Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1989 Sep;98(1):225–235. doi: 10.1111/j.1476-5381.1989.tb16886.x

2-chloroadenosine attenuates kainic acid-induced toxicity within the rat straitum: relationship to release of glutamate and Ca2+ influx.

B Arvin 1, L F Neville 1, J Pan 1, P J Roberts 1
PMCID: PMC1854680  PMID: 2804547

Abstract

1. The mechanism by which 2-chloroadenosine (2-chloroado) exerts a neuroprotective action against the excitotoxic effect of kainic acid (KA) when injected into the rat striatum was investigated. 2. Histological examination two weeks after a single injection of KA (2.2 nmol) into rat striatum revealed widespread neuronal damage. Co-injection of 2-chloroado (6-25 nmol) with the neurotoxin afforded dose-dependent neuroprotection. This effect was reversed by administration of an equimolar concentration of the adenosine receptor antagonist theophylline. 3. Both K+ (30 mM) and KA (1 mM) enhanced the release of endogenous glutamate from guinea-pig purified cerebrocortical synaptosomes in a predominantly (approximately 70%) Ca2+-dependent manner. 2-Chloroado (10 nM-1 microM) inhibited the release of glutamate evoked by both KA and K+. These effects were partially reversed by the selective A1-adenosine receptor antagonist 8-cyclopentyltheophylline (CPT) (1 microM). 4. Crude rat cortical synaptosomes were loaded with the fluorescent calcium indicator quin-2 and Ca2+ influx monitored following two successive depolarising stimuli (30 mM K+; 'S1' and 'S2'). 2-Chloroado (10 nM-1 microM) produced a dose-dependent reduction in the S2:S1 ratio when added before the S2 period of stimulation. This effect was reversed by 1 microM theophylline. However, KA (1 mM) failed to enhance Ca2+ influx in the same preparation. 5. These results suggest that the anti-excitotoxic action of 2-chloroado is mediated primarily through a specific presynaptic receptor mechanism involving reduction of transmitter glutamate release, possibly occurring through an inhibition of Ca2+ influx.

Full text

PDF
225

Images in this article

230Figure 2
on p.230
228Figure 1
on p.228
229Figure 2
on p.229

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berger M., Sperk G., Hornykiewicz O. Serotonergic denervation partially protects rat striatum from kainic acid toxicity. Nature. 1982 Sep 16;299(5880):254–256. doi: 10.1038/299254a0. [DOI] [PubMed] [Google Scholar]
  2. Bradford H. F., Peterson D. W. Current views of the pathobiochemistry of epilepsy. Mol Aspects Med. 1987;9(2):119–172. doi: 10.1016/0098-2997(87)90022-7. [DOI] [PubMed] [Google Scholar]
  3. Burgoyne R. D., Pearce I. A., Cambray-Deakin M. N-methyl-D-aspartate raises cytosolic calcium concentration in rat cerebellar granule cells in culture. Neurosci Lett. 1988 Aug 15;91(1):47–52. doi: 10.1016/0304-3940(88)90247-9. [DOI] [PubMed] [Google Scholar]
  4. Butcher S. P., Lazarewicz J. W., Hamberger A. In vivo microdialysis studies on the effects of decortication and excitotoxic lesions on kainic acid-induced calcium fluxes, and endogenous amino acid release, in the rat striatum. J Neurochem. 1987 Nov;49(5):1355–1360. doi: 10.1111/j.1471-4159.1987.tb00999.x. [DOI] [PubMed] [Google Scholar]
  5. Connick J. H., Stone T. W. Quinolinic acid effects on amino acid release from the rat cerebral cortex in vitro and in vivo. Br J Pharmacol. 1988 Apr;93(4):868–876. doi: 10.1111/j.1476-5381.1988.tb11474.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Connick J. H., Stone T. W. The effect of kainic, quinolinic and beta-kainic acids on the release of endogenous amino acids from rat brain slices. Biochem Pharmacol. 1986 Oct 15;35(20):3631–3635. doi: 10.1016/0006-2952(86)90636-2. [DOI] [PubMed] [Google Scholar]
  7. Corradetti R., Lo Conte G., Moroni F., Passani M. B., Pepeu G. Adenosine decreases aspartate and glutamate release from rat hippocampal slices. Eur J Pharmacol. 1984 Sep 3;104(1-2):19–26. doi: 10.1016/0014-2999(84)90364-9. [DOI] [PubMed] [Google Scholar]
  8. Coyle J. T. Kainic acid: insights into excitatory mechanisms causing selective neuronal degeneration. Ciba Found Symp. 1987;126:186–203. doi: 10.1002/9780470513422.ch12. [DOI] [PubMed] [Google Scholar]
  9. Coyle J. T. Neurotoxic action of kainic acid. J Neurochem. 1983 Jul;41(1):1–11. doi: 10.1111/j.1471-4159.1983.tb11808.x. [DOI] [PubMed] [Google Scholar]
  10. Coyle J. T., Schwarcz R. Lesion of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature. 1976 Sep 16;263(5574):244–246. doi: 10.1038/263244a0. [DOI] [PubMed] [Google Scholar]
  11. Crowder J. M., Croucher M. J., Bradford H. F., Collins J. F. Excitatory amino acid receptors and depolarization-induced Ca2+ influx into hippocampal slices. J Neurochem. 1987 Jun;48(6):1917–1924. doi: 10.1111/j.1471-4159.1987.tb05756.x. [DOI] [PubMed] [Google Scholar]
  12. Dolphin A. C., Archer E. R. An adenosine agonist inhibits and a cyclic AMP analogue enhances the release of glutamate but not GABA from slices of rat dentate gyrus. Neurosci Lett. 1983 Dec 23;43(1):49–54. doi: 10.1016/0304-3940(83)90127-1. [DOI] [PubMed] [Google Scholar]
  13. Dolphin A. C., Prestwich S. A. Pertussis toxin reverses adenosine inhibition of neuronal glutamate release. Nature. 1985 Jul 11;316(6024):148–150. doi: 10.1038/316148a0. [DOI] [PubMed] [Google Scholar]
  14. Dragunow M., Goddard G. V., Laverty R. Is adenosine an endogenous anticonvulsant? Epilepsia. 1985 Sep-Oct;26(5):480–487. doi: 10.1111/j.1528-1157.1985.tb05684.x. [DOI] [PubMed] [Google Scholar]
  15. Engelsen B. Neurotransmitter glutamate: its clinical importance. Acta Neurol Scand. 1986 Nov;74(5):337–355. doi: 10.1111/j.1600-0404.1986.tb03524.x. [DOI] [PubMed] [Google Scholar]
  16. Evans M. C., Swan J. H., Meldrum B. S. An adenosine analogue, 2-chloroadenosine, protects against long term development of ischaemic cell loss in the rat hippocampus. Neurosci Lett. 1987 Dec 29;83(3):287–292. doi: 10.1016/0304-3940(87)90101-7. [DOI] [PubMed] [Google Scholar]
  17. Fastbom J., Fredholm B. B. Inhibition of [3H] glutamate release from rat hippocampal slices by L-phenylisopropyladenosine. Acta Physiol Scand. 1985 Sep;125(1):121–123. doi: 10.1111/j.1748-1716.1985.tb07698.x. [DOI] [PubMed] [Google Scholar]
  18. Ferkany J. W., Coyle J. T. Evoked release of aspartate and glutamate: disparities between prelabeling and direct measurement. Brain Res. 1983 Nov 14;278(1-2):279–282. doi: 10.1016/0006-8993(83)90254-8. [DOI] [PubMed] [Google Scholar]
  19. Ferkany J. W., Zaczek R., Coyle J. T. Kainic acid stimulates excitatory amino acid neurotransmitter release at presynaptic receptors. Nature. 1982 Aug 19;298(5876):757–759. doi: 10.1038/298757a0. [DOI] [PubMed] [Google Scholar]
  20. Gallo V., Suergiu R., Giovannini C., Levi G. Glutamate receptor subtypes in cultured cerebellar neurons: modulation of glutamate and gamma-aminobutyric acid release. J Neurochem. 1987 Dec;49(6):1801–1809. doi: 10.1111/j.1471-4159.1987.tb02439.x. [DOI] [PubMed] [Google Scholar]
  21. Goldberg M. P., Monyer H., Weiss J. H., Choi D. W. Adenosine reduces cortical neuronal injury induced by oxygen or glucose deprivation in vitro. Neurosci Lett. 1988 Jul 8;89(3):323–327. doi: 10.1016/0304-3940(88)90547-2. [DOI] [PubMed] [Google Scholar]
  22. Goodman R. R., Kuhar M. J., Hester L., Snyder S. H. Adenosine receptors: autoradiographic evidence for their location on axon terminals of excitatory neurons. Science. 1983 May 27;220(4600):967–969. doi: 10.1126/science.6302841. [DOI] [PubMed] [Google Scholar]
  23. Johnston G. A., Kennedy S. M., Twitchin B. Action of the neurotoxin kainic acid on high affinity uptake of L-glutamic acid in rat brain slices. J Neurochem. 1979 Jan;32(1):121–127. doi: 10.1111/j.1471-4159.1979.tb04518.x. [DOI] [PubMed] [Google Scholar]
  24. Krespan B., Berl S., Nicklas W. J. Alteration in neuronal-glial metabolism of glutamate by the neurotoxin kainic acid. J Neurochem. 1982 Feb;38(2):509–518. doi: 10.1111/j.1471-4159.1982.tb08657.x. [DOI] [PubMed] [Google Scholar]
  25. Kudo Y., Ogura A. Glutamate-induced increase in intracellular Ca2+ concentration in isolated hippocampal neurones. Br J Pharmacol. 1986 Sep;89(1):191–198. doi: 10.1111/j.1476-5381.1986.tb11135.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lazarewicz J. W., Lehmann A., Hamberger A. Effects of Ca2+ entry blockers on kainate-induced changes in extracellular amino acids and Ca2+ in vivo. J Neurosci Res. 1987;18(2):341–344. doi: 10.1002/jnr.490180211. [DOI] [PubMed] [Google Scholar]
  27. MacDermott A. B., Mayer M. L., Westbrook G. L., Smith S. J., Barker J. L. NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. 1986 May 29-Jun 4Nature. 321(6069):519–522. doi: 10.1038/321519a0. [DOI] [PubMed] [Google Scholar]
  28. McGeer E. G., McGeer P. L. Duplication of biochemical changes of Huntington's chorea by intrastriatal injections of glutamic and kainic acids. Nature. 1976 Oct 7;263(5577):517–519. doi: 10.1038/263517a0. [DOI] [PubMed] [Google Scholar]
  29. McGeer E. G., McGeer P. L., Singh K. Kainate-induced degeneration of neostriatal neurons: dependency upon corticostriatal tract. Brain Res. 1978 Jan 13;139(2):381–383. doi: 10.1016/0006-8993(78)90941-1. [DOI] [PubMed] [Google Scholar]
  30. Meldolesi J., Huttner W. B., Tsien R. Y., Pozzan T. Free cytoplasmic Ca2+ and neurotransmitter release: studies on PC12 cells and synaptosomes exposed to alpha-latrotoxin. Proc Natl Acad Sci U S A. 1984 Jan;81(2):620–624. doi: 10.1073/pnas.81.2.620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Murphy S. N., Thayer S. A., Miller R. J. The effects of excitatory amino acids on intracellular calcium in single mouse striatal neurons in vitro. J Neurosci. 1987 Dec;7(12):4145–4158. doi: 10.1523/JNEUROSCI.07-12-04145.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Nadler J. V., Cuthbertson G. J. Kainic acid neurotoxicity toward hippocampal formation: dependence on specific excitatory pathways. Brain Res. 1980 Aug 11;195(1):47–56. doi: 10.1016/0006-8993(80)90865-3. [DOI] [PubMed] [Google Scholar]
  33. Nicholls D. G. Calcium transport and porton electrochemical potential gradient in mitochondria from guinea-pig cerebral cortex and rat heart. Biochem J. 1978 Mar 15;170(3):511–522. doi: 10.1042/bj1700511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Nicholls D. G., Sihra T. S., Sanchez-Prieto J. Calcium-dependent and -independent release of glutamate from synaptosomes monitored by continuous fluorometry. J Neurochem. 1987 Jul;49(1):50–57. doi: 10.1111/j.1471-4159.1987.tb03393.x. [DOI] [PubMed] [Google Scholar]
  35. Nicklas W. J., Krespan B., Berl S. Effect of kainate on ATP levels and glutamate metabolism in cerebellar slices. Eur J Pharmacol. 1980 Mar 21;62(2-3):209–213. doi: 10.1016/0014-2999(80)90278-2. [DOI] [PubMed] [Google Scholar]
  36. Notman H., Whitney R., Jhamandas K. Kainic acid evoked release of D-[3H]aspartate from rat striatum in vitro: characterization and pharmacological modulation. Can J Physiol Pharmacol. 1984 Sep;62(9):1070–1077. doi: 10.1139/y84-179. [DOI] [PubMed] [Google Scholar]
  37. Pastuszko A., Wilson D. F., Erecińska M. Effects of kainic acid in rat brain synaptosomes: the involvement of calcium. J Neurochem. 1984 Sep;43(3):747–754. doi: 10.1111/j.1471-4159.1984.tb12796.x. [DOI] [PubMed] [Google Scholar]
  38. Phillis J. W., Wu P. H. The role of adenosine and its nucleotides in central synaptic transmission. Prog Neurobiol. 1981;16(3-4):187–239. doi: 10.1016/0301-0082(81)90014-9. [DOI] [PubMed] [Google Scholar]
  39. Pocock J. M., Murphie H. M., Nicholls D. G. Kainic acid inhibits the synaptosomal plasma membrane glutamate carrier and allows glutamate leakage from the cytoplasm but does not affect glutamate exocytosis. J Neurochem. 1988 Mar;50(3):745–751. doi: 10.1111/j.1471-4159.1988.tb02977.x. [DOI] [PubMed] [Google Scholar]
  40. Poli A., Contestabile A., Migani P., Rossi L., Rondelli C., Virgili M., Bissoli R., Barnabei O. Kainic acid differentially affects the synaptosomal release of endogenous and exogenous amino acidic neurotransmitters. J Neurochem. 1985 Dec;45(6):1677–1686. doi: 10.1111/j.1471-4159.1985.tb10522.x. [DOI] [PubMed] [Google Scholar]
  41. Retz K. C., Coyle J. T. The differential effects of excitatory amino acids on uptake of 45CaCl2 by slices from mouse striatum. Neuropharmacology. 1984 Jan;23(1):89–94. doi: 10.1016/0028-3908(84)90222-3. [DOI] [PubMed] [Google Scholar]
  42. Ribeiro J. A., Sá-Almeida A. M., Namorado J. M. Adenosine and adenosine triphosphate decrease 45Ca uptake by synaptosomes stimulated by potassium. Biochem Pharmacol. 1979 Apr 15;28(8):1297–1300. doi: 10.1016/0006-2952(79)90428-3. [DOI] [PubMed] [Google Scholar]
  43. Riveros N., Orrego F. N-methylaspartate-activated calcium channels in rat brain cortex slices. Effect of calcium channel blockers and of inhibitory and depressant substances. Neuroscience. 1986 Mar;17(3):541–546. doi: 10.1016/0306-4522(86)90029-1. [DOI] [PubMed] [Google Scholar]
  44. Robinson M. B., Coyle J. T. Glutamate and related acidic excitatory neurotransmitters: from basic science to clinical application. FASEB J. 1987 Dec;1(6):446–455. doi: 10.1096/fasebj.1.6.2890549. [DOI] [PubMed] [Google Scholar]
  45. Schwarcz R., Meldrum B. Excitatory aminoacid antagonists provide a therapeutic approach to neurological disorders. Lancet. 1985 Jul 20;2(8447):140–143. doi: 10.1016/s0140-6736(85)90238-7. [DOI] [PubMed] [Google Scholar]
  46. Streit P., Stella M., Cuenod M. Kainate-induced lesion in the optic tectum: dependency upon optic nerve afferents or glutamate. Brain Res. 1980 Apr 7;187(1):47–57. doi: 10.1016/0006-8993(80)90493-x. [DOI] [PubMed] [Google Scholar]
  47. Watkins J. C., Evans R. H. Excitatory amino acid transmitters. Annu Rev Pharmacol Toxicol. 1981;21:165–204. doi: 10.1146/annurev.pa.21.040181.001121. [DOI] [PubMed] [Google Scholar]
  48. Wojcik W. J., Neff N. H. Differential location of adenosine A1 and A2 receptors in striatum. Neurosci Lett. 1983 Oct 31;41(1-2):55–60. doi: 10.1016/0304-3940(83)90222-7. [DOI] [PubMed] [Google Scholar]
  49. Wroblewski J. T., Nicoletti F., Costa E. Different coupling of excitatory amino acid receptors with Ca2+ channels in primary cultures of cerebellar granule cells. Neuropharmacology. 1985 Sep;24(9):919–921. doi: 10.1016/0028-3908(85)90046-2. [DOI] [PubMed] [Google Scholar]
  50. Wu P. H., Phillis J. W., Thierry D. L. Adenosine receptor agonists inhibit K+-evoked Ca2+ uptake by rat brain cortical synaptosomes. J Neurochem. 1982 Sep;39(3):700–708. doi: 10.1111/j.1471-4159.1982.tb07949.x. [DOI] [PubMed] [Google Scholar]
  51. Young A. M., Bradford H. F. Excitatory amino acid neurotransmitters in the corticostriate pathway: studies using intracerebral microdialysis in vivo. J Neurochem. 1986 Nov;47(5):1399–1404. doi: 10.1111/j.1471-4159.1986.tb00771.x. [DOI] [PubMed] [Google Scholar]
  52. Young A. M., Crowder J. M., Bradford H. F. Potentiation by kainate of excitatory amino acid release in striatum: complementary in vivo and in vitro experiments. J Neurochem. 1988 Feb;50(2):337–345. doi: 10.1111/j.1471-4159.1988.tb02918.x. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES