated through the 𝛾-aminobutyric acid(A) receptor,” Journal of Pharmacology and ExperimentalTherapeutics, vol. 295, no. 3, pp. 1051–1060, 2000. [29] T. Ikeda, “Pharmacological effects of ivermectin, an antiparasitic agent for intestinal strongyloidiasis: its mode of action and clinical efficacy,” Nihon Yakurigaku Zasshi, vol. 122, no. 6, pp. 527–538, 2003. [30] R. J. Ricart Arbona, N. S. Lipman, E. R. Riedel, and F. R. Wolf, “Treatment and eradication of murine fur mites. I: toxicologic evaluation of ivermectin-compounded feed,” Journal of the American Association for Laboratory Animal Science, vol. 49, no. 5, pp. 564–570, 2010. [31] M. M. Yardley, L. Wyatt, S. Khoja et al., “Ivermectin reduces alcohol intake and preference in mice,” Neuropharmacology, vol. 63, no. 2, pp. 190–201, 2012. [32] M. D. Levitt and D. G. Levitt, “Use of a two-compartment model to assess the pharmacokinetics of human ethanol metabolism,” Alcoholism: Clinical and Experimental Research, vol. 22, no. 8, pp. 1680–1688, 1998. [33] P. M. Loughnan, D. S. Sitar, R. I. Ogilvie, and A. H. Neims, “The two compartment open system kinetic model: a review of its clinical implications and applications,” Journal of Pediatrics, vol. 88, no. 5, pp. 869–873, 1976. [34] H. P. Rang, M. M. Dale, J. M. Ritter, R. J. Flower, and G. Henderson, Rang and Dales Pharmacology, Elsevier, 2011. [35] A. Gonzalez Canga, A. Sahagun, M. J. Diez, N. Fernandez, M. Sierra, and J. J. Garcia, “Bioavailabitlity of a commercial formulation of ivermectin after subcutaneous administration to sheep,” American Journal of Veterinary Research, vol. 68, no. 1, pp. 101–106, 2007. [36] A. Lespine, M. Alvinerie, J. Sutra, I. Pors, and C. Chartier, “Influence of the route of administration on efficacy and tissue distribution of ivermectin in goat,” Veterinary Parasitology, vol. 128, no. 3-4, pp. 251–260, 2005.