新生大鼠反复惊厥对皮质区糖皮质激素受体表达的影响
摘要
目的现今普遍认为除兴奋毒性机制氧自由基损伤外炎症在发育中脑损伤病理生理过程中占有重要地位。糖皮质激素(glucocorticoid,GC)作为强有力的抗炎物质,能有效地抑制致炎症信号和相关基因表达,但在脑发育期不恰当应用GC可能严重影响脑发育。在脑内,GC是通过糖皮质激素受体(glucocorticoidreceptor,GR)发挥作用。本实验通过研究新生期大鼠反复惊厥对皮质区GR表达的影响,探讨脑内GR和发育期脑损伤变化之间关系。
方法48只生后7天(postnatal day 7,PN-7d)的SD大鼠随机分成惊厥组和对照组,每组24只,惊厥组每日吸入三氟乙醚诱导惊厥发作1次,每次持续30 min,连续6d;对照组同样操作但不吸入三氟乙醚。两组大鼠于反复惊厥后(after recurrent seizures,ARS)1d、3d、7d随机各选取8只大鼠断头去脑,分别采用Western blots及免疫组织化学方法观察大鼠大脑皮层GR表达的变化。
结果(1)通过Western blots发现在大脑皮质区GR生后即有表达,随着日龄的增加大脑皮层GR的表达呈现一定的规律性。在生后早期新生大鼠GR主要表达于胞浆,而后胞核中表达迅速增加。与正常对照组相比较,惊厥组大鼠ARS—1d(PN—13d)及ARS-7 d(PN—19d)时,胞浆蛋白中GR表达无显著性差异(P＞0.05);ARS—3d(PN—15d)惊厥组大鼠皮层胞浆蛋白中GR表达显著降低(P＜0.05)。与正常对照组相比较,惊厥组大鼠ARS—1d(PN—13d)及ARS-3d(PN-15d)时皮层胞核蛋白中均未检出GR的表达,ARS-7 d(PN-19d)时惊厥大鼠皮层胞核蛋白中GR表达显著降低(P＜0.05)。(2)通过免疫组织化学方法发现GR在皮质表达丰富,随着日龄的增加大脑皮层各叶GR的表达呈现一定时相性和区域性。在PN—13d时,GR阳性部位为胞浆,在PN—15d、PN—19d时胞核区也出现阳性表达。在ARS-1d(PN—13d)时,惊厥组大鼠顶叶区GR免疫化学累计光密度(accumulate optical density,AOD)明显低于正常对照组(P＜0.05),而在额叶、颞叶区两组无显著性差异(P＞0.05):在ARS-3d(PN—15d)时,惊厥组大鼠皮层顶叶、颞叶区GR免疫化学AOD明显低于正常对照组(P＜0.05),在额叶区无显著性差异(P＞0.05);在ARS-7d(PN—19d)时,惊厥组大鼠皮层顶叶、颞叶和额叶区GR免疫化学AOD明显低于正常对照组(P＜0.05)。
结论(1)皮质区GR随脑发育成熟表达呈现一定规律性及分布特点,与脑发育过程密切相关。(2)新生大鼠反复惊厥造成大脑皮层GR表达的异常,可能参与反复惊厥所致发育期脑急性损伤。
Objective:To investigate the short-term effects of flurothyl-induced neonatal recurrent seizures on glucocorticoid receptor(GR)expressions in rat brain.
Methods:48 of postnatal(PN-)7d Sprague-Dawley rats were divided randomly into two groups:the control group and the seizure group.Seizures were induced by inhalant flurothyl daily in six consecutive days.The brains of rats were sampled on after-recurrent-seizure(ARS)- ld(PN-13d),ARS-3d(PN-15d)and ARS-7d(PN-19d).The expressions of GR protein in cerebral cortex were detected by immunohistochemistry and Western blots methods.
Results:The expression of GR in the cerebral cortex of rat pup has been found by western blot and immunohistochemistry method since PN-13d.The expression of GR was found in the cellular plasma on PN-13d,and that was found in the cellular nucleus and plasma on PN-15d and PN-19d.By western blot method,we found that the expressions of GR in the cellular plasma of cerebral_Ⅱcortex were similar in between two group on ARS-1d(PN-13d)and ARS-7d(PN-19d)(P＞0.05),but the expressions of GR in the cellular plasma of cerebral cortex decreased significantly in seizure rats than those in control rats on PRS-3d(PN-15d) (P＜0.05);the GR proteins were hardly expressed in the nucleus of seizure rat cortex on ARS-1d and ARS-3d,and the expressions of GR in the cellular nucleus of cerebral cortex decreased significantly in seizure rats than those in control rats on ARS-7d(PN-19d)(P＜0.05).On ARS-1d (PN-13d),the immunochemical accumulate optical densify(AOD)of GR protein in the parietal cortex decreased significantly in seizure rats than those in the control rats(P＜0.05),but the immunochemical AODs of GR protein were similar between two groups in the temporal cortex and frontal cortex(P＞0.05).On ARS-3d(PN-15d),the immunochemical AOD of GR protein in the parietal cortex and temporal cortex decreased significantly in seizure rats than those in control rats(P＜0.05),but the immunochemical AODs of GR protein were similar between two groups in the frontal cortex(P＞0.05).On ARS-7d(PN-19d),the immunochemical AODs of GR protein in the parietal cortex,temporal cortex,and frontal cortex were decreased significantly in seizure rats than those in control rats(P＜0.05).
Conclusions:Recurrent seizures in neonatal rats modify GR expression in the developmental rat brain.This phenomenon raised the possibility that abnormal GR expression might play an important role in developmental brain injury.
方法48只生后7天(postnatal day 7,PN-7d)的SD大鼠随机分成惊厥组和对照组,每组24只,惊厥组每日吸入三氟乙醚诱导惊厥发作1次,每次持续30 min,连续6d;对照组同样操作但不吸入三氟乙醚。两组大鼠于反复惊厥后(after recurrent seizures,ARS)1d、3d、7d随机各选取8只大鼠断头去脑,分别采用Western blots及免疫组织化学方法观察大鼠大脑皮层GR表达的变化。
结果(1)通过Western blots发现在大脑皮质区GR生后即有表达,随着日龄的增加大脑皮层GR的表达呈现一定的规律性。在生后早期新生大鼠GR主要表达于胞浆,而后胞核中表达迅速增加。与正常对照组相比较,惊厥组大鼠ARS—1d(PN—13d)及ARS-7 d(PN—19d)时,胞浆蛋白中GR表达无显著性差异(P＞0.05);ARS—3d(PN—15d)惊厥组大鼠皮层胞浆蛋白中GR表达显著降低(P＜0.05)。与正常对照组相比较,惊厥组大鼠ARS—1d(PN—13d)及ARS-3d(PN-15d)时皮层胞核蛋白中均未检出GR的表达,ARS-7 d(PN-19d)时惊厥大鼠皮层胞核蛋白中GR表达显著降低(P＜0.05)。(2)通过免疫组织化学方法发现GR在皮质表达丰富,随着日龄的增加大脑皮层各叶GR的表达呈现一定时相性和区域性。在PN—13d时,GR阳性部位为胞浆,在PN—15d、PN—19d时胞核区也出现阳性表达。在ARS-1d(PN—13d)时,惊厥组大鼠顶叶区GR免疫化学累计光密度(accumulate optical density,AOD)明显低于正常对照组(P＜0.05),而在额叶、颞叶区两组无显著性差异(P＞0.05):在ARS-3d(PN—15d)时,惊厥组大鼠皮层顶叶、颞叶区GR免疫化学AOD明显低于正常对照组(P＜0.05),在额叶区无显著性差异(P＞0.05);在ARS-7d(PN—19d)时,惊厥组大鼠皮层顶叶、颞叶和额叶区GR免疫化学AOD明显低于正常对照组(P＜0.05)。
结论(1)皮质区GR随脑发育成熟表达呈现一定规律性及分布特点,与脑发育过程密切相关。(2)新生大鼠反复惊厥造成大脑皮层GR表达的异常,可能参与反复惊厥所致发育期脑急性损伤。
Objective:To investigate the short-term effects of flurothyl-induced neonatal recurrent seizures on glucocorticoid receptor(GR)expressions in rat brain.
Methods:48 of postnatal(PN-)7d Sprague-Dawley rats were divided randomly into two groups:the control group and the seizure group.Seizures were induced by inhalant flurothyl daily in six consecutive days.The brains of rats were sampled on after-recurrent-seizure(ARS)- ld(PN-13d),ARS-3d(PN-15d)and ARS-7d(PN-19d).The expressions of GR protein in cerebral cortex were detected by immunohistochemistry and Western blots methods.
Results:The expression of GR in the cerebral cortex of rat pup has been found by western blot and immunohistochemistry method since PN-13d.The expression of GR was found in the cellular plasma on PN-13d,and that was found in the cellular nucleus and plasma on PN-15d and PN-19d.By western blot method,we found that the expressions of GR in the cellular plasma of cerebral_Ⅱcortex were similar in between two group on ARS-1d(PN-13d)and ARS-7d(PN-19d)(P＞0.05),but the expressions of GR in the cellular plasma of cerebral cortex decreased significantly in seizure rats than those in control rats on PRS-3d(PN-15d) (P＜0.05);the GR proteins were hardly expressed in the nucleus of seizure rat cortex on ARS-1d and ARS-3d,and the expressions of GR in the cellular nucleus of cerebral cortex decreased significantly in seizure rats than those in control rats on ARS-7d(PN-19d)(P＜0.05).On ARS-1d (PN-13d),the immunochemical accumulate optical densify(AOD)of GR protein in the parietal cortex decreased significantly in seizure rats than those in the control rats(P＜0.05),but the immunochemical AODs of GR protein were similar between two groups in the temporal cortex and frontal cortex(P＞0.05).On ARS-3d(PN-15d),the immunochemical AOD of GR protein in the parietal cortex and temporal cortex decreased significantly in seizure rats than those in control rats(P＜0.05),but the immunochemical AODs of GR protein were similar between two groups in the frontal cortex(P＞0.05).On ARS-7d(PN-19d),the immunochemical AODs of GR protein in the parietal cortex,temporal cortex,and frontal cortex were decreased significantly in seizure rats than those in control rats(P＜0.05).
Conclusions:Recurrent seizures in neonatal rats modify GR expression in the developmental rat brain.This phenomenon raised the possibility that abnormal GR expression might play an important role in developmental brain injury.
引文
[1]Ferriem DM.Neonatal brain injury.N Engl J Med,2004,351(19):1985-1995.
[2]Turrin NP,Rivest S.Innate immune reaction in response to seizures:implications for the neuropathology associated with epilepsy.Neurobiol Dis,2004,16:321-334.
[3]刘利群,毛定安,薄涛,等.发育期大鼠反复惊厥后皮质caspase-1、IL-18、IL-1B的表达及其意义.中华儿科杂志,2006,44(05):380-382。
[4]Vezzani A,Granata T.Brain Inflammation in Epilepsy:Experimental and Clinical Evidence.Epilepsia,2005,46(11):1724-1743.
[5]Colangelo AM,Mallei A,Johnson PF,et al.Synergistic effect of dexamethasone and beta-adrenergic receptor agonists on the nerve growth factor gene transcription.Brain Res Mol Brain Res,2004,124(2):97-104.
[6]李梅,蔡方成.自由基在幼年鼠内毒素性脑水肿发病机理中的作用及地塞米松、IVIG对其影响研究.中华儿科杂志,2003,41(6):448-52.
[7]Montilla P,Tunez I,Munoz MC,et al.Effect of glucocorticoids on 3-nitropropionic acid-induced oxidative stress in synaptosomes.Eur J PHarmacol,2004,488(1):19-25.
[8]Uno H,Lohmiller L,Theime C,et al.Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques hippocampus.Brain Res Dev Brain Res,1990,53:157-167.
[9]Quinlivan JA,Dunlop SA,Newnham J,et al.Repeated,but not single,maternal administration of corticosteroids delays myelination in the brain of fetal sheep.Prennat Neonat Med,1999,4:47-55.
[10]Dammon O,Matthews SG.The effects of repeated antenatal glucocorticoid therapy in the developing brain[commentary].Pediatr Res,2001,50:563-564.
[11]DE Kloet ER,Oitzl MS,Joels M.Stress and cognition:Are corticosteroids good or bad guys? Trends Neurosci,1999,22:422-426.
[12]Donley MP,Schμlkin J,Rosen JB.Glucocorticoid receptor antagonism in the basolateral amygdala and ventral hippocampus interferes with long-term memory of contextual fear. Behav Brain Res, 2005,164(2): 197-205.
[13] Marini F, Pozzato C, Andreetta V, et al. Single exposure to social defeat increases corticotropin-releasing factor and glucocorticoid receptor mRNA expression in rat hippocampus. Brain Res, 2006,1067: 25-35.
[14] Holmes GL,Gairsa JL,Chevassus-Au-Louis N,et al.Consequences of neonatal seizures in the rat:morphofogical and behavioral effects[J].Ann Neurol,1998, 44:845-857.
[15] Andreas W,Jean MF,Hanns M,et al.NMDA receptor heterogeneity during postnatal development of he rat brain:differential expression of the NR2A, NR2 B,and NR2C subunit proteins[J].J Neurochem,1997,68:469-478.
[16] Wong HK ,Iiu XB,Matos MF,et al.Temporal and regional expression of NMDA receptor subunit NR3 A in the mammalian brian [J].J Comp Neuiol,2002, 450:303-317.
[17] Sarkisian MR ,Tandon P,Iiu Z,et ah Multiple kainic acid seizures in the im mature and adult brain:ictal manifestations and long-term effects on learning and memory[J],Epifepsia,1997,38:1157-1166
[18] Jensen FE,Holmes GL,Lombroso CT,et al.Age-dependent changes in long-term seizure susce. ptibifity and behavior after hypox-ia in rats[J]. Epifepsia, 1992, 33 (6):971-980.
[19] Jiang W, Duong TM , de Lanerolle NC. The neuropathology of hyperthermic seizures in the rat. Epilepsia, 1999,40 (1): 5 -19.
[20] Boissier JR, Simon P,Villeneuve A,et al.Effects of a convμlsivant,flurothyl, on the behavior of the mouse and the rat.Interaction with psychotropic substances. Therapie, 1967,22(4): 757-769.
[21] Sperber EF, Hass KZ, Romero MT, et al. Flurothyl status epilepticus in developing rats:behavioral,electrograpHic histological and electropHysiological studies.Brain Res Dev Brain Res,1999,116(1):59-68.
[22] De Kloet ER ,V reugdenhil E,Oitzl MS,Joels M.Brain corticosteroid receptor balance in health and disease [J].Endocr Rev,1998,19(3):269-301.
[23] Nishi M, Kawata M. Dynamics of glucocorticoid receptor and mineralocorti coid receptor: implications from live cell imaging studies. Neuroendocrinology. 2007; 85(3): 186-92.
[24] Donley MP, Schμlkin J, Rosen JB. Glucocorticoid receptor antagonism in the basolateral amygdala and ventral hippocampus interferes with long-term memory of contextual fear. Behav Brain Res, 2005,164(2):197-205.
[25] Velisek L.Prenatal corticosteroid impact on hippocampus: implication for postnatal outcomes. Epliepsy Behav, 2005,7(1): 57-67.
[26] Marin F,Pozz to C,Andreetta V, Jansson B,A rban R,DomeniciE,etal.Single exposure to social defeat increases corticotrop in-releas ing factor and glucocorticoid receptor on RNA expression in rat hippocam pus[J] .Brain Res,2006,1067(1):25-35.
[27]Tamura G ,Olson D,Miron J,Clark TG .Tolloid-like I is negatively regulated by stress and glucocorticoid[J]. Brain Res Mol Brain Res,2005,142(2):81-90.
[28 Lsgor C,Kabbaj M,Akil H,Watson SJ.Delayed effects of chronic variable stress during peripube rtaf juvenile period on hippocam-palmorphology and on cognitive and stress axis functions in rats[J].Hippocampus,2004,14(5):636-648.
[29]Pofetto R,Steibel JP,Siegford JM,Zanella AP.Effects of early weaning and social isolation on the expression of glucocorticoid and mineralocoticoid receptor and 11 beta-hydroxysteroid dehydrogenase 1 and 2 on mRNAs in the frontal cortex and hippocampus of piglets [J].Brian Res,2006,1067(1):36-42
[30] Yang CH, Huang CC, Hsu KS. Behavioral stress modifies hippocampal synaptic plasticity through corticosterone-induced sustained extracellular signal-regulated kinase/mitogen-activated protein kinase activation. J Neurosci., 2004, 24(49): 11029-11034.
[31]Shari RB, Aaron GH, Jemmifer CL, et al. J Neurosci, 1995,15(1): 61-69.
[1]Christoph Kellendonk,Peter Gass,Oliver Kretz.Corticosteroid receptors in the brain:Gene targeting studies[J].Brain Res,2002,57(1):73-74
[2]Han F,Ozawa H,Matsuda K,Nishi M,Kawata M.Colocafization of mineraloco-rticoid receptor and glucocorticoid receptor in the hippocampus and hypophala-oius.Neurosci Res,2005,51(4):371-381
[3]Pryce CR,Feldon J,Fuchs E,Knuesel I,Oertle T,Sengstag C,et al.Postnatal ontogeny of hippocampal expression of the mineralocorticoid and glucocorticoid receptor in the common monkey[J].Eur J Neurosci,2005,21(6):1521-1535.
[4]Patel PD,Lopez JF,Lyons DM,Burke S,Wallace M,Schatzberg AF.Glucocorticoid and mineralocorticoid receptor Mrna expression in squirrel monkey brain[J].J Psychlat Res,2000,34(6):383-392.
[5]De Kloet ER,V reugdenhil E,Oitzl MS,Joels M.Brain corticosteroid receptor balance in health and disease[J].Endocr Rev,1998,19(3):269-301.
[6]StepHen GM.Dynamic changes in glucocorticoid and mineralocorticoid receptor mRNA in the developing guinea pig brain.Developmental Brain Research,1998,107:123-132.
[7]Banjanin S,Kapoor A,StepHen GM.Prenatal glucocorticoid exposure alters hypothalamic-pituitary-adrenal function and blood pressure in mature male guinea pigs.J PHysiol,2004,558(1):305-318.
[8]Kretz O,Schmid W,Berger S,et al.The mineralocorticoid receptor expression in the mouse CNS is conserved during development.Neuroreport,2001,12(6):1133-1137.
[9]Speirs HJ,Seckl JR,Brown RW.Ontogeny of glucocorticoid receptor and 11beta -hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development[J].Endocrinol,2004,181(1):105-16.
[10]Donley MP,Schulkin J,Rosen JB.Glucocorticoid receptor antagonism in the basolateral amygdala and ventral hippocampus interferes with long-term memory of contextual fear.Behav Brain Res,2005,164(2):197-205.
[11]Fujioka A,Fujioka T,Ishida Y,Maekawa t,Nakamum S.Differential effects of prenantal steess on the morphological maturation of hippocampal neurons[J].Neuroscience,2006,141(2):907-915.
[12]Yang J,Han H,Cao J,LiL,Xu L.Prenantal stress modifies hippocampal synaptic plasticity and spatial learning in young rat offspring[J].Hippocampus,2006,16(50:431-436.
[13]Yang CH,Huang CC,Hsu KS.Behavioral stress modifies hippocampal synaptic plasticity through corticosterone-induced sustained extracellular signal-regulated kinase/mitogen-activated protein kinase activation.J Neurosci.,2004,24(49):11029-11034.
[14]Webster MJ,Knable MB,O'Grady J,Orthmann J,Weickert CS.Regional specificity of brian glucocorticoid receptor Mrna alterations in subjects with sch izophrenia and mood disorders[J].Molpsychia try,2002,7(9).985-994.
[15]Young AH,Gallagher P,Watson S,Del-Estal D,Owen BM,Ferrier IN.Improvements in neurocognitive function and mood following adhunctive treatment with mifepristone(RU 486)in bipofar disorder[J].Neuropsychop-hamacology,2004,29(8):1538-1545.
[16]Watson S,Thompson JM,Ritchie JC,Nicol Ferrier I,YoungAH.Neuropsychological impairment in bipolar disorder the relationship with glucocorticoid receptor function[J].Bipolar Disorder,2006,8(10:85-90.
[17]Herman JP, Cμllinan WE. Nettrocircuitry of stress: central control of the hypothalamopituitary-adrenocortical axis. Trends Neurosei,1997,20:78—84.
[18]Jacohsoa L, Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamic—pituitary—adrenocorticalaxis. Endocr Rev,1991,12:118.
[19] Jacohsoa L, Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamic—pituitary—adrenocorticalaxis. Endocr Rev,1991,12:118.
[20]Diaz R,Brown RW,Seckl JR.Distinct ontogeny of glucocorticiod and mineral-ocortioid receptor and 11β-hydroxysteroid dehydrogenase type I and II mRNA in the fetal rat brain suggest a complex control of glucocorticoid actions.The Journal of Neuroscience,1998,18(7):2570-2580.
[21]Weidenfeld J, Feldman S. Glucccorticoid feedback regulation of adrenocortical responses to neural stimμli : Role CRF-41 and corticostercold type I and type II receptors. Neuroendocrlnology, 1993,58:49.
[22]Meaney MJ, Diorio J, Francis D, et al. Postnatal handling increases the expre of cAMP-inducible transcription factors in the rat hippocampus: The effects of thyroid hormones and serotonin.J Neurosci,2000,20:3926-3935
[23]Seckl JR,Chapman KE.The 11β-hydrorysterroid dehydrogenase systerm,a determinant of glucocorticoid and mineralocorticoid action.Eur J Biochem, 1997, 249: 361-306.
[24]Isgor C, Kabbaj M, Akil H, Watson SJ. Delayed effects of chronic variable stress during peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats[J]. Hippocampus, 2004,14(5):636-48
[25] Krugers HJ, Alfarez DN, Karst H, et al. Corticosterone shifts different forms of synaptic potentiation in opposite directions[J]. Hippocampus, 2005, 15(6):697-703.
[26]Seckl JR,Chapman KE.The 116-hydrorysterroid dehydrogenase systerm,a determinant of glucocorticoid and mineralocorticoid action.Eur J Biochem, 1997, 249: 361-306.
[27]Marini F, Pozzato C, Andreetta V, et al. Single exposure to social defeat increases corticotropin-releasing factor and glucocorticoid receptor mRNA expres-sion in rat hippocampus.Brain Res,2006,1067:25-35.
[28]Hwang IK,Lee YB,Yoo KY,et al.seizure-induced changes of mineralocorticoid and glucocorticoid receptors in the hippocampus in seizure sensitive gerbils.Neurosci Res,2005,53(1):14-24.
[29]Berger S,Wolfer DP,Selbach O,et al.Loss of the limbic mineralocorticoid receptor impairs behavioral plasticity.Proc Natl Acad Sci USA,2006,103(1):195-200.
[30]王庆松,王正国,朱佩芳.创伤后应激障碍样行为异常大鼠皮质糖皮质激素和盐皮质激素受体表达研究.中华创伤杂志,2003,19(3)179-182.
[31]Hwang IK,Yoo KY,Nam YS,et al.Mineralocorticoid and glucocorticoid receptor expressions in astrocytes and microglia in the hippocampal CA1 region after ischemic insμlt.Neurosci Res,2006,54(4):319-327.
[32]Hugin-Flores ME,Steimer T,Aubert ML,et al.Mineralo- and glucocorticoid receptor minas are differently regulated by corticosterone in the rat hippocampus and anterior pituitary.Neuroendocdnology,2004,79(4):174-184.
[33]Uys JD,Muller CJ,Marais L,et al.Early life trauma decreases glucocorticoid receptors in rat dentate gyrus upon adμlt re-stress:Reversal by escitalopram.Neuroscience,2006,137(2):619-625.
[34]Poletto R,Steibel JP,Siegford JM.Effects of early weaning and social isolation on the expression of glucocorticoid and mineralocorticoid receptor and 11betahydroxysteroid dehydrogenase 1 and 2 mRNAs in the frontal cortex and hippocampus of piglets.Brain Res,2006,1067:36-42.
[35]Trautman PD,Meyer-Bahlburg HF,Postelnek J,et al.Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children:resμlts of a pilot study.Psychoneuroendocorinology,1995,20(4):439-449.
[36]江载芳.小儿惊厥.见:许积德,主编.小儿内科学.第3版.北京:人民卫生出版社,1996,123-129.
[37]Holmes GL,Khazipov R,Ben-Ari Y.New concepts in neonatal seizures.Neuroreport,2002,13(1):A3-8.
[38]罗强,吴希如.NMDA受体与癫痫.国际医学儿科学分册,2000,27(6):298-301.
[39]单巍松,吴希如,梁卫兰.谷氨酸NMDA受体与惊厥.生理科学进展,1994,25(3):245-248.
[40]Yang CH,Huang CC,Hsu KS.Behavioral stress modifies hippocampal synaptic plasticity through corticosterone-induced sustained extracellμlar signal-regμlated kinase/mitogen-activated protein kinase activation.J Neurosci,2004,24(49):11029-11034.
[41]陆建华,党建,黎海蒂,等.NMDA受体对烫伤应激大鼠皮质糖皮质激素受体基因表达的影响.第三军医大学学报,2003,25(2):138-140.
[2]Turrin NP,Rivest S.Innate immune reaction in response to seizures:implications for the neuropathology associated with epilepsy.Neurobiol Dis,2004,16:321-334.
[3]刘利群,毛定安,薄涛,等.发育期大鼠反复惊厥后皮质caspase-1、IL-18、IL-1B的表达及其意义.中华儿科杂志,2006,44(05):380-382。
[4]Vezzani A,Granata T.Brain Inflammation in Epilepsy:Experimental and Clinical Evidence.Epilepsia,2005,46(11):1724-1743.
[5]Colangelo AM,Mallei A,Johnson PF,et al.Synergistic effect of dexamethasone and beta-adrenergic receptor agonists on the nerve growth factor gene transcription.Brain Res Mol Brain Res,2004,124(2):97-104.
[6]李梅,蔡方成.自由基在幼年鼠内毒素性脑水肿发病机理中的作用及地塞米松、IVIG对其影响研究.中华儿科杂志,2003,41(6):448-52.
[7]Montilla P,Tunez I,Munoz MC,et al.Effect of glucocorticoids on 3-nitropropionic acid-induced oxidative stress in synaptosomes.Eur J PHarmacol,2004,488(1):19-25.
[8]Uno H,Lohmiller L,Theime C,et al.Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques hippocampus.Brain Res Dev Brain Res,1990,53:157-167.
[9]Quinlivan JA,Dunlop SA,Newnham J,et al.Repeated,but not single,maternal administration of corticosteroids delays myelination in the brain of fetal sheep.Prennat Neonat Med,1999,4:47-55.
[10]Dammon O,Matthews SG.The effects of repeated antenatal glucocorticoid therapy in the developing brain[commentary].Pediatr Res,2001,50:563-564.
[11]DE Kloet ER,Oitzl MS,Joels M.Stress and cognition:Are corticosteroids good or bad guys? Trends Neurosci,1999,22:422-426.
[12]Donley MP,Schμlkin J,Rosen JB.Glucocorticoid receptor antagonism in the basolateral amygdala and ventral hippocampus interferes with long-term memory of contextual fear. Behav Brain Res, 2005,164(2): 197-205.
[13] Marini F, Pozzato C, Andreetta V, et al. Single exposure to social defeat increases corticotropin-releasing factor and glucocorticoid receptor mRNA expression in rat hippocampus. Brain Res, 2006,1067: 25-35.
[14] Holmes GL,Gairsa JL,Chevassus-Au-Louis N,et al.Consequences of neonatal seizures in the rat:morphofogical and behavioral effects[J].Ann Neurol,1998, 44:845-857.
[15] Andreas W,Jean MF,Hanns M,et al.NMDA receptor heterogeneity during postnatal development of he rat brain:differential expression of the NR2A, NR2 B,and NR2C subunit proteins[J].J Neurochem,1997,68:469-478.
[16] Wong HK ,Iiu XB,Matos MF,et al.Temporal and regional expression of NMDA receptor subunit NR3 A in the mammalian brian [J].J Comp Neuiol,2002, 450:303-317.
[17] Sarkisian MR ,Tandon P,Iiu Z,et ah Multiple kainic acid seizures in the im mature and adult brain:ictal manifestations and long-term effects on learning and memory[J],Epifepsia,1997,38:1157-1166
[18] Jensen FE,Holmes GL,Lombroso CT,et al.Age-dependent changes in long-term seizure susce. ptibifity and behavior after hypox-ia in rats[J]. Epifepsia, 1992, 33 (6):971-980.
[19] Jiang W, Duong TM , de Lanerolle NC. The neuropathology of hyperthermic seizures in the rat. Epilepsia, 1999,40 (1): 5 -19.
[20] Boissier JR, Simon P,Villeneuve A,et al.Effects of a convμlsivant,flurothyl, on the behavior of the mouse and the rat.Interaction with psychotropic substances. Therapie, 1967,22(4): 757-769.
[21] Sperber EF, Hass KZ, Romero MT, et al. Flurothyl status epilepticus in developing rats:behavioral,electrograpHic histological and electropHysiological studies.Brain Res Dev Brain Res,1999,116(1):59-68.
[22] De Kloet ER ,V reugdenhil E,Oitzl MS,Joels M.Brain corticosteroid receptor balance in health and disease [J].Endocr Rev,1998,19(3):269-301.
[23] Nishi M, Kawata M. Dynamics of glucocorticoid receptor and mineralocorti coid receptor: implications from live cell imaging studies. Neuroendocrinology. 2007; 85(3): 186-92.
[24] Donley MP, Schμlkin J, Rosen JB. Glucocorticoid receptor antagonism in the basolateral amygdala and ventral hippocampus interferes with long-term memory of contextual fear. Behav Brain Res, 2005,164(2):197-205.
[25] Velisek L.Prenatal corticosteroid impact on hippocampus: implication for postnatal outcomes. Epliepsy Behav, 2005,7(1): 57-67.
[26] Marin F,Pozz to C,Andreetta V, Jansson B,A rban R,DomeniciE,etal.Single exposure to social defeat increases corticotrop in-releas ing factor and glucocorticoid receptor on RNA expression in rat hippocam pus[J] .Brain Res,2006,1067(1):25-35.
[27]Tamura G ,Olson D,Miron J,Clark TG .Tolloid-like I is negatively regulated by stress and glucocorticoid[J]. Brain Res Mol Brain Res,2005,142(2):81-90.
[28 Lsgor C,Kabbaj M,Akil H,Watson SJ.Delayed effects of chronic variable stress during peripube rtaf juvenile period on hippocam-palmorphology and on cognitive and stress axis functions in rats[J].Hippocampus,2004,14(5):636-648.
[29]Pofetto R,Steibel JP,Siegford JM,Zanella AP.Effects of early weaning and social isolation on the expression of glucocorticoid and mineralocoticoid receptor and 11 beta-hydroxysteroid dehydrogenase 1 and 2 on mRNAs in the frontal cortex and hippocampus of piglets [J].Brian Res,2006,1067(1):36-42
[30] Yang CH, Huang CC, Hsu KS. Behavioral stress modifies hippocampal synaptic plasticity through corticosterone-induced sustained extracellular signal-regulated kinase/mitogen-activated protein kinase activation. J Neurosci., 2004, 24(49): 11029-11034.
[31]Shari RB, Aaron GH, Jemmifer CL, et al. J Neurosci, 1995,15(1): 61-69.
[1]Christoph Kellendonk,Peter Gass,Oliver Kretz.Corticosteroid receptors in the brain:Gene targeting studies[J].Brain Res,2002,57(1):73-74
[2]Han F,Ozawa H,Matsuda K,Nishi M,Kawata M.Colocafization of mineraloco-rticoid receptor and glucocorticoid receptor in the hippocampus and hypophala-oius.Neurosci Res,2005,51(4):371-381
[3]Pryce CR,Feldon J,Fuchs E,Knuesel I,Oertle T,Sengstag C,et al.Postnatal ontogeny of hippocampal expression of the mineralocorticoid and glucocorticoid receptor in the common monkey[J].Eur J Neurosci,2005,21(6):1521-1535.
[4]Patel PD,Lopez JF,Lyons DM,Burke S,Wallace M,Schatzberg AF.Glucocorticoid and mineralocorticoid receptor Mrna expression in squirrel monkey brain[J].J Psychlat Res,2000,34(6):383-392.
[5]De Kloet ER,V reugdenhil E,Oitzl MS,Joels M.Brain corticosteroid receptor balance in health and disease[J].Endocr Rev,1998,19(3):269-301.
[6]StepHen GM.Dynamic changes in glucocorticoid and mineralocorticoid receptor mRNA in the developing guinea pig brain.Developmental Brain Research,1998,107:123-132.
[7]Banjanin S,Kapoor A,StepHen GM.Prenatal glucocorticoid exposure alters hypothalamic-pituitary-adrenal function and blood pressure in mature male guinea pigs.J PHysiol,2004,558(1):305-318.
[8]Kretz O,Schmid W,Berger S,et al.The mineralocorticoid receptor expression in the mouse CNS is conserved during development.Neuroreport,2001,12(6):1133-1137.
[9]Speirs HJ,Seckl JR,Brown RW.Ontogeny of glucocorticoid receptor and 11beta -hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development[J].Endocrinol,2004,181(1):105-16.
[10]Donley MP,Schulkin J,Rosen JB.Glucocorticoid receptor antagonism in the basolateral amygdala and ventral hippocampus interferes with long-term memory of contextual fear.Behav Brain Res,2005,164(2):197-205.
[11]Fujioka A,Fujioka T,Ishida Y,Maekawa t,Nakamum S.Differential effects of prenantal steess on the morphological maturation of hippocampal neurons[J].Neuroscience,2006,141(2):907-915.
[12]Yang J,Han H,Cao J,LiL,Xu L.Prenantal stress modifies hippocampal synaptic plasticity and spatial learning in young rat offspring[J].Hippocampus,2006,16(50:431-436.
[13]Yang CH,Huang CC,Hsu KS.Behavioral stress modifies hippocampal synaptic plasticity through corticosterone-induced sustained extracellular signal-regulated kinase/mitogen-activated protein kinase activation.J Neurosci.,2004,24(49):11029-11034.
[14]Webster MJ,Knable MB,O'Grady J,Orthmann J,Weickert CS.Regional specificity of brian glucocorticoid receptor Mrna alterations in subjects with sch izophrenia and mood disorders[J].Molpsychia try,2002,7(9).985-994.
[15]Young AH,Gallagher P,Watson S,Del-Estal D,Owen BM,Ferrier IN.Improvements in neurocognitive function and mood following adhunctive treatment with mifepristone(RU 486)in bipofar disorder[J].Neuropsychop-hamacology,2004,29(8):1538-1545.
[16]Watson S,Thompson JM,Ritchie JC,Nicol Ferrier I,YoungAH.Neuropsychological impairment in bipolar disorder the relationship with glucocorticoid receptor function[J].Bipolar Disorder,2006,8(10:85-90.
[17]Herman JP, Cμllinan WE. Nettrocircuitry of stress: central control of the hypothalamopituitary-adrenocortical axis. Trends Neurosei,1997,20:78—84.
[18]Jacohsoa L, Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamic—pituitary—adrenocorticalaxis. Endocr Rev,1991,12:118.
[19] Jacohsoa L, Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamic—pituitary—adrenocorticalaxis. Endocr Rev,1991,12:118.
[20]Diaz R,Brown RW,Seckl JR.Distinct ontogeny of glucocorticiod and mineral-ocortioid receptor and 11β-hydroxysteroid dehydrogenase type I and II mRNA in the fetal rat brain suggest a complex control of glucocorticoid actions.The Journal of Neuroscience,1998,18(7):2570-2580.
[21]Weidenfeld J, Feldman S. Glucccorticoid feedback regulation of adrenocortical responses to neural stimμli : Role CRF-41 and corticostercold type I and type II receptors. Neuroendocrlnology, 1993,58:49.
[22]Meaney MJ, Diorio J, Francis D, et al. Postnatal handling increases the expre of cAMP-inducible transcription factors in the rat hippocampus: The effects of thyroid hormones and serotonin.J Neurosci,2000,20:3926-3935
[23]Seckl JR,Chapman KE.The 11β-hydrorysterroid dehydrogenase systerm,a determinant of glucocorticoid and mineralocorticoid action.Eur J Biochem, 1997, 249: 361-306.
[24]Isgor C, Kabbaj M, Akil H, Watson SJ. Delayed effects of chronic variable stress during peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats[J]. Hippocampus, 2004,14(5):636-48
[25] Krugers HJ, Alfarez DN, Karst H, et al. Corticosterone shifts different forms of synaptic potentiation in opposite directions[J]. Hippocampus, 2005, 15(6):697-703.
[26]Seckl JR,Chapman KE.The 116-hydrorysterroid dehydrogenase systerm,a determinant of glucocorticoid and mineralocorticoid action.Eur J Biochem, 1997, 249: 361-306.
[27]Marini F, Pozzato C, Andreetta V, et al. Single exposure to social defeat increases corticotropin-releasing factor and glucocorticoid receptor mRNA expres-sion in rat hippocampus.Brain Res,2006,1067:25-35.
[28]Hwang IK,Lee YB,Yoo KY,et al.seizure-induced changes of mineralocorticoid and glucocorticoid receptors in the hippocampus in seizure sensitive gerbils.Neurosci Res,2005,53(1):14-24.
[29]Berger S,Wolfer DP,Selbach O,et al.Loss of the limbic mineralocorticoid receptor impairs behavioral plasticity.Proc Natl Acad Sci USA,2006,103(1):195-200.
[30]王庆松,王正国,朱佩芳.创伤后应激障碍样行为异常大鼠皮质糖皮质激素和盐皮质激素受体表达研究.中华创伤杂志,2003,19(3)179-182.
[31]Hwang IK,Yoo KY,Nam YS,et al.Mineralocorticoid and glucocorticoid receptor expressions in astrocytes and microglia in the hippocampal CA1 region after ischemic insμlt.Neurosci Res,2006,54(4):319-327.
[32]Hugin-Flores ME,Steimer T,Aubert ML,et al.Mineralo- and glucocorticoid receptor minas are differently regulated by corticosterone in the rat hippocampus and anterior pituitary.Neuroendocdnology,2004,79(4):174-184.
[33]Uys JD,Muller CJ,Marais L,et al.Early life trauma decreases glucocorticoid receptors in rat dentate gyrus upon adμlt re-stress:Reversal by escitalopram.Neuroscience,2006,137(2):619-625.
[34]Poletto R,Steibel JP,Siegford JM.Effects of early weaning and social isolation on the expression of glucocorticoid and mineralocorticoid receptor and 11betahydroxysteroid dehydrogenase 1 and 2 mRNAs in the frontal cortex and hippocampus of piglets.Brain Res,2006,1067:36-42.
[35]Trautman PD,Meyer-Bahlburg HF,Postelnek J,et al.Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children:resμlts of a pilot study.Psychoneuroendocorinology,1995,20(4):439-449.
[36]江载芳.小儿惊厥.见:许积德,主编.小儿内科学.第3版.北京:人民卫生出版社,1996,123-129.
[37]Holmes GL,Khazipov R,Ben-Ari Y.New concepts in neonatal seizures.Neuroreport,2002,13(1):A3-8.
[38]罗强,吴希如.NMDA受体与癫痫.国际医学儿科学分册,2000,27(6):298-301.
[39]单巍松,吴希如,梁卫兰.谷氨酸NMDA受体与惊厥.生理科学进展,1994,25(3):245-248.
[40]Yang CH,Huang CC,Hsu KS.Behavioral stress modifies hippocampal synaptic plasticity through corticosterone-induced sustained extracellμlar signal-regμlated kinase/mitogen-activated protein kinase activation.J Neurosci,2004,24(49):11029-11034.
[41]陆建华,党建,黎海蒂,等.NMDA受体对烫伤应激大鼠皮质糖皮质激素受体基因表达的影响.第三军医大学学报,2003,25(2):138-140.