THE N-METHYL-D-ASPARTATE ANTAGONIST, MK-801, FAILS TO PROTECT AGAINST NEURONAL DAMAGE CAUSED BY TRANSIENT, SEVERE FOREBRAIN ISCHEMIA IN ADULT-RATS

被引:0
|
作者
BUCHAN, A
LI, H
PULSINELLI, WA
机构
[1] CORNELL UNIV,MED CTR,DEPT NEUROL & NEUROSCI,CEREBROVASC DIS RES CTR,1300 YORK AVE,NEW YORK,NY 10021
[2] CORNELL UNIV,MED CTR,DEPT NEUROL & NEUROSCI,RAYMOND & BEVERLY SACKLER FDN INC,NEW YORK,NY 10021
[3] UNIV WESTERN ONTARIO HOSP,DEPT CLIN NEUROL SCI,ROBARTS RES INST,CEREBRAL ISCHEMIA LAB,LONDON N6A 5A5,ONTARIO,CANADA
来源
JOURNAL OF NEUROSCIENCE | 1991年 / 11卷 / 04期
关键词
D O I
暂无
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The neuroprotective effects of dizocilipine maleate (MK-801), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor/channel, were tested in the 4-vessel occlusion rat model of forebrain ischemia. Adult Wistar rats, treated intraperitoneally with MK-801 or saline using several different treatment paradigms were subjected to 5 (n = 208) or 15 (n = 62) min of severe, transient forebrain ischemia. In saline-treated animals, 15 min of ischemia (n = 13) produced extensive and consistent loss of pyramidal neurons in the CA 1 zone of hippocampus. The degree and distribution of cell loss were not reduced by single dose preischemic administration of MK-801 at 1 (n = 7), 2.5 (n = 4), or 5 mg/kg (n = 8). In other animals subjected to 15 min of forebrain ischemia, multiple doses of MK-801 (5, 2.5, and 2.5 mg/kg) given immediately and at approximately 8 and 20 hr after cerebral reperfusion (n = 5) did not alter CA 1 injury compared to saline-treated controls (n = 5). Five minutes of forebrain ischemia in saline-treated animals, (n = 82) resulted in significantly fewer (p < 0.001) dead CA 1 pyramidal cells and a greater variance compared to animals subjected to 15 min of ischemia. Power analysis of the preliminary saline-treated animals subjected to 5 min of ischemia (n = 22) indicated that 60 animals per group were necessary to detect a 15% difference between MK-801 and vehicle-treated groups. Multidose treatment with MK-801 (1 mg/kg) given 1 hr prior to 5 min of ischemia (n = 60) and again at approximately 8 and 16 hr after recirculation failed to attenuate hippocampal injury. Despite doses of MK-801 that produced marked behavioral abnormalities in the rats, no protection against ischemic injury to CA 1 neurons was observed with any of the treatment paradigms. These data fail to support a singular role for the NMDA receptor/channel in the pathogenesis of injury to neurons from even brief periods of severe ischemia.
引用
收藏
页码:1049 / 1056
页数:8
相关论文
共 50 条
  • [21] THE N-METHYL-D-ASPARTATE ANTAGONIST MK-801 INCREASES STRIATAL DOPAMINE RELEASE IN THE RAT - A MICRODIALYSIS STUDY
    KISS, JP
    TOTH, E
    LAJTHA, A
    VIZI, ES
    JOURNAL OF NEUROCHEMISTRY, 1993, 61 : S204 - S204
  • [23] Effects of the N-methyl-D-aspartate receptor antagonist, MK-801, on spatial memory and influence of the route of administration
    Svalbe, Baiba
    Stelfa, Gundega
    Vavers, Edijs
    Zvejniece, Baiba
    Grinberga, Solveiga
    Sevostjanovs, Eduards
    Pugovics, Osvalds
    Dambrova, Maija
    Zvejniece, Liga
    BEHAVIOURAL BRAIN RESEARCH, 2019, 372
  • [24] Synthesis of a 11C-labelled derivative of the N-methyl-D-aspartate receptor antagonist MK-801
    Andersson, Y
    Tyrefors, N
    Sihver, S
    Onoe, H
    Watanabe, Y
    Tsukada, H
    Langstrom, B
    JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 1998, 41 (06): : 567 - 576
  • [25] N-methyl-D-aspartate prevented memory deficits induced by MK-801 in mice
    Hlinák, Z
    Krejcí, I
    PHYSIOLOGICAL RESEARCH, 2003, 52 (06) : 809 - 812
  • [26] THE INTERACTION BETWEEN MK-801 AND RECEPTORS FOR N-METHYL-D-ASPARTATE - FUNCTIONAL CONSEQUENCES
    WOODRUFF, GN
    FOSTER, AC
    GILL, R
    KEMP, JA
    WONG, EHF
    IVERSEN, LL
    NEUROPHARMACOLOGY, 1987, 26 (7B) : 903 - 909
  • [27] Differential effects of MK-801, a N-methyl-D-aspartate noncompetitive antagonist, on the dorsal horn neuron hyperactivity and hyperexcitability in neuropathic rats
    Sotgiu, ML
    Biella, G
    NEUROSCIENCE LETTERS, 2000, 283 (02) : 153 - 156
  • [28] HEMODYNAMIC-EFFECTS OF IV INJECTIONS OF THE NONCOMPETITIVE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR ANTAGONIST MK-801 IN CONSCIOUS RATS
    JACOB, HJ
    BARRES, C
    BRODY, MJ
    LEWIS, SJ
    FASEB JOURNAL, 1992, 6 (04): : A1523 - A1523
  • [29] INDUCTION OF FOS AND JUN PROTEINS AFTER FOCAL ISCHEMIA IN THE RAT - DIFFERENTIAL EFFECT OF THE N-METHYL-D-ASPARTATE RECEPTOR ANTAGONIST MK-801
    GASS, P
    SPRANGER, M
    HERDEGEN, T
    BRAVO, R
    KOCK, P
    HACKE, W
    KIESSLING, M
    ACTA NEUROPATHOLOGICA, 1992, 84 (05) : 545 - 553
  • [30] BLOCKADE OF N-METHYL-D-ASPARTATE RECEPTORS BY MK-801 (DIZOCILPINE MALEATE) RESCUES MOTONEURONS IN DEVELOPING RATS
    GREENSMITH, L
    MENTIS, GZ
    VRBOVA, G
    DEVELOPMENTAL BRAIN RESEARCH, 1994, 81 (02): : 162 - 170