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. 1995 Aug;115(8):1425–1432. doi: 10.1111/j.1476-5381.1995.tb16633.x

Neuroprotective properties of lifarizine compared with those of other agents in a mouse model of focal cerebral ischaemia.

C M Brown 1, C Calder 1, C Linton 1, C Small 1, B A Kenny 1, M Spedding 1, L Patmore 1
PMCID: PMC1908884  PMID: 8564201

Abstract

1. Changes in the peripheral type benzodiazepine binding site density following middle cerebral artery occlusion in the mouse, have been used as a marker of neuronal damage. These sites can be identified using the selective ligand [3H]-PK 11195 located on non neuronal cells, macrophages and astroglia, within the CNS. Glial cell proliferation and macrophage invasion is an unvoidable sequelae to cerebral ischaemic injury, secondary to neuronal loss. Following occlusion of the left middle cerebral artery (left MCA) a reproducible lesion was found in the parietal cortex within 7 days which gave rise to a significant increase in [3H]-PK 11195 binding. 2. Treatment of animals with the sodium channel blocker, lifarizine, significantly reduced the ischaemia-induced increase in [3H]-PK 11195 binding when given either 30 min pre-ischaemia and three times daily for 7 days at 0.5 mg kg-1, i.p. (P < 0.01) or delayed until 15 min post-ischaemia and three times daily for 7 days at 0.5 mg kg-1, i.p. (P < 0.001). Lifarizine was an effective neuroprotective agent in this model of focal ischaemia in the mouse. 3. Lifarizine also showed a dose-related protection against the ischaemia-induced increase in [3H]-PK 11195 binding with significant protection at doses of 0.1 mg kg-1, i.p. (P < 0.05), 0.25 mg kg-1, i.p. (P < 0.01) or 0.5 mg kg-1, i.p. (P < 0.01) 15 min post-ischaemia and b.i.d. for 7 days.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Anholt R. R., Pedersen P. L., De Souza E. B., Snyder S. H. The peripheral-type benzodiazepine receptor. Localization to the mitochondrial outer membrane. J Biol Chem. 1986 Jan 15;261(2):576–583. [PubMed] [Google Scholar]
  2. Artru A. A., Michenfelder J. D. Anoxic cerebral potassium accumulation reduced by phenytoin: mechanism of cerebral protection? Anesth Analg. 1981 Jan;60(1):41–45. [PubMed] [Google Scholar]
  3. Artru A. A., Michenfelder J. D. Cerebral protective, metabolic, and vascular effects of phenytoin. Stroke. 1980 Jul-Aug;11(4):377–382. doi: 10.1161/01.str.11.4.377. [DOI] [PubMed] [Google Scholar]
  4. Ashton D., Willems R., Marrannes R., Janssen P. A. Extracellular ions during veratridine-induced neurotoxicity in hippocampal slices: neuroprotective effects of flunarizine and tetrodotoxin. Brain Res. 1990 Oct 1;528(2):212–222. doi: 10.1016/0006-8993(90)91660-9. [DOI] [PubMed] [Google Scholar]
  5. Awad M., Gavish M. Binding of [3H]Ro 5-4864 and [3H]PK 11195 to cerebral cortex and peripheral tissues of various species: species differences and heterogeneity in peripheral benzodiazepine binding sites. J Neurochem. 1987 Nov;49(5):1407–1414. doi: 10.1111/j.1471-4159.1987.tb01007.x. [DOI] [PubMed] [Google Scholar]
  6. Benavides J., Capdeville C., Dauphin F., Dubois A., Duverger D., Fage D., Gotti B., MacKenzie E. T., Scatton B. The quantification of brain lesions with an omega 3 site ligand: a critical analysis of animal models of cerebral ischaemia and neurodegeneration. Brain Res. 1990 Jul 9;522(2):275–289. doi: 10.1016/0006-8993(90)91472-s. [DOI] [PubMed] [Google Scholar]
  7. Benavides J., Cornu P., Dennis T., Dubois A., Hauw J. J., MacKenzie E. T., Sazdovitch V., Scatton B. Imaging of human brain lesions with an omega 3 site radioligand. Ann Neurol. 1988 Dec;24(6):708–712. doi: 10.1002/ana.410240603. [DOI] [PubMed] [Google Scholar]
  8. Boening J. A., Kass I. S., Cottrell J. E., Chambers G. The effect of blocking sodium influx on anoxic damage in the rat hippocampal slice. Neuroscience. 1989;33(2):263–268. doi: 10.1016/0306-4522(89)90205-4. [DOI] [PubMed] [Google Scholar]
  9. Cheng Y., Prusoff W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973 Dec 1;22(23):3099–3108. doi: 10.1016/0006-2952(73)90196-2. [DOI] [PubMed] [Google Scholar]
  10. Demerlé-Pallardy C., Duverger D., Spinnewyn B., Pirotzky E., Braquet P. Peripheral type benzodiazepine binding sites following transient forebrain ischemia in the rat: effect of neuroprotective drugs. Brain Res. 1991 Nov 29;565(2):312–320. doi: 10.1016/0006-8993(91)91663-l. [DOI] [PubMed] [Google Scholar]
  11. Dubois A., Bénavidès J., Peny B., Duverger D., Fage D., Gotti B., MacKenzie E. T., Scatton B. Imaging of primary and remote ischaemic and excitotoxic brain lesions. An autoradiographic study of peripheral type benzodiazepine binding sites in the rat and cat. Brain Res. 1988 Mar 29;445(1):77–90. doi: 10.1016/0006-8993(88)91076-1. [DOI] [PubMed] [Google Scholar]
  12. Gelmers H. J. Calcium-channel blockers: effects on cerebral blood flow and potential uses for acute stroke. Am J Cardiol. 1985 Jan 25;55(3):144B–148B. doi: 10.1016/0002-9149(85)90623-x. [DOI] [PubMed] [Google Scholar]
  13. Germano I. M., Bartkowski H. M., Cassel M. E., Pitts L. H. The therapeutic value of nimodipine in experimental focal cerebral ischemia. Neurological outcome and histopathological findings. J Neurosurg. 1987 Jul;67(1):81–87. doi: 10.3171/jns.1987.67.1.0081. [DOI] [PubMed] [Google Scholar]
  14. Germano I. M., Pitts L. H., Meldrum B. S., Bartkowski H. M., Simon R. P. Kynurenate inhibition of cell excitation decreases stroke size and deficits. Ann Neurol. 1987 Dec;22(6):730–734. doi: 10.1002/ana.410220609. [DOI] [PubMed] [Google Scholar]
  15. Gill R., Brazell C., Woodruff G. N., Kemp J. A. The neuroprotective action of dizocilpine (MK-801) in the rat middle cerebral artery occlusion model of focal ischaemia. Br J Pharmacol. 1991 Aug;103(4):2030–2036. doi: 10.1111/j.1476-5381.1991.tb12371.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gotti B., Benavides J., MacKenzie E. T., Scatton B. The pharmacotherapy of focal cortical ischaemia in the mouse. Brain Res. 1990 Jul 9;522(2):290–307. doi: 10.1016/0006-8993(90)91473-t. [DOI] [PubMed] [Google Scholar]
  17. Gotti B., Duverger D., Bertin J., Carter C., Dupont R., Frost J., Gaudilliere B., MacKenzie E. T., Rousseau J., Scatton B. Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents. I. Evidence for efficacy in models of focal cerebral ischemia. J Pharmacol Exp Ther. 1988 Dec;247(3):1211–1221. [PubMed] [Google Scholar]
  18. Hall E. D., McCall J. M., Means E. D. Therapeutic potential of the lazaroids (21-aminosteroids) in acute central nervous system trauma, ischemia and subarachnoid hemorrhage. Adv Pharmacol. 1994;28:221–268. doi: 10.1016/s1054-3589(08)60497-4. [DOI] [PubMed] [Google Scholar]
  19. Hansen A. J. Effect of anoxia on ion distribution in the brain. Physiol Rev. 1985 Jan;65(1):101–148. doi: 10.1152/physrev.1985.65.1.101. [DOI] [PubMed] [Google Scholar]
  20. Hass W. K. The cerebral ischemic cascade. Neurol Clin. 1983 Feb;1(1):345–353. [PubMed] [Google Scholar]
  21. Hebert T., Drapeau P., Pradier L., Dunn R. J. Block of the rat brain IIA sodium channel alpha subunit by the neuroprotective drug riluzole. Mol Pharmacol. 1994 May;45(5):1055–1060. [PubMed] [Google Scholar]
  22. Kenny B. A., Fraser S., Kilpatrick A. T., Spedding M. Selective antagonism of calcium channel activators by fluspirilene. Br J Pharmacol. 1990 Jun;100(2):211–216. doi: 10.1111/j.1476-5381.1990.tb15784.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kinouchi H., Imaizumi S., Yoshimoto T., Motomiya M. Phenytoin affects metabolism of free fatty acids and nucleotides in rat cerebral ischemia. Stroke. 1990 Sep;21(9):1326–1332. doi: 10.1161/01.str.21.9.1326. [DOI] [PubMed] [Google Scholar]
  24. Kucharczyk J., Mintorovitch J., Moseley M. E., Asgari H. S., Sevick R. J., Derugin N., Norman D. Ischemic brain damage: reduction by sodium-calcium ion channel modulator RS-87476. Radiology. 1991 Apr;179(1):221–227. doi: 10.1148/radiology.179.1.2006281. [DOI] [PubMed] [Google Scholar]
  25. Le Fur G., Vaucher N., Perrier M. L., Flamier A., Benavides J., Renault C., Dubroeucq M. C., Guérémy C., Uzan A. Differentiation between two ligands for peripheral benzodiazepine binding sites, [3H]RO5-4864 and [3H]PK 11195, by thermodynamic studies. Life Sci. 1983 Aug 1;33(5):449–457. doi: 10.1016/0024-3205(83)90794-4. [DOI] [PubMed] [Google Scholar]
  26. May G. R., Rowand W. S., McCormack J. G., Sheridan R. D. Neuroprotective profile of lifarizine (RS-87476) in rat cerebrocortical neurones in culture. Br J Pharmacol. 1995 Apr;114(7):1365–1370. doi: 10.1111/j.1476-5381.1995.tb13357.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. McCulloch J. Ischaemic brain damage--prevention with competitive and non-competitive antagonists of N-methyl-D-aspartate receptors. Arzneimittelforschung. 1991 Mar;41(3A):319–324. [PubMed] [Google Scholar]
  28. McGivern J. G., Patmore L., Sheridan R. D. Actions of the novel neuroprotective agent, lifarizine (RS-87476), on voltage-dependent sodium currents in the neuroblastoma cell line, N1E-115. Br J Pharmacol. 1995 Apr;114(8):1738–1744. doi: 10.1111/j.1476-5381.1995.tb14965.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. McNamara J. O., Rigsbee L. C., Butler L. S., Shin C. Intravenous phenytoin is an effective anticonvulsant in the kindling model. Ann Neurol. 1989 Nov;26(5):675–678. doi: 10.1002/ana.410260514. [DOI] [PubMed] [Google Scholar]
  30. Mohamed A. A., Gotoh O., Graham D. I., Osborne K. A., McCulloch J., Mendelow A. D., Teasdale G. M., Harper A. M. Effect of pretreatment with the calcium antagonist nimodipine on local cerebral blood flow and histopathology after middle cerebral artery occlusion. Ann Neurol. 1985 Dec;18(6):705–711. doi: 10.1002/ana.410180613. [DOI] [PubMed] [Google Scholar]
  31. Morioka T., Kalehua A. N., Streit W. J. The microglial reaction in the rat dorsal hippocampus following transient forebrain ischemia. J Cereb Blood Flow Metab. 1991 Nov;11(6):966–973. doi: 10.1038/jcbfm.1991.162. [DOI] [PubMed] [Google Scholar]
  32. Munson P. J., Rodbard D. Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem. 1980 Sep 1;107(1):220–239. doi: 10.1016/0003-2697(80)90515-1. [DOI] [PubMed] [Google Scholar]
  33. Myers R., Manjil L. G., Cullen B. M., Price G. W., Frackowiak R. S., Cremer J. E. Macrophage and astrocyte populations in relation to [3H]PK 11195 binding in rat cerebral cortex following a local ischaemic lesion. J Cereb Blood Flow Metab. 1991 Mar;11(2):314–322. doi: 10.1038/jcbfm.1991.64. [DOI] [PubMed] [Google Scholar]
  34. Osborne K. A., Shigeno T., Balarsky A. M., Ford I., McCulloch J., Teasdale G. M., Graham D. I. Quantitative assessment of early brain damage in a rat model of focal cerebral ischaemia. J Neurol Neurosurg Psychiatry. 1987 Apr;50(4):402–410. doi: 10.1136/jnnp.50.4.402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Park C. K., Nehls D. G., Graham D. I., Teasdale G. M., McCulloch J. The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat. Ann Neurol. 1988 Oct;24(4):543–551. doi: 10.1002/ana.410240411. [DOI] [PubMed] [Google Scholar]
  36. Pauwels P. J., Leysen J. E., Janssen P. A. Ca++ and Na+ channels involved in neuronal cell death. Protection by flunarizine. Life Sci. 1991;48(20):1881–1893. doi: 10.1016/0024-3205(91)90220-6. [DOI] [PubMed] [Google Scholar]
  37. Pulsinelli W. Pathophysiology of acute ischaemic stroke. Lancet. 1992 Feb 29;339(8792):533–536. doi: 10.1016/0140-6736(92)90347-6. [DOI] [PubMed] [Google Scholar]
  38. Rasool N., Faroqui M., Rubinstein E. H. Lidocaine accelerates neuroelectrical recovery after incomplete global ischemia in rabbits. Stroke. 1990 Jun;21(6):929–935. doi: 10.1161/01.str.21.6.929. [DOI] [PubMed] [Google Scholar]
  39. Rogawski M. A., Porter R. J. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev. 1990 Sep;42(3):223–286. [PubMed] [Google Scholar]
  40. Roman R., Bartkowski H., Simon R. The specific NMDA receptor antagonist AP-7 attenuates focal ischemic brain injury. Neurosci Lett. 1989 Sep 25;104(1-2):19–24. doi: 10.1016/0304-3940(89)90322-4. [DOI] [PubMed] [Google Scholar]
  41. Schwarz J. R., Grigat G. Phenytoin and carbamazepine: potential- and frequency-dependent block of Na currents in mammalian myelinated nerve fibers. Epilepsia. 1989 May-Jun;30(3):286–294. doi: 10.1111/j.1528-1157.1989.tb05300.x. [DOI] [PubMed] [Google Scholar]
  42. Shokunbi M. T., Gelb A. W., Wu X. M., Miller D. J. Continuous lidocaine infusion and focal feline cerebral ischemia. Stroke. 1990 Jan;21(1):107–111. doi: 10.1161/01.str.21.1.107. [DOI] [PubMed] [Google Scholar]
  43. Siesjö B. K. Cell damage in the brain: a speculative synthesis. J Cereb Blood Flow Metab. 1981;1(2):155–185. doi: 10.1038/jcbfm.1981.18. [DOI] [PubMed] [Google Scholar]
  44. Siesjö B. K. Historical overview. Calcium, ischemia, and death of brain cells. Ann N Y Acad Sci. 1988;522:638–661. doi: 10.1111/j.1749-6632.1988.tb33410.x. [DOI] [PubMed] [Google Scholar]
  45. Simon R. P., Griffiths T., Evans M. C., Swan J. H., Meldrum B. S. Calcium overload in selectively vulnerable neurons of the hippocampus during and after ischemia: an electron microscopy study in the rat. J Cereb Blood Flow Metab. 1984 Sep;4(3):350–361. doi: 10.1038/jcbfm.1984.52. [DOI] [PubMed] [Google Scholar]
  46. Smith M. L., Kågström E., Rosén I., Siesjö B. K. Effect of the calcium antagonist nimodipine on the delayed hypoperfusion following incomplete ischemia in the rat. J Cereb Blood Flow Metab. 1983 Dec;3(4):543–546. doi: 10.1038/jcbfm.1983.83. [DOI] [PubMed] [Google Scholar]
  47. Spedding M., Kilpatrick A. T., Alps B. J., Speddings M. Activators and inactivators of calcium channels: effects in the central nervous system. Fundam Clin Pharmacol. 1989;3 (Suppl):3s–29s. doi: 10.1111/j.1472-8206.1989.tb00472.x. [DOI] [PubMed] [Google Scholar]
  48. Taft W. C., Clifton G. L., Blair R. E., DeLorenzo R. J. Phenytoin protects against ischemia-produced neuronal cell death. Brain Res. 1989 Mar 27;483(1):143–148. doi: 10.1016/0006-8993(89)90045-0. [DOI] [PubMed] [Google Scholar]
  49. Umemura K., Wada K., Uematsu T., Mizuno A., Nakashima M. Effect of 21-aminosteroid lipid peroxidation inhibitor, U74006F, in the rat middle cerebral artery occlusion model. Eur J Pharmacol. 1994 Jan 4;251(1):69–74. doi: 10.1016/0014-2999(94)90444-8. [DOI] [PubMed] [Google Scholar]
  50. Vornov J. J., Tasker R. C., Coyle J. T. Delayed protection by MK-801 and tetrodotoxin in a rat organotypic hippocampal culture model of ischemia. Stroke. 1994 Feb;25(2):457–465. doi: 10.1161/01.str.25.2.457. [DOI] [PubMed] [Google Scholar]
  51. Wauquier A., Ashton D., Clincke G. H. Brain ischemia as a target for Ca2+ entry blockers. Ann N Y Acad Sci. 1988;522:478–490. doi: 10.1111/j.1749-6632.1988.tb33387.x. [DOI] [PubMed] [Google Scholar]
  52. Welsh F. A., Sakamoto T., McKee A. E., Sims R. E. Effect of lactacidosis on pyridine nucleotide stability during ischemia in mouse brain. J Neurochem. 1987 Sep;49(3):846–851. doi: 10.1111/j.1471-4159.1987.tb00971.x. [DOI] [PubMed] [Google Scholar]
  53. Willow M., Gonoi T., Catterall W. A. Voltage clamp analysis of the inhibitory actions of diphenylhydantoin and carbamazepine on voltage-sensitive sodium channels in neuroblastoma cells. Mol Pharmacol. 1985 May;27(5):549–558. [PubMed] [Google Scholar]
  54. Yamasaki Y., Kogure K., Hara H., Ban H., Akaike N. The possible involvement of tetrodotoxin-sensitive ion channels in ischemic neuronal damage in the rat hippocampus. Neurosci Lett. 1991 Jan 2;121(1-2):251–254. doi: 10.1016/0304-3940(91)90697-r. [DOI] [PubMed] [Google Scholar]
  55. Zavala F., Lenfant M. Benzodiazepines and PK 11195 exert immunomodulating activities by binding on a specific receptor on macrophages. Ann N Y Acad Sci. 1987;496:240–249. doi: 10.1111/j.1749-6632.1987.tb35772.x. [DOI] [PubMed] [Google Scholar]

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