Hostname: page-component-745bb68f8f-lrblm Total loading time: 0 Render date: 2025-01-22T11:34:52.737Z Has data issue: false hasContentIssue false
  • English
  • Français

Pre- and Post-Ischemic Administration of Dizocilpine (MK-801) Reduces Cerebral Necrosis in the Rat

Published online by Cambridge University Press:  18 September 2015

M.R. Rod  and
R.N. Auer
M.R. Rod
Affiliation:
Departments of Pathology and Clinical Neurosciences, Neuroscience Research Group, Health Sciences Centre, University of Calgary, Calgary, Alberta, Canada T2N 4N1
R.N. Auer*
Affiliation:
Departments of Pathology and Clinical Neurosciences, Neuroscience Research Group, Health Sciences Centre, University of Calgary, Calgary, Alberta, Canada T2N 4N1
*
Neuropathology, Health Sciences Centre, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1
Rights & Permissions [Opens in a new window]

Abstract:

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

The purpose of this study was to determine the effectiveness of the non-competitive N-methyl-D-aspartate receptor antagonist dizocilpine, or (+)-5-methyl-10,l l-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801) in mitigating ischemic neuronal necrosis in the rat. Ten minutes of transient forebrain ischemia was induced by a combination of bilateral carotid clamping and hypotension to 50 mm Hg. Control animals received intravenous saline, whereas treated animals received dizocilpine, either 1 mg/kg iv 20 min. pre ischemia, 1 mg/kg iv 20 min. post ischemia, 10 mg/kg iv 20 min. post ischemia, 10 mg/kg ip 2 hrs. post ischemia, 10 mg/kg ip 24 hrs. post ischemia. The groups receiving dizocilpine before or up to 20 min. after ischemia all showed a significant reduction in the number of dead neurons as assessed by quantitative histopathology in hippocampus, caudate nucleus and cerebral cortex after one week of recovery. However, dizocilpine administered either 2 or 24 hrs. after ischemia afforded no protection. These results suggest that the potent non-competitive NMDA antagonist dizocilpine may have some value in protecting the brain from hippocampal and cortical neuronal necrosis after a short insult consisting of dense transient cerebral ischemia. Noteworthy is the fact that pharmacologic intervention in the post-ischemic period was successful in preventing neuronal death, provided that drug administration occurred within dizocilpine's “therapeutic window”.

Type
Original Articles
Information
Canadian Journal of Neurological Sciences , Volume 16 , Issue 3 , August 1989 , pp. 340 - 344
Copyright
Copyright © Canadian Neurological Sciences Federation 1989

References

REFERENCES

1.Simon, RP, Swan, JH, Griffiths, T, et al. Blockade of N-methyl-Daspartatereceptors may protect against ischemic damage in the brain. Science 1984; 226: 850–852.CrossRefGoogle ScholarPubMed
2.Gill, R, Foster, AC, Woodruff, GN. Systemic administration of MK- 801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil. J Neurosci 1987; 7: 3343–3349.CrossRefGoogle ScholarPubMed
3.Rothman, S. Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. J Neurosci 1984; 4: 1884–1891.CrossRefGoogle ScholarPubMed
4.Wong, EHF, Kemp, JA, Priestley, T, et al. The anticonvulsant MK- 801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci USA 1986; 83: 7104–7104.CrossRefGoogle ScholarPubMed
5.Woodruff, GN, Foster, AC, Gill, R, et al. The interaction between MK-801 and receptors for N-methyl-D-aspartate: Functional consequences. Neuropharmacology 1987; 26: 903–909.CrossRefGoogle ScholarPubMed
6.Foster, AC, Gill, R, Kemp, JA, et al. Systemic administration of MK-801 prevents N-methyl-D-aspartate-induced neuronal degeneration in rat brain. Neurosci Lett 1987; 76: 307–311.CrossRefGoogle ScholarPubMed
7.Clineschmidt, BV, Martin, GE, Bunting, PR. Anticonvulsant activity of (+)-5-methyl-10,l l-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine (MK-801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties. Drug Dev Res 1982; 2: 123–134.CrossRefGoogle Scholar
8.Clineschmidt, BV, Martin, GE, Bunting, PR, et al. Central sympathomimetic activity of (+)-5-methyl-10,l l-dihydro-5Hdibenzo[ a,d]cyclohepten-5,10-imine (MK-801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties. Drug Dev Res 1982; 2: 135–145.CrossRefGoogle Scholar
9.Clineschmidt, BV, Williams, M, Witoslawski, JJ, et al. Restoration of shock-suppressed behavior by treatment with (+)-5-methyl- 10,1 l-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK- 801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties. Drug Dev Res 1982; 2: 147–163.CrossRefGoogle Scholar
10.Coan, EJ, Saywood, W, Collingridge, GL. MK-801 blocks NMDA receptor-mediated synaptic transmission and long term potentiation in rat hippocampal slices. Neurosci Lett 1987; 80: 111–114.CrossRefGoogle ScholarPubMed
11.Olney, J, Price, M, Salles, S, et al. MK-801 powerfully protects against N-methyl aspartate neurotoxicity. Eur J Pharmacol 1987; 141: 357–361.CrossRefGoogle ScholarPubMed
12.Foster, AC, Wong, EHF. The novel anticonvulsant MK-801 binds to the activated state of the N-methyl-D-aspartate receptor in rat brain. Br J Pharmacol 1987; 91: 403–409.CrossRefGoogle Scholar
13.Davies, SN, Martin, D, Millar, JD, et al. Differences in results from in vivo and in vitro studies on the use-dependency of N-methylaspartate antagonism by MK-801 and other phencyclidine receptor ligands. Eur J Pharmacol 1988; 145: 141–151.CrossRefGoogle ScholarPubMed
14.Mckernan, RM, Castro, S, Poat, JA, et al. Solubilization of the Nmethyl- D-aspartate receptor channel complex from rat and porcine brain. J Neurochem 1989; 52: 777–785.CrossRefGoogle Scholar
15.Gill, R, Foster, AC, Woodruff, GN. MK-801 is neuroprotective in gerbils when administered in the post-ischaemic period. Neuroscience 1988; 25: 847–855.CrossRefGoogle ScholarPubMed
16.Ozyurt, E, Graham, DI, Woodruff, GN, et al. Protective effect of the glutamate antagonist, MK-801 in focal cerebral ischemia in the cat. J Cereb Blood Flow Metabol 1988; 8: 138–143.CrossRefGoogle ScholarPubMed
17.Park, CK, Nehls, DG, Graham, DI, et al. Focal cerebral ischaemia in the cat: Treatment with the glutamate antagonist MK-801 after induction of ischaemia. J Cereb Blood Flow Metabol 1988; 8: 757–762.CrossRefGoogle ScholarPubMed
18.Kochar, A, Zivin, JA, Lyden, PD, et al. Glutamate antagonist therapy reduces neurologic deficits produced by focal central nervous system ischemia. Arch Neurol 1988; 45: 148–153.CrossRefGoogle Scholar
19.Bendek, Smith M-L, Dahlgren, N, Lyden, PD, et al. Models for studying long term recovery following forebrain ischemia in the rat. 2. A 2-vessel occlusion model. Acta Neurol Scand 1984; 69: 385–401.Google Scholar
20.Auer, RN, Kalimo, H, Olsson, Y, et al. The temporal evolution of hypoglycemic brain damage. I. Light and electron microscopic findings in the rat cerebral cortex. Acta Neuropathol (Beri) 1985; 67: 13–24.CrossRefGoogle ScholarPubMed
21.Whishaw, IQ, Auer, RN. Immediate and long-lasting effects of MK 801 on motor activity, spatial navigation in a swimming pool and EEG in the rat. Psychopharmacology 1989; in press.CrossRefGoogle Scholar
22.Koek, W, Kleer, E, Mudar, PJ, et al. Phencyclidine-like catalepsy induced by the excitatory amino acid antagonist DL-2-amino-5-phosphonovalerate. Behav Brain Res 1986; 29: 257–259.CrossRefGoogle Scholar
23.Koek, W, Woods, JH, Mattson, MV, et al. Excitatory amino acid antagonists induce a phencyclidine-like catalepsy in pigeons: structure-activity studies. Neuropharmacology 1987; 26: 1261–1265.CrossRefGoogle ScholarPubMed
24.Mcdonald, JW, Silverstein, FS, Johnston, MV. MK-801 protects the neonatal brain from hypoxic-ischemic damage. Eur J Pharmacol 1987; 140: 359–361.CrossRefGoogle ScholarPubMed
25.Ito, U, Spatz, M, Walker, TJ Jr, et al, Experimental cerebral ischemia in Mongolian gerbils. I. Light microscopic observations. Acta Neuropathol (Beri) 1975; 32: 209–223.CrossRefGoogle ScholarPubMed
26.Kirino, T. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 1982; 239: 57–69.CrossRefGoogle ScholarPubMed
27.Kirino, T, Sano, K. Selective vulnerability in the gerbil hippocampus following transient ischemia. Acta Neuropathol (Berl) 1984; 62: 201–208.CrossRefGoogle ScholarPubMed
28.Kirino, T, Sano, K. Fine structural nature of delayed neuronal death following ischemia in the gerbil hippocampus. Acta Neuropathol (Berl) 1984; 62: 209–218.CrossRefGoogle ScholarPubMed
29.Kirino, T, Tamura, A, Sano, K. Delayed neuronal death in the rat hippocampus following transient forebrain ischemia. Acta Neuropathol (Berl) 1984; 64: 139–147.CrossRefGoogle ScholarPubMed
30.Petito, CK, Feldman, E, Pulsinelli, WA, et al. Delayed hippocampal damage in humans following cardiorespiratory arrest. Neurology 1987; 37: 1281–1286.CrossRefGoogle ScholarPubMed
31.Mandel, MM, Berry, RG. Human brain changes in cardiac arrest. Surg Gynecol Obstet 1959; 108: 692–696.Google ScholarPubMed
32.Muramoto, O, Kuru, Y, Sugishita, M, et al. Pure memory loss with hippocampal lesions. A pneumoencephalographic study. Arch Neurol 1979; 36: 54–56.CrossRefGoogle ScholarPubMed
33.Cummings, JL, Tomiyasu, U, Read, S, Amnesia with hippocampal lesions after cardiopulmonary arrest. Neurology 1984; 34: 679–681.CrossRefGoogle ScholarPubMed
34.Zola-Morgan, S, Squire, LR, Amaral, DG. Human amnesia and the medial temporal region: Enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. J Neurosci 1986; 6: 2950–2967.CrossRefGoogle ScholarPubMed
35.Cole, G, Cowie, VA. Long survival after cardiac arrest: Case report and neuropathological findings. Clin Neuropathol 1987; 6: 104–109.Google ScholarPubMed
36.Earnest, M, Yarnell, PR, Merrill, S, et al. Long-term survival and neurologic status after resuscitation from out-of-hospital cardiac arrest. Neurology 1980; 30: 1298–1302.CrossRefGoogle ScholarPubMed
37.Volpe, BT, Hirst, W. The characterization of an amnesic syndrome following hypoxic ischemic injury. Arch Neurol 1983; 40: 436–440.CrossRefGoogle ScholarPubMed
38.Auer, RN, Jensen, ML, Whishaw, IQ. Neurobehavioural deficit due to ischemic brain damage limited to half of the CA1 sector of the hippocampus. J Neurosci 1989; (in press).CrossRefGoogle ScholarPubMed
39.Zar, JH. Data transformations. Biostatistical Analysis. New Jersey, U.S.A.: Prentice-Hall, Inc., 1974; 185–186.Google Scholar