N-甲基-D-天冬氨酸受体在梗阻性黄疸时中枢神经系统损伤中的作用
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摘要
目的评价N-甲基-D-天冬氨酸(NMDA)受体在机体梗阻性黄疸时中枢神经系统损伤中的作用。方法收集近年来国内外关于NMDA受体及高胆红素血症时中枢神经系统损伤的相关文献并进行综述。结果高胆红素血症时神经系统损伤的发生与NMDA受体的过度活化有关,由于NMDA受体的过度激活导致了神经细胞的变性和坏死,应用NMDA受体阻滞剂MK-801可减轻高胆红素血症时的神经系统损伤。结论 NMDA受体在高胆红素血症时中枢神经系统损伤过程中发挥重要作用,MNDA受体阻滞剂对此有保护作用,但目前仍无临床应用MK-801的研究报道。
Objective To evaluate the role of N-methyl-D-aspartate(NMDA) receptor in central nervous system(CNS) injury of obstructive jaundice. Method The related literatures about NMDA receptor and the CNS injury caused by hyperbilirubinemia were retrieved and reviewed. Results The CNS injury of obstructive jaundice was related to overactivation of NMDA receptor, which finally resulted in degeneration and necrosis of nerve cells. The NMDA receptor antagonist MK-801 could relieve the CNS injury of obstructive jaundice. Conclusions NMDA receptor plays an important role in the CNS injury caused by hyperbilirubinemia, and the blocker of NMDA receptor has protective effects in this process. However, there is no report of MK-801 in clinical application when hyperbilirubinemia happened.
Objective To evaluate the role of N-methyl-D-aspartate(NMDA) receptor in central nervous system(CNS) injury of obstructive jaundice. Method The related literatures about NMDA receptor and the CNS injury caused by hyperbilirubinemia were retrieved and reviewed. Results The CNS injury of obstructive jaundice was related to overactivation of NMDA receptor, which finally resulted in degeneration and necrosis of nerve cells. The NMDA receptor antagonist MK-801 could relieve the CNS injury of obstructive jaundice. Conclusions NMDA receptor plays an important role in the CNS injury caused by hyperbilirubinemia, and the blocker of NMDA receptor has protective effects in this process. However, there is no report of MK-801 in clinical application when hyperbilirubinemia happened.
引文
1 Qin LX,Tang ZY.Hepatocellular carcinoma with obstructive jaundice:diagnosis,treatment and prognosis.World J Gastroenterol,2003,9(3):385-391.
2 Iskander I,Gamaleldin R,El Houchi S,et al.Serum bilirubin and bilirubin/albumin ratio as predictors of bilirubin encephalopathy.Pediatrics,2014,134(5):e1330-e1339.
3 Diamond I,Schmid R.The pathogenesis of bilirubin encephalopathy:experimental models in newborn and adult animals.Trans Am Neurol Assoc,1965,90:38-41.
4 Song S,Hu Y,Gu X,et al.A novel newborn rat kernicterus model created by injecting a bilirubin solution into the cisterna magna.PLo S One,2014,9(5):e96171.
5 Gao X,Yang X,Zhang B.Neuroprotection of taurine against bilirubininduced elevation of apoptosis and intracellular free calcium ion in vivo.Toxicol Mech Methods,2011,21(5):383-387.
6 Hachiya Y,Hayashi M.Bilirubin encephalopathy:a study of neuronal subpopulations and neurodegenerative mechanisms in 12autopsy cases.Brain Dev,2008,30(4):269-278.
7 Silva RF,Rodrigues CM,Brites D.Rat cultured neuronal and glial cells respond differently to toxicity of unconjugated bilirubin.Pediatr Res,2002,51(4):535-541.
8 Hank?E,Hansen TW,Almaas R,et al.Bilirubin induces apoptosis and necrosis in human NT2-N neurons.Pediatr Res,2005,57(2):179-184.
9 Tabarki B,Khalifa M,Yacoub M,et al.Cerebellar symptoms heralding bilirubin encephalopathy in Crigler-Najjar syndrome.Pediatr Neurol,2002,27(3):234-236.
10 Furukawa Y.Histological changes in the brain due to experimental obstructive jaundice.Nihon Geka Gakkai Zasshi,1991,92(1):37-45.
11 Chroni E,Patsoukis N,Karageorgos N,et al.Brain oxidative stress induced by obstructive jaundice in rats.J Neuropathol Exp Neurol,2006,65(2):193-198.
12 Lau CG,Zukin RS.NMDA receptor traffi cking in synaptic plasticity and neuropsychiatric disorders.Nat Rev Neurosci,2007,8(6):413-426.
13 Xu B,Xu Z,Deng Y,et al.MK-801 protects against intracellular Ca(2+)overloading and improves N-methyl-D-aspartate receptor expression in cerebral cortex of methylmercury-poisoned rats.J Mol Neurosci,2013,49(1):162-171.
14 Cull-Candy S,Brickley S,Farrant M.NMDA receptor subunits:diversity,development and disease.Curr Opin Neurobiol,2001,11(3):327-335.
15 Fan MM,Raymond LA.N-methyl-D-aspartate(NMDA)receptor function and excitotoxicity in Huntington,s disease.Prog Neurobiol,2007,81(5/6):272-293.
16 Paoletti P.Molecular basis of NMDA receptor functional diversity.Eur J Neurosci,2011,33(8):1351-1365.
17 Kew JN,Kemp JA.Ionotropic and metabotropic glutamate receptor structure and pharmacology.Psychopharmacology(Berl),2005,179(1):4-29.
18 Hardingham GE,Bading H.The yin and yang of NMDA receptor signalling.Trends Neurosci,2003,26(2):81-89.
19 Massey PV,Johnson BE,Moult PR,et al.Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression.J Neurosci,2004,24(36):7821-7828.
20 Kosenko E,Venediktova N,Kaminsky Y,et al.Sources of oxygen radicals in brain in acute ammonia intoxication in vivo.Brain Res,2003,981(1/2):193-200.
21 Marcaida G,Felipo V,Hermenegildo C,et al.Acute ammonia toxicity is mediated by the NMDA type of glutamate receptors.FEBS Lett,1992,296(1):67-68.
22 Hermenegildo C,Marcaida G,Montoliu C,et al.NMDA receptor antagonists prevent acute ammonia toxicity in mice.Neurochem Res,1996,21(10):1237-1244.
23 Novelli A,Reilly JA,Lysko PG,et al.Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced.Brain Res,1988,451(1/2):205-212.
24 Lee JM,Zipfel GJ,Choi DW.The changing landscape of ischaemic brain injury mechanisms.Nature,1999,399(6738 Suppl):A7-A14.
25 Ikonomidou C,Bosch F,Miksa M,et al.Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain.Science,1999,283(5398):70-74.
26 Palmer C,Smith MB.Assessing the risk of kernicterus using nuclear magnetic resonance.Clin Perinatol,1990,17(2):307-329.
27 Mc Donald JW,Shapiro SM,Silverstein FS,et al.Role of glutamate receptor-mediated excitotoxicity in bilirubin-induced brain injury in the Gunn rat model.Exp Neurol,1998,150(1):21-29.
28 Grojean S,Koziel V,Vert P,et al.Bilirubin induces apoptosis via activation of NMDA receptors in developing rat brain neurons.Exp Neurol,2000,166(2):334-341.
29 Wennberg RP,Hance AJ.Experimental bilirubin encephalopathy:importance of total bilirubin,protein binding,and blood-brain barrier.Pediatr Res,1986,20(8):789-792.
30 Sarici SU,Saldir M.Genetic factors in neonatal hyperbilirubinemia and kernicterus.Turk J Pediatr,2007,49(3):245-249.
31 Lee CH,LüW,Michel JC,et al.NMDA receptor structures reveal subunit arrangement and pore architecture.Nature,2014,511(758):191-197.
32 Wu Q,Zheng R,Srisai D,et al.NR2B subunit of the NMDA glutamate receptor regulates appetite in the parabrachial nucleus.Proc Natl Acad Sci U S A,2013,110(36):14765-14770.
33 Mishizen-Eberz AJ,Rissman RA,Carter TL,et al.Biochemical and molecular studies of NMDA receptor subunits NR1/2A/2B in hippocampal subregions throughout progression of Alzheimer’s disease pathology.Neurobiol Dis,2004,15(1):80-92.
34 Dunah AW,Wang Y,Yasuda RP,et al.Alterations in subunit expression,composition,and phosphorylation of striatal N-methylD-aspartate glutamate receptors in a rat 6-hydroxydopamine model of Parkinson,s disease.Mol Pharmacol,2000,57(2):342-352.
35 Paoletti P,Bellone C,Zhou Q.NMDA receptor subunit diversity:impact on receptor properties,synaptic plasticity and disease.Nat Rev Neurosci,2013,14(6):383-400.
36 Thomas CG,Miller AJ,Westbrook GL.Synaptic and extrasynaptic NMDA receptor NR2 subunits in cultured hippocampal neurons.J Neurophysiol,2006,95(3):1727-1734.
37 Hardingham GE,Bading H.Synaptic versus extrasynaptic NMDA receptor signalling:implications for neurodegenerative disorders.Nat Rev Neurosci,2010,11(10):682-696.
38 Mazumder M K,Borah A.Piroxicam inhibits NMDA receptormediated excitotoxicity through allosteric inhibition of the Glu N2B subunit:an in silico study elucidating a novel mechanism of action of the drug.Med Hypotheses,2014,83(6):740-746.
39 Liu Y,Wong TP,Aarts M,et al.NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo.J Neurosci,2007,27(11):2846-2857.
40 Chen M,Lu TJ,Chen XJ,et al.Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance.Stroke,2008,39(11):3042-3048.
41 Lu C,Chan SL,Haughey N,et al.Selective and biphasic effect of the membrane lipid peroxidation product 4-hydroxy-2,3-nonenal on N-methyl-D-aspartate channels.J Neurochem,2001,78(3):577-589.
42 Yang L,Li X B,Yang Q,et al.The neuroprotective effect of praeruptorin C against NMDA-induced apoptosis through downregulating of Glu N2B-containing NMDA receptors.Toxicol In Vitro,2013,27(2):908-914.
43 Papadia S,Hardingham GE.The dichotomy of NMDA receptor signaling.Neuroscientist,2007,13(6):572-579.
44 Lafon-Cazal M,Pietri S,Culcasi M,et al.NMDA-dependent superoxide production and neurotoxicity.Nature,1993,364(6437):535-537.
45 Betzen C,White R,Zehendner CM,et al.Oxidative stress upregulates the NMDA receptor on cerebrovascular endothelium.Free Radic Biol Med,2009,47(8):1212-1220.
46 Dawson TM,Dawson VL,Snyder SH.A novel neuronal messenger molecule in brain:the free radical,nitric oxide.Ann Neurol,1992,32(3):297-311.
47 Saraf MK,Prabhakar S,Anand A.Bacopa monniera alleviates N(omega)-nitro-L-arginine arginine-induced but not MK-801-induced amnesia:a mouse Morris watermaze study.Neuroscience,2009,160(1):149-155.
48 Kosenko E,Kaminski Y,Lopata O,et al.Blocking NMDA receptors prevents the oxidative stress induced by acute ammonia intoxication.Free Radic Biol Med,1999,26(11/12):1369-1374.
49 Gáspárová-KvaltínováZ,Stolc S.Effect of antioxidants and NMDA antagonists on the density of NMDA binding sites in rat hippocampal slices exposed to hypoxia/reoxygenation.Methods Find Exp Clin Pharmacol,2003,25(1):17-25.
50 Mizoguchi H,Komatsu T,Iwata Y,et al.Partial involvement of NMDA receptors and glial cells in the nociceptive behaviors induced by intrathecally administered histamine.Neurosci Lett,2011,495(2):83-87.
51 Furuya T,Pan Z,Kashiwagi K.Role of retinal glial cell glutamate transporters in retinal ganglion cell survival following stimulation of NMDA receptor.Curr Eye Res,2012,37(3):170-178.
52 Jun SB,Smith KL,Shain W,et al.Optical monitoring of neural networks evoked by focal electrical stimulation on microelectrode arrays using FM dyes.Med Biol Eng Comput,2010,48(9):933-940.
53 Hires SA,Zhu Y,Tsien RY.Optical measurement of synaptic glutamate spillover and reuptake by linker optimized glutamatesensitive fluorescent reporters.Proc Natl Acad Sci U S A,2008,105(11):4411-4416.
54 Romón T,Planas AM,Adell A.Blockade of MK-801-induced heat shock protein 72/73 in rat brain by antipsychotic and monoaminergic agents targeting D2,5-HT1A,5-HT2A andα1-adrenergic receptors.CNS Neurol Disord Drug Targets,2014,13(1):104-111.
55 Hoffman DJ,Zanelli SA,Kubin J,et al.The in vivo effect of bilirubin on the N-methyl-D-aspartate receptor/ion channel complex in the brains of newborn piglets.Pediatr Res,1996,40(6):804-808.
56 Jara-Prado A,Ortega-Vazquez A,Martinez-Ruano L,et al.Homocysteine-induced brain lipid peroxidation:effects of NMDA receptor blockade,antioxidant treatment,and nitric oxide synthase inhibition.Neurotox Res,2003,5(4):237-243.
57 崔红梅,常秀丽,徐甫,等.MK801抑制乐果诱导的大鼠皮层神经元凋亡的作用研究.卫生研究,2011,40(5):568-572.
58 Liang CL,Yang LC,Lu K,et al.Neuroprotective synergy of N-methyl-D-aspartate receptor antagonist(Mk801)and protein synthesis inhibitor(cycloheximide)on spinal cord ischemiareperfusion injury in rats.J Neurotrauma,2003,20(2):195-206.
59 Fletcher PJ,Rizos Z,Noble K,et al.Impulsive action induced by amphetamine,cocaine and Mk801 is reduced by 5-HT(2C)receptor stimulation and 5-HT(2A)receptor blockade.Neuropharmacology,2011,61(3):468-477.
2 Iskander I,Gamaleldin R,El Houchi S,et al.Serum bilirubin and bilirubin/albumin ratio as predictors of bilirubin encephalopathy.Pediatrics,2014,134(5):e1330-e1339.
3 Diamond I,Schmid R.The pathogenesis of bilirubin encephalopathy:experimental models in newborn and adult animals.Trans Am Neurol Assoc,1965,90:38-41.
4 Song S,Hu Y,Gu X,et al.A novel newborn rat kernicterus model created by injecting a bilirubin solution into the cisterna magna.PLo S One,2014,9(5):e96171.
5 Gao X,Yang X,Zhang B.Neuroprotection of taurine against bilirubininduced elevation of apoptosis and intracellular free calcium ion in vivo.Toxicol Mech Methods,2011,21(5):383-387.
6 Hachiya Y,Hayashi M.Bilirubin encephalopathy:a study of neuronal subpopulations and neurodegenerative mechanisms in 12autopsy cases.Brain Dev,2008,30(4):269-278.
7 Silva RF,Rodrigues CM,Brites D.Rat cultured neuronal and glial cells respond differently to toxicity of unconjugated bilirubin.Pediatr Res,2002,51(4):535-541.
8 Hank?E,Hansen TW,Almaas R,et al.Bilirubin induces apoptosis and necrosis in human NT2-N neurons.Pediatr Res,2005,57(2):179-184.
9 Tabarki B,Khalifa M,Yacoub M,et al.Cerebellar symptoms heralding bilirubin encephalopathy in Crigler-Najjar syndrome.Pediatr Neurol,2002,27(3):234-236.
10 Furukawa Y.Histological changes in the brain due to experimental obstructive jaundice.Nihon Geka Gakkai Zasshi,1991,92(1):37-45.
11 Chroni E,Patsoukis N,Karageorgos N,et al.Brain oxidative stress induced by obstructive jaundice in rats.J Neuropathol Exp Neurol,2006,65(2):193-198.
12 Lau CG,Zukin RS.NMDA receptor traffi cking in synaptic plasticity and neuropsychiatric disorders.Nat Rev Neurosci,2007,8(6):413-426.
13 Xu B,Xu Z,Deng Y,et al.MK-801 protects against intracellular Ca(2+)overloading and improves N-methyl-D-aspartate receptor expression in cerebral cortex of methylmercury-poisoned rats.J Mol Neurosci,2013,49(1):162-171.
14 Cull-Candy S,Brickley S,Farrant M.NMDA receptor subunits:diversity,development and disease.Curr Opin Neurobiol,2001,11(3):327-335.
15 Fan MM,Raymond LA.N-methyl-D-aspartate(NMDA)receptor function and excitotoxicity in Huntington,s disease.Prog Neurobiol,2007,81(5/6):272-293.
16 Paoletti P.Molecular basis of NMDA receptor functional diversity.Eur J Neurosci,2011,33(8):1351-1365.
17 Kew JN,Kemp JA.Ionotropic and metabotropic glutamate receptor structure and pharmacology.Psychopharmacology(Berl),2005,179(1):4-29.
18 Hardingham GE,Bading H.The yin and yang of NMDA receptor signalling.Trends Neurosci,2003,26(2):81-89.
19 Massey PV,Johnson BE,Moult PR,et al.Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression.J Neurosci,2004,24(36):7821-7828.
20 Kosenko E,Venediktova N,Kaminsky Y,et al.Sources of oxygen radicals in brain in acute ammonia intoxication in vivo.Brain Res,2003,981(1/2):193-200.
21 Marcaida G,Felipo V,Hermenegildo C,et al.Acute ammonia toxicity is mediated by the NMDA type of glutamate receptors.FEBS Lett,1992,296(1):67-68.
22 Hermenegildo C,Marcaida G,Montoliu C,et al.NMDA receptor antagonists prevent acute ammonia toxicity in mice.Neurochem Res,1996,21(10):1237-1244.
23 Novelli A,Reilly JA,Lysko PG,et al.Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced.Brain Res,1988,451(1/2):205-212.
24 Lee JM,Zipfel GJ,Choi DW.The changing landscape of ischaemic brain injury mechanisms.Nature,1999,399(6738 Suppl):A7-A14.
25 Ikonomidou C,Bosch F,Miksa M,et al.Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain.Science,1999,283(5398):70-74.
26 Palmer C,Smith MB.Assessing the risk of kernicterus using nuclear magnetic resonance.Clin Perinatol,1990,17(2):307-329.
27 Mc Donald JW,Shapiro SM,Silverstein FS,et al.Role of glutamate receptor-mediated excitotoxicity in bilirubin-induced brain injury in the Gunn rat model.Exp Neurol,1998,150(1):21-29.
28 Grojean S,Koziel V,Vert P,et al.Bilirubin induces apoptosis via activation of NMDA receptors in developing rat brain neurons.Exp Neurol,2000,166(2):334-341.
29 Wennberg RP,Hance AJ.Experimental bilirubin encephalopathy:importance of total bilirubin,protein binding,and blood-brain barrier.Pediatr Res,1986,20(8):789-792.
30 Sarici SU,Saldir M.Genetic factors in neonatal hyperbilirubinemia and kernicterus.Turk J Pediatr,2007,49(3):245-249.
31 Lee CH,LüW,Michel JC,et al.NMDA receptor structures reveal subunit arrangement and pore architecture.Nature,2014,511(758):191-197.
32 Wu Q,Zheng R,Srisai D,et al.NR2B subunit of the NMDA glutamate receptor regulates appetite in the parabrachial nucleus.Proc Natl Acad Sci U S A,2013,110(36):14765-14770.
33 Mishizen-Eberz AJ,Rissman RA,Carter TL,et al.Biochemical and molecular studies of NMDA receptor subunits NR1/2A/2B in hippocampal subregions throughout progression of Alzheimer’s disease pathology.Neurobiol Dis,2004,15(1):80-92.
34 Dunah AW,Wang Y,Yasuda RP,et al.Alterations in subunit expression,composition,and phosphorylation of striatal N-methylD-aspartate glutamate receptors in a rat 6-hydroxydopamine model of Parkinson,s disease.Mol Pharmacol,2000,57(2):342-352.
35 Paoletti P,Bellone C,Zhou Q.NMDA receptor subunit diversity:impact on receptor properties,synaptic plasticity and disease.Nat Rev Neurosci,2013,14(6):383-400.
36 Thomas CG,Miller AJ,Westbrook GL.Synaptic and extrasynaptic NMDA receptor NR2 subunits in cultured hippocampal neurons.J Neurophysiol,2006,95(3):1727-1734.
37 Hardingham GE,Bading H.Synaptic versus extrasynaptic NMDA receptor signalling:implications for neurodegenerative disorders.Nat Rev Neurosci,2010,11(10):682-696.
38 Mazumder M K,Borah A.Piroxicam inhibits NMDA receptormediated excitotoxicity through allosteric inhibition of the Glu N2B subunit:an in silico study elucidating a novel mechanism of action of the drug.Med Hypotheses,2014,83(6):740-746.
39 Liu Y,Wong TP,Aarts M,et al.NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo.J Neurosci,2007,27(11):2846-2857.
40 Chen M,Lu TJ,Chen XJ,et al.Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance.Stroke,2008,39(11):3042-3048.
41 Lu C,Chan SL,Haughey N,et al.Selective and biphasic effect of the membrane lipid peroxidation product 4-hydroxy-2,3-nonenal on N-methyl-D-aspartate channels.J Neurochem,2001,78(3):577-589.
42 Yang L,Li X B,Yang Q,et al.The neuroprotective effect of praeruptorin C against NMDA-induced apoptosis through downregulating of Glu N2B-containing NMDA receptors.Toxicol In Vitro,2013,27(2):908-914.
43 Papadia S,Hardingham GE.The dichotomy of NMDA receptor signaling.Neuroscientist,2007,13(6):572-579.
44 Lafon-Cazal M,Pietri S,Culcasi M,et al.NMDA-dependent superoxide production and neurotoxicity.Nature,1993,364(6437):535-537.
45 Betzen C,White R,Zehendner CM,et al.Oxidative stress upregulates the NMDA receptor on cerebrovascular endothelium.Free Radic Biol Med,2009,47(8):1212-1220.
46 Dawson TM,Dawson VL,Snyder SH.A novel neuronal messenger molecule in brain:the free radical,nitric oxide.Ann Neurol,1992,32(3):297-311.
47 Saraf MK,Prabhakar S,Anand A.Bacopa monniera alleviates N(omega)-nitro-L-arginine arginine-induced but not MK-801-induced amnesia:a mouse Morris watermaze study.Neuroscience,2009,160(1):149-155.
48 Kosenko E,Kaminski Y,Lopata O,et al.Blocking NMDA receptors prevents the oxidative stress induced by acute ammonia intoxication.Free Radic Biol Med,1999,26(11/12):1369-1374.
49 Gáspárová-KvaltínováZ,Stolc S.Effect of antioxidants and NMDA antagonists on the density of NMDA binding sites in rat hippocampal slices exposed to hypoxia/reoxygenation.Methods Find Exp Clin Pharmacol,2003,25(1):17-25.
50 Mizoguchi H,Komatsu T,Iwata Y,et al.Partial involvement of NMDA receptors and glial cells in the nociceptive behaviors induced by intrathecally administered histamine.Neurosci Lett,2011,495(2):83-87.
51 Furuya T,Pan Z,Kashiwagi K.Role of retinal glial cell glutamate transporters in retinal ganglion cell survival following stimulation of NMDA receptor.Curr Eye Res,2012,37(3):170-178.
52 Jun SB,Smith KL,Shain W,et al.Optical monitoring of neural networks evoked by focal electrical stimulation on microelectrode arrays using FM dyes.Med Biol Eng Comput,2010,48(9):933-940.
53 Hires SA,Zhu Y,Tsien RY.Optical measurement of synaptic glutamate spillover and reuptake by linker optimized glutamatesensitive fluorescent reporters.Proc Natl Acad Sci U S A,2008,105(11):4411-4416.
54 Romón T,Planas AM,Adell A.Blockade of MK-801-induced heat shock protein 72/73 in rat brain by antipsychotic and monoaminergic agents targeting D2,5-HT1A,5-HT2A andα1-adrenergic receptors.CNS Neurol Disord Drug Targets,2014,13(1):104-111.
55 Hoffman DJ,Zanelli SA,Kubin J,et al.The in vivo effect of bilirubin on the N-methyl-D-aspartate receptor/ion channel complex in the brains of newborn piglets.Pediatr Res,1996,40(6):804-808.
56 Jara-Prado A,Ortega-Vazquez A,Martinez-Ruano L,et al.Homocysteine-induced brain lipid peroxidation:effects of NMDA receptor blockade,antioxidant treatment,and nitric oxide synthase inhibition.Neurotox Res,2003,5(4):237-243.
57 崔红梅,常秀丽,徐甫,等.MK801抑制乐果诱导的大鼠皮层神经元凋亡的作用研究.卫生研究,2011,40(5):568-572.
58 Liang CL,Yang LC,Lu K,et al.Neuroprotective synergy of N-methyl-D-aspartate receptor antagonist(Mk801)and protein synthesis inhibitor(cycloheximide)on spinal cord ischemiareperfusion injury in rats.J Neurotrauma,2003,20(2):195-206.
59 Fletcher PJ,Rizos Z,Noble K,et al.Impulsive action induced by amphetamine,cocaine and Mk801 is reduced by 5-HT(2C)receptor stimulation and 5-HT(2A)receptor blockade.Neuropharmacology,2011,61(3):468-477.