Glutamate Receptor Antagonists in Experimental Focal Cerebral Ischaemia

  • James McCulloch
  • E. Ozyurt
  • C. Kun Park
  • D. G. Nehls
  • G. M. Teasdale
  • D. I. Graham
Conference paper
Part of the Acta Neurochirurgica book series (NEUROCHIRURGICA, volume 57)


Excessive activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor has been implicated in the sequence of neurochemical events in cerebral ischaemia that results in irreversible neuronal damage. The effects of the NMDA antagonist MK 801 upon the amount of ischaemic brain damage has been assessed quantitatively in a cat and in a rat model of focal cerebral ischaemia.

In chloralose-anaesthetised cats, focal cerebral ischaemia was produced by permanent occlusion of one middle cerebral artery (MCA) and the animal sacrificed 6 hours later. Pretreatment with the non-competitive NMDA antagonist, MK-801 (5 mg/kg, i.v.) reduced significantly the volume of ischaemic damage in the cerebral cortex by 57% compared to vehicle-treated cats. A similar degree of neuroprotection could be demonstrated in the cat MCA occlusion model if treatment with MK-801 was initiated 2 hours after the induction of ischaemia.

In halothanc-anaesthetised rats, focal cerebral ischacmia was produced by permanent MCA occlusion and the animals sacrificed 3 hours later. Pretreatment with MK-801 (0.5 mg/kg, i.v.) reduced the volume of ischaemic damage in the cerebral cortex by 38%; treatment with MK-801 initiated 30 minutes after MCA occlusion was equally effective in reducing cortical damage.

In contrast to calcium entry blockers such as nimodipine in the rat MCA occlusion model, the improved histopathological outcome with MK-801 is not associated with improvement in cerebral tissue perfusion to the ischaemic tissue. The increasing evidence that NMDA receptor antagonists are beneficial in experimental focal cerebral ischaemia is reviewed.


Focal cerebral ischemia infarct formation NMDA-receptor MK-801 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Barnett GH, Bose B, Little JR,Jones SC, Friel HT (1986)Effects of nimodipineonacute focal cerebral ischemia. Stroke 17: 884–890PubMedCrossRefGoogle Scholar
  2. 2.
    Benveniste H,Drejer J, Schousboe A, Diemer NH (1984) Elevation of the extracellularconcentrations of glutamate and aspartate in rat hippocampus during transientcerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43:1369–1374PubMedCrossRefGoogle Scholar
  3. 3.
    Berger L, Hakim AM(1988) Calcium channel blockers correct acidosis in ischemic rat brainwithout altering cerebral blood flow. Stroke 19: 1257–1261PubMedCrossRefGoogle Scholar
  4. 4.
    Carter C,Benavides J, Legendre P, Vincent JD, Noel F, Thuret F, Lloyd KG, Arbilla S, Zivkovic B, MacKenzie ET, Scatton B, Langer SZ (1988)Ifenprodil and SL 82.0715 as cerebral antiischaemic agents II Evidence for NMDAreceptor antagonist properties. J Pharm Expt Ther 247: 1222–1232Google Scholar
  5. 5.
    Coyle P (1989)Altered cerebral collaterals and protection from infarction. In: Hartmann A, Kuschinsky W(eds) Cerebral ischemia and calcium metabolism. Springer, Berlin Heidelberg NewYork Tokyo, pp 69–78Google Scholar
  6. 6.
    Davies J, EvansRH, Herrling PL, Jones AW, Olverman HJ, Pook P, Watkins JC (1986) CPP, a newpotent and selective NMDA antagonist Depression of central neuron resposes, affinity for [3H] D-AP5 binding sites on brain membranes andanticonvulsant activity. Brain Res 382: 169–173PubMedCrossRefGoogle Scholar
  7. 7.
    Germano IM, Pitts IH, MeldrumBS, Bartkowski HM, Simon RP (1987) Kynurenate inhibition of cell excitationdecreases stroke size and deficits, Ann Neurol 22: 730–734PubMedCrossRefGoogle Scholar
  8. 8.
    Gill R, FosterAC, Woodruff GN (1987) Systemic administration of MK-801 protects againstischemia-induced hippocampal neurodegeneration in the gerbil. J Neurosci 7:3343–3349PubMedGoogle Scholar
  9. 9.
    Gotoh O, Mohamed AA, McCulloch J, Graham DI, Harper AM, Teasdale GM (1986) Nimodipine and the haemodynamic and histopathological consequences of middlecerebral artery occlusion in the rat. J Cereb Blood Flow Metabol 6: 321–331CrossRefGoogle Scholar
  10. 10.
    Gotti B,Duverger D, Bertin J, Carter C, Dupoint R, Frost J, Gaudilliere B, MacKenzie ET, Rousseau J,Scatton B, Wick A (1988). Ifenprodil and SL 82.0715 as cerebral anti-ischaemicagents I. Evidence for efficacy in models of focal cerebral ischaemia. J PharmExp Ther 247: 1211–1221Google Scholar
  11. 11.
    Greenamyre JT,Olson JMM, Penney JB (Jr), Young AB (1985) Autoradiographic characterizationof N-methyl-D-Aspartate Quisqualate- and Kainate-Sensitive glutamate bindingsites. J Pharmacol Exp Ther 233: 254–263PubMedGoogle Scholar
  12. 12.
    Hamar J, ReivichM, Greenberg JH, Shearmen GT (1988). Tissue blood flow and metabolic changes ofthe brain in ischaemia and reperfusion: effect of a glutamate antagonist(MK-801) treatment. Abstract presented to 11th Annual Conference on Shock. Fontana, Wisconsin 5–8 June,1988Google Scholar
  13. 13.
    Hossmann KA (1982)Treatment of experimental cerebral ischaemia. J Cereb Blood Flow Metabol 2:275–297CrossRefGoogle Scholar
  14. 14.
    Lanier WL, Perkins WJ,Ruud B, MildeJH,Michenfelder JD (1988) Effect of the excitatory amino acid antagonist MK-801 onneurologic function following complete cerebral ischemia in primates.Anesthesiology 69: A846CrossRefGoogle Scholar
  15. 15.
    Mohamed A A,Gotoh O, Graham DI, Osborne KA, McCulloch J, Mendelow AD, Teasdale GM, HarperAM (1985) Effect of pretreatment with the calcium antagonist nimodipine onlocal cerebral blood flow and histopathology after middle cerebral arteryocclusion. Ann Neurol 18: 705–711PubMedCrossRefGoogle Scholar
  16. 16.
    Nehls DG, ParkCK, McCulloch J (1989) Cerebral circulatory effects of dizocilpine (MK-801) inthe rat. J Cereb Blood Flow Metabol 9 [Suppl I]: S376Google Scholar
  17. 17.
    Ozyurt E, GrahamDI, Woodruff GN, McCulloch J (1988) Protective effect of the glutamateantagonist, MK-801 in focal cerebral ischemia in the cat. J Cereb Blood FlowMetabol 8: 138–143CrossRefGoogle Scholar
  18. 18.
    Park CK, NehlsDG, Graham DI, Teasdale GM, McCulloch J (1988a) The glutamate antagonist MK-801reduces focal ischemic brain damage in the rat. Ann Neurol 24: 543–551PubMedCrossRefGoogle Scholar
  19. 19.
    Park CK, NehlsDG, Graham DI, Teasdale GM, McCulloch J (1988b) Focal cerebral ischaemia in thecat: treatment with the glutamate antagonist MK-801 after induction ofischaemia. J Cereb Blood Flow Metabol 8: 757–762CrossRefGoogle Scholar
  20. 20.
    Petruk KC, West M, Mohr G, Weir BKA, Benoit BG,Gentili F, Disney LB, Khan MI, Grace M, Holness RO, Karwon MS, Ford RM, CameronGS, Tucker WS,PurvesGB, Miller JDR, Hunter KM, Richard MT, Durity FA, Chan R, Clein LJ, Maroun FB,Gordon A (1988) Nimodipine treatment in poor-grade aneurysm patients JNeurosurg 68: 505–517PubMedCrossRefGoogle Scholar
  21. 21.
    Pickard JD,Murray GD, Illingworth R, Shaw MDM, Teasdale GM, Foy PM, Humphrey PRD, Lang DA,Nelson R, Richards P, Sinar J, Bailey S, Skene A (1989) Effect of oralnimodipine on cerebral infarction and outcome after subarachnoid haemorrhage:British aneurysm nimodipine trial. BMJ 298: 636–642PubMedCrossRefGoogle Scholar
  22. 22.
    Sakabe T, NagaiI, Ishikawa T, Takeshita H, Masuda T, Matsumoto M, Tateishi A (1986)Nicardipine increases cerebral blood flow but does not improve neurologicrecovery in a canine model of complete cerebral ischemia. J Cereb Blood Flow Metabol 6: 684–690CrossRefGoogle Scholar
  23. 23.
    Rothman SM, OlneyJW (1986) Glutamate and the pathophysiology of hypoxic-ischemic brain damage.Ann Neurol 19: 105–111PubMedCrossRefGoogle Scholar
  24. 24.
    Simon RP, SwanJH, Griffiths T, MeldrumBS(1984) Blockade of N-methyl-D-aspartate receptors may protect against ischemicdamage in the brain. Science 226: 850–852PubMedCrossRefGoogle Scholar
  25. 25.
    Steen PA, NewbergLA,Milde JH,Michenfelder JD (1983) Nimodipine improves cerebral blood flow and neurologicrecovery after complete cerebral ischemia in the dog. J Cereb Blood FlowMetabol 3: 38–43CrossRefGoogle Scholar
  26. 26.
    Steinberg GK,Saleh J, Kunis D (1988) Delayed treatment with dextromethorphan and dextrorphanreduces cerebral damage after transient focal ischemia. Neurosci Lett 89:193–197PubMedCrossRefGoogle Scholar
  27. 27.
    Wong EHF, Kemp JA, Priestley T,Knight AR,WoodruffGN, Iversen LL (1986) The anticonvulsant MK-801 is a potent Nmethyl-D-aspartate antagonist. Proc Natl Acad Sci USA 83: 7104–7108PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • James McCulloch
    • 1
  • E. Ozyurt
    • 1
  • C. Kun Park
    • 1
  • D. G. Nehls
    • 1
  • G. M. Teasdale
    • 1
  • D. I. Graham
    • 1
  1. 1.Wellcome Neuroscience Group, Wellcome Surgical Institute, and Hugh Fraser Neuroscience LaboratoriesUniversity of GlasgowGlasgowUK

Personalised recommendations