摘要
研究背景
癫痫持续状态(SE)是指一次癫痫发作持续30分钟以上,或连续多次发作、发作间期意识和神经功能未恢复至通常水平,是神经科常见急症之一,若处理稍有不当,就会给患者带来终身残疾,甚至危及生命。从年龄分布看,SE在婴幼儿期发病率高：37%的SE发生于1岁以内,73%发生于3岁以内,83%发生于5岁以内。幼年时期发生的SE是否会损伤患儿的脑功能、影响患儿以后的智力行为发育是儿科医生和患儿家属关注的问题。
早年的临床研究及动物实验表明：与成年人(鼠)相比,SE对幼儿(鼠)的未成熟脑造成的损伤较小。这具体表现在：与成年人相比,发生SE的幼儿死亡率低、神经系统后遗症发生率低、较少遗留神经行为缺陷；对SE模型的研究表明幼鼠SE后几乎无神经元损伤、苔藓纤维出芽等神经病理改变。然而,对癫痫二次打击模型的研究说明未成熟脑并非完全不受SE的影响。新生期有惊厥史的大鼠在青春期SE后,其脑损伤较新生期无惊厥大鼠更严重。同样,生后15天(P15)和生后45天(P45)各经历一次SE的大鼠,神经元损伤和空间学习记忆能力损伤比只在P45经历SE的大鼠严重。二次打击模型的研究结果说明幼年期的SE导致大脑对成年期SE的易损性增强。Somera-Molina发现大鼠在P15经历SE后海马区小胶质细胞短暂激活,星形胶质细胞可持续激活,且胶质细胞激活是导致大鼠对P45第二次SE的易损性增加的原因。然而激活的胶质细胞导致易损性增高的机制目前尚不明确。
小胶质细胞和星形胶质细胞的激活表现为细胞形态的改变和一些特定的标志物的表达(小胶质细胞标志物为Iba-1,星形胶质细胞标志物为GFAP、S100β)。小胶质细胞激活是一个复杂的过程,包括药理学和电生理特性的改变、细胞迁移和增殖的改变以及释放一系列的炎症介质。激活的星形胶质细胞也有多种功能改变,包括谷氨酸的释放功能、代谢功能和转运功能、以及对细胞外水和钾离子的调节功能的变化；此外星形胶质细胞和小胶质细胞一样,也是脑组织内产生炎症因子的主要来源之一。越来越多的证据表明炎症反应参与了许多急性和慢性脑部疾病,其中包括与惊厥相关的神经系统疾病。在颞叶癫痫手术切除组织中可检测到炎症物质的表达增高。在颞叶癫痫的动物模型中也观察到海马区炎性细胞因子和固有免疫的标志物升高(白介素1β、白介素6、肿瘤坏死因子α、核因子κB、环氧合酶2、前列腺素、Toll样受体),这些物质在SE后1小时即可表达增高且可以持续数天。但对于惊厥后细胞因子表达的研究多集中于成年人或成年动物,对未成熟大脑的研究较少。对幼年期大鼠在SE之后海马细胞因子的表达改变尚未有系统研究,且海马细胞因子与海马易损性增强之间的关系尚有待于明确。
幼年儿童经历一次癫痫持续状态后应该应用抗癫痫药物进行治疗。本研究将从脑保护角度探索,幼年期大鼠经历一次SE后给予不同抗癫痫药物,对大鼠海马部位的胶质细胞激活情况及细胞因子表达情况是否有所影响,以及应用抗癫痫药物后海马对第二次惊厥打击的易损性是否有所改变。
纳洛酮是一种在儿科应用较广泛的药物,用于新生儿窒息的复苏及促醒。近几年的研究发现纳洛酮具有抑制炎症反应和保护神经元的作用。介于P15大鼠在SE后短期内小胶质细胞激活、而星形胶质细胞长期激活,且胶质细胞可产生细胞因子,我们猜想应用纳洛酮也可抑制幼年期SE后海马内的炎症反应,并对海马的易损性产生一定的影响。
目的
1研究幼年期(P15)大鼠经历SE后,在急性期和慢性期,海马区各种细胞因子在翻译和蛋白表达水平上的变化。
2应用相应的细胞因子抗体研究细胞因子与海马易损性增强之间的关系。
3在P15大鼠经历SE后,连续给予苯巴比妥、丙戊酸钠、托吡酯、拉莫三嗪、左乙拉西坦进行单药治疗,观察慢性期星形胶质细胞激活情况和细胞因子的变化及应用这些药物后大鼠对二次惊厥打击易损性的变化。
4在P15大鼠经历SE后,给予纳洛酮治疗,观察急、慢性期胶质细胞激活情况和细胞因子的变化及大鼠对二次惊厥打击易损性的变化。
方法
1幼年期(P15)大鼠经历SE后海马细胞因子表达的改变：将P15大鼠随机分为2组,SE组(60只),对照组(60只)；SE组和对照组又各自分为6小组(每小组10只),在不同的时间点处死,取出海马组织进行细胞因子的检测。SE组给予海人藻酸(KA) 5mg/kg腹腔注射致SE,对照组给予同样体积的生理盐水腹腔注射。在模型建立后12小时、24小时、3天、10天、20天、30天6个时间点,分别取SE组和对照组中的10只大鼠,提取海马中的蛋白和1mRNA,应用酶联免疫吸附实验(Elisa)和荧光实时定量聚合酶链反应(RT-PCR)检测白介素1β(IL-1β)、白介素2(IL-2)、白介素4(IL-4)、白介素6(IL-6)、白介素10(IL-10)、白介素12(IL-12)、肿瘤坏死因子α(TNFα)、干扰素γ(IFNγ)的表达。
2表达增高的细胞因子与大鼠海马易损性增强之间的关系：将P15大鼠分为SE组(10只)、干预组(40只)、对照组(10只)。其中干预组分为4小组(每小组10只)。SE组给予KA 5mg/kg腹腔注射致SE；干预组分别在KA致SE后12小时给予IL-1β抗体侧脑室内注射,20天时给予IL-1β抗体、IL-10抗体、TNFα抗体侧脑室内注射；对照组在P15时给予同等体积生理盐水腹腔注射。各组大鼠在P45时给予KA 15mg/kg腹腔注射致SE,P50时行Morris水迷宫测试,P55时原位末端标记(TUNEL)法标记海马凋亡细胞。
3抗癫痫药物对幼年期SE后慢性期星形胶质细胞激活、细胞因子表达及易损性的影响：将P15大鼠分为6组,SE组、苯巴比妥治疗组、丙戊酸钠治疗组、托吡酯治疗组、拉莫三嗪治疗组、左乙拉西坦治疗组(每组20只)。SE组大鼠给予KA腹腔注射致SE。五个药物治疗组分别在P15经历SE后,连续给药7天(苯巴比妥30mg/kg/天、丙戊酸钠200mg/kg/天、托吡酯40mg/kg/天、拉莫三嗪50mg/kg/天、左乙拉西坦200mg/kg/天)。在P45每组取10只大鼠对星形胶质细胞标志物(GFAP)和细胞因子进行检测,每组剩余10只给予KA 15mg/kg腹腔注射后致第
二次SE,P55时检测海马凋亡细胞。
4纳洛酮对幼年期经历SE大鼠的保护作用：P15大鼠分为SE组、纳洛酮治疗组、对照组。SE组大鼠P15时给予KA 5mg/kg致SE,纳洛酮治疗组大鼠在P15时致SE后皮下植入微泵12小时内泵入不同剂量纳洛酮,生理盐水对照组大鼠腹腔注射与KA同等体积生理盐水。应用免疫印迹检测大鼠海马区急慢性期胶质细胞标志物(Iba-1、GFAP、S100β)表达情况,应用酶联免疫吸附试验、荧光实时定量PCR技术检测细胞因子表达情况。各组大鼠在P45时均再次给予KA 15mg/kg腹腔注射致SE,P50时行Morris水迷宫测试,P55时观察比较海马区凋亡细胞。
结果
1幼年期(P15)大鼠SE后细胞因子表达的改变：幼年期SE可导致海马区细胞因子在不同时段的改变。IL-1β在幼年期SE后早期(P<0.001)及慢性期(P<0.001)均表达显著增高,而IL-10(P<0.01)和TNFα(P<0.01)在幼年期SE后慢性期较对照组大鼠表达显著增高。其余细胞因子在各检测时间点无明显表达改变(P>0.05)。
2表达增高的细胞因子与大鼠海马易损性增强之间的关系：SE组大鼠(在P15和P45均经历SE)水迷宫测试表现差于对照组大鼠(只在P45经历SE)(P<0.001)、SE组大鼠海马区凋亡细胞数显著高于对照组大鼠(P<0.01)；大鼠在P15经历SE后12小时和20天侧脑室内注射IL-1β抗体均可改善大鼠在水迷宫测试中的表现(P<0.01)、显著减少其在P45第二次SE后海马区凋亡细胞数(P<0.05)；在P15大鼠经历SE后20天海马内注射IL-10抗体可加剧大鼠在水迷宫测试中空间记忆能力减退(P<0.05)、明显增加其在P45第二次SE后海马凋亡细胞(P<0.05)；而SE后20天侧脑室内注射TNFα抗体可改善大鼠在水迷宫测试中的表现(P<0.05)、显著减少大鼠在P45第二次SE后海马凋亡细胞(P<0.01)。
3抗癫痫药物对幼年期SE后慢性期星形胶质细胞激活、细胞因子表达及易损性的影响：苯巴比妥和拉莫三嗪治疗对P15大鼠经历SE后慢性期GFAP表达、细胞因子表达及易损性均无显著影响(P>0.05)。丙戊酸钠治疗对慢性期GFAP表达无明显影响(P>0.05),但可减少慢性期海马内IL-1β、IL-10、TNFα的表达(P<0.05),并减少其在P45时SE后凋亡细胞数(P<0.01)。托吡酯治疗组大鼠与SE组大鼠相比,GFAP和细胞因子表达无明显差异(P>0.05),但托吡酯治疗组大鼠在P45经历SE后海马区凋亡细胞数显著少于SE组大鼠(P<0.05)。左乙拉西坦治疗组大鼠慢性期海马内GFAP含量较SE组明显减少(P<0.01),且IL-1β、TNFα表达显著减少(P<0.01),在经历P 45时SE后海马内凋亡细胞数少于SE组大鼠(P<0.01)。
4纳洛酮对幼年期经历SE大鼠的保护作用：P15大鼠经历SE后12小时内皮下微泵注射纳洛酮可显著降低急性期海马内Iba-1、GFAP、S100β表达水平(P<0.01),降低慢性期GFAP、S100β表达水平(P<0.001)。纳洛酮治疗可使急性期海马内IL-1β和慢性期海马内IL-1β、TNFα、IL-10表达减少(P<0.01)。纳洛酮治疗可改善大鼠在P 45第二次SE后在Morris水迷宫测试中的表现(P<0.01),使海马区凋亡细胞数显著减少(P<0.01)。
结论
1大鼠在幼年期(P15)经历SE可导致海马区急性期IL-1β表达增高,慢性期海马区IL-1β、IL-10、TNFα表达增高。
2大鼠在P15经历SE后急性期及慢性期海马区增高的IL-1β增加了海马对P45时第二次SE的易损性；慢性期增高的IL-10对海马起保护作用,可以减轻海马对第二次SE打击的易损性；慢性期增高的TNFα可增加海马对成年期二次惊厥的易损性。
3幼年期(P15)大鼠经历SE后给予苯巴比妥、拉莫三嗪治疗对于其海马易损性增强无改善作用；丙戊酸钠可通过抑制慢性期海马内细胞因子表达减轻其易损性；托吡酯虽然对星形胶质细胞激活和细胞因子表达无影响,仍可减轻海马易损性；左乙拉西坦可抑制慢性期海马内星形胶质细胞激活和细胞因子高表达并减轻海马易损性。
4幼年期SE后急性期内给予纳洛酮治疗可以抑制急慢性期胶质细胞激活,并抑制急慢性期细胞因子的高表达,减轻大鼠对成年期第二次SE打击的易损性。
Background
Status epilepticus(SE) is defined as one continuous unremitting seizure lasting longer than 30 minutes, or recurrent seizures without regaining consciousness between seizures for greater than 30 minutes. It is one of the common emergencies in neurology department. The mortality rate and disability rate of SE is very high especially if treatment is not intiated quickly and properly. A high proportion of SE occur in younger people:37% occur in infants,73% in children younger than 3 years old,83% in children younger than 5 years old. Whether SE in childhood would change brain architecture and function and further influence intelligence and behavior development is a concern by parents and pediatricians. Previous clinical and animal studies indicated the immature brain is relatively resistant to seizure-induced brain damage. The mortality and incidence of sequelae following SE are low in children in the absence of an acute neurologic insult or progressive neurologic disorder. Similarly, long-term behavioral deficits or neuropathologic changes have not been found in immature rats in several seizure models. However, several two-hit seizure model studies demonstrate that the immature brain does not appear to be immune to injury following prolonged seizures. Schmid et al. reported that SE in adolescent rats with a history of neonatal seizures caused substantially more damage than in animals without a history of neonatal seizures. Likewise, Koh et al. found that although SE on postnatal day (P) 15 did not result in any detectable cell death or impairment of spatial learning, it predisposed rats to more extensive neuronal injury and worse performance in Morris water maze after the second seizure on P45. Recently, Somera-Molina explored the molecular events after kainic acid (KA)-induced early life seizures and found that transient microglial activation and persistent astrocyte activation may result in increased vulnerability to seizures in adulthood. However, the definite mechanism by which activated glia lead to increased vulnerability is unclear.
Microglia and astrocyte activation are demonstrated as cell morphology change and expression of specific markers(Iba-1 for microglia and GFAP for astrocytes). Microglia activation is a complex process, including changes in pharmacological and electrophysiological properties, changes in migration and proliferation. Activated astrocytes also show many functional alterations, including glutamate release function, metabolism of glutamate, glutamate transport, water and potassium balance regulation. Apart from all above function changes, microglia and astrocytes are the two main sources of inflammatory factors in brain. More and more studies reveal that inflammation is involved in many acute and chronic brain diseases, including the diseases related to seizure. The expression of inflamamtory factors are elevated in resected tissue from temporal lope epilepsy patients. Likewise, inflammatory cytokines and markers for innate immunity(IL-1β, IL-6, TNFα, NF-κB system, COX-2, prostaglandins, Toll-like receptors) are upregulated in 1 hour after SE and persist for several days in hippocampus in temporal lope epilepsy animal models. The information about cytokine expression after seizure are mostly from studies in human adults and adult rats. There are few studies on immature brain. The cytokine expression after SE in immature brain have not been widely explored. The relationship between cytokine expression and increased vulnerability deserves further studies.
Antiepileptic drugs are necessary after for children after SE in clinical practice. In this study, we will deliver several different antiepileptic drugs after SE in immature rats and observe whether these drugs would change cytokine expression and alleviate the increased vulnerability to second SE.
Naloxone is a traditional drug in pediatrics, mainly used in neonatal resuscitation and wake promoting. Recent studies find that naloxone possesses inflammation-inhibitory and neuron protective property. Because transient microglial activation and persistent astrocyte activation appear after SE in P15 rats, we suppose that naloxone could inhibit inflammatory reaction in hippocampus after P15 SE and further change the increased vulnerability to second SE hit in adulthood.
Objectives
1. To investigate cytokine transcription and expression at acute and chronic stage after P15 SE.
2. To explore the relationship of upregulated cytokines and increased vulnerability after P15 SE by application of cytokine antibodies.
3. To observe after P15 SE, the effects of phenobarbital, depakine, topiramate, lamotrigine, levetiracetam monotherapy on chronic cytokine expression and vulnerability to second SE hit.
4. To test the influence of naloxone on glia activation, cytokine expression and increased vulnerability after P15 SE.
Methods
1. Cytokine expression after P15 SE:P15 rats were randomly assigned to two groups:SE group(n=60) and Control group(n=60). Rats in SE group and Control group were further randomly divided into 6 groups(n=10 in each group) and sacrificed at 6 different time points for cytokine detection in hippocampus. Rats in SE group were intraperitoneally injected with kainic acid(KA) 5mg/kg to induce SE. Rats in control group were intraperitoneally injected with the identical volume of saline. Ten rats from each groups were sacrificed at 12h,24h,3d, 10d,20d,30d after administration of KA or saline. Hippocampal protein and mRNA were extracted. The cytokine(IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, TNFα, IFNγ)transcription level were determined by real-time PCR and the cytokine protein expression were determined by enzyme linked immunoabsorbent assay(Elisa).
2. The relationship between increased cytokines(IL-1β, IL-10, TNFα) and increased vulnerability:P15 rats were randomly divided into SE group(n=10), Antibody intervention group(n=40) and Control group(n=10). Antibody intervention group were further divided into 4 intervention groups(n=10 in each group). Rats in SE group were given KA(5mg/kg injected i.p.) to induce SE. Rats in control group were injected intraperitoneally with the same volume of saline. Rats in four Antibody intervention groups were intracerebroventricularly injected with IL-1βantibody at 12h after SE, IL-1βantibody at 20d after SE, IL-10 antibody at 20d after SE, TNFa antibody at 20d after KA-induced SE at P15, respectively. Rats from all groups were injected with KA 15mg/kg intraperitoneally to induce SE at P45. Rats were tested for spatial learning and memory by Morris water maze on P50 and sacrificed on P55 for apoptosis detection by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL).
3. The effect of antiepileptic monotherapy on cytokine expression at chronic stage and increased vulnerability after P15 SE. P15 rats were randomly divided into six groups:SE group, phenobarbital group, sodium valproate group, topiramate group, lamotrigine group, levetiracetam group(n=20 in each group). Rats in SE group were injected with KA (5mg/kg) intraperitoneally to induce SE. Rats in four antiepileptic monotherapy groups were dosed with phenobarbital(30mg/kg/day), sodium valproate(200mg/kg/day), topiramate(40mg/kg/day), lamotrigine(50mg/kg/day), levetiracetam(200mg/kg/day) respectively for 7 days after P15 SE. At P 45, ten rats from each group were tested for astrocyte activation and cytokine expression. The residual ten rats from each group were injected with KA(15mg/kg) to induce second SE at P45 and went on TUNEL examination on P55.
4. The protective effect of naloxone after P15 SE. P15 rats were divided into three groups:SE group, naloxone group and control group. Rats in SE group were injected with KA 5mg/kg to induce SE at P15. Rats from naloxone group were implanted subcutaneously with naloxone minipump of different doses after P15 SE. Rats from control group were intraperitoneally injected with saline. Glia activation states were examined by western blotting of Iba-1, GFAP and S100β. De novo synthesis of cytokines were assayed by real-time PCR and Elisa. Rats from each group were intraperitoneally injected with KA(15mg/kg) to induce SE at P 45 and compared for spatial learning ability in Morris water maze and neuron injury in TUNEL assay.
Results
1. Cytokine expression after P 15 SE. P 15 SE caused certain changes of cytokines in hippocampus at different time points. IL-1βwas significantly upregulated at both early(P<0.001) and chronic stage(P<0.001) after P15 SE. IL-10 and TNFαwere enhanced at chronic stage(P<0.01) after P15 SE compared with control group. However, the expression of IL-2, IL-4, IL-6, IL-12, IFNγwere not significantly changed after P15 SE at all time points examined(P>0.05).
2. The relationship between increased cytokines(IL-1β, IL-10 and TNFα) and increased vulnerability to second SE. Rats in SE group performed worse in Morris water maze than rats in control group(P<0.001) and exhibited more apoptotic cells in hippocampus than rats in control group(P<0.01). Intracerebroventricular administration of IL-1βat both 12h and 20d after P 15 SE could improve performance in Morris water maze(P<0.01) and reduce the apoptotic cells in hippocampus after second SE at P45(P<0.05). Antagonism of IL-10 at 20 days after P15 SE could deteriorate learning ability(P<0.05) and aggravate apoptosis after second SE at P45(P<0.05). Administration of TNFαantibody intracerebroventricularly at 20 days after P15 SE improved performance in Morris water maze(P<0.05) and reduced the number of apoptotic cells in hippocampus after second SE at P45(P<0.01).
3. The effect of antiepileptic monotherapy on glial activation, cytokine expression increased vulnerability after P15 SE. Phenobarbital or lamotrigine monotherapy after PI5 SE did not change the glia activation states, cytokines(IL-1β, IL-10, TNFα) expression and hippocampal vulnerability to second SE(P>0.05). Although sodium valproate monotherapy had no influence on glia activation states(P>0.05), it reduced expression of IL-1β,IL-10 and TNFα(P<0.05) and mitigate apoptosis after second SE (P<0.01). Glia activation states and cytokine(IL-1β, IL-10, TNFα) expression were not different between topiramate group and SE group(P>0.05). The number of apoptotic cells was significantly reduced in topiramate group compared with SE group(P<0.05). Glia activation states and expression of cytokines(IL-1β, TNFα) were mitigated by levetiracetam monotherapy(P<0.01). Tunel-positive cells in hippocampus was reduced by levetiracetam treatment(P<0.01).
4. The protective effect of naloxone after P15 SE. Subcutaneous minipump administration of naloxone could inhibit Iba-1, GFAP and S100βupregulation at acute stage(P<0.01) and reduce GFAP and and S100βexpression in hippocampus at chronic stage(P<0.001). IL-β, TNFαand IL-10 expression in hippocampus were reduced in naloxone-treated rats(P<0.01). Rats with naloxone treatment exhibited better performance in Morris water maze after P 45 SE(P<0.01). The apoptotic cells in hippocampus were greatly reduced after second SE in nalxone-treated rats(P<0.01).
Conclusions
1. P15 SE could induce IL-1βexpression at acute stage in hippocampus and induce IL-1β, TNF-αand IL-10 expression at chronic stage in hippocampus.
2. IL-1βproduction at acute and chronic stages after P15 SE increased the hippocampal vulnerability to second SE at P45. Increased IL-10 at chornic stage is a protective cytokine in hippocampus, alleviating the vulnerability to second SE at P45. Upregulation of TNFαat chronic stage after P15 SE aggravates hippocampal vulnerability to second SE at P45.
3. Phenobarbital and lamotrigine monotherapy has no influence on increased vulnerability after P15 SE. Sodium valproate could decrease hippocampal vulnerability by inhibiting cytokine expression. Topiramate mitigate vulnerability to second SE through unknown mechanisms. Levetiracetam could decrease the vulnerability to second SE by depressing astrocyte activation and inhibiting cytokine expression.
4. Naloxone treatment could alleviate glia activation and cytokine expression after P15 SE. Naloxone could alleviate the increased vulnerability to P 45 SE after P 15 SE.
引文
[1]Koh S, Storey TW, Santos TC, Mian AY, Cole AJ. Early-life seizures in rats increase susceptibility to seizure-induced brain injury in adulthood Neurology.1999,53(5): 915-921.
[2]Somera-Molina KC, Robin B, Somera CA, Anderson C, Stine C, Koh S, Behanna HA, Van Eldik LJ, Watterson DM, Wainwright MS. Glial activation links early-life seizures and long-term neurologic dysfunction:evidence using a small molecule inhibitor of proinflammatory cytokine upregulation. Epilepsia.2007,48(9):1785-1800.
[3]Patton HK, Benveniste EN, Benos DJ.Astrocytes and the AIDS dementia complex. J NeuroAIDS.1996,1(1):111-131.
[4]Hafiz FB, Brown DR. A model for the mechanism of astrogliosis in prion disease. Mol Cell Neurosci.2000,16(3):221-232.
[5]Brambilla R, Persaud T, Hu X, Karmally S, Shestopalov VI, Dvoriantchikova G, Ivanov D, Nathanson L, Barnum SR, Bethea JR. Transgenic inhibition of astroglial NF-kappa B improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. J Immunol.2009,182(5):2628-2640.
[6]Chen Y, Swanson RA. Astrocytes and brain injury. J Cereb Blood Flow Metab.2003, 23(2):137-149.
[7]Minagar A, Shapshak P, Fujimura R, Ownby R, Heyes M, Eisdorfer C. The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. J Neurol Sci.2002, 202(1-2):13-23.
[8]Plata-Salaman CR, Ilyin SE, Turrin NP, Gayle D, Flynn MC, Romanovitch AE, Kelly ME, Bureau Y, Anisman H, Mclntyre DC. Kindling modulates the IL-lbeta system, TNF-alpha, TGF-betal, and neuropeptide mRNAs in specific brain regions. Brain Res Mol Brain Res.2000,75(2):248-258.
[9]De Simoni MG, Perego C, Ravizza T, Moneta D, Conti M, Marchesi F, De Luigi A, Garattini S, Vezzani A. Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur J Neurosci.2000,12(7):2623-2633.
[10]Lehtimaki KA, Peltola J, Koskikallio E, Keranen T, Honkaniemi J. Expression of cytokines and cytokine receptors in the rat brain after kainic acid-induced seizures. Brain Res Mol Brain Res.2003,110(2):253-260.
[11]Rizzi M, Perego C, Aliprandi M, Richichi C, Ravizza T, Colella D, Veliskovd J, Moshe SL, De Simoni MG, Vezzani A. Glia activation and cytokine increase in rat hippocampus by kainic acid-induced status epilepticus during postnatal development. Neurobiol Dis.2003,14(3):494-503.
[12]Ravizza T, Rizzi M, Perego C, Richichi C, Veliskova J, Moshe SL, De Simoni MG, Vezzani A. Inflammatory response and glia activation in developing rat hippocampus after status epilepticus. Epilepsia.2005,46(Suppl 5):113-117.
[13]Sheng JG, Boop FA, Mrak RE, Griffin WS. Increased neuronal beta-amyloid precursor protein expression in human temporal lobe epilepsy:association with interleukin-1 alpha immunoreactivity. J Neurochem.1994,63(5):1872-1879.
[14]Crespel A, Coubes P, Rousset MC, Brana C, Rougier A, Rondouin G, Bockaert J, Baldy-Moulinier M, Lerner-Natoli M. Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis. Brain Res.2002,952(2):159-169.
[15]Vezzani A, Granata T. Brain inflammation in epilepsy:experimental and clinical evidence. Epilepsia.2005,46(11):1724-1743.
[16]Chew LJ, Takanohashi A, Bell M. Microglia and inflammation:impact on developmental brain injuries. Ment Retard Dev Disabil Res Rev.2006,12(2):105-112.
[17]Eddleston M, Mucke L. Molecular profile of reactive astrocytes--implications for their role in neurologic disease. Neuroscience.1993,54(1):15-36.
[18]John GR, Lee SC, Song X, Rivieccio M, Brosnan CF. IL-1-regulated responses in astrocytes:relevance to injury and recovery. Glia.2005,49(2):161-176.
[19]Scantlebury MH, Heida JG, Hasson HJ, Veliskova J, Velisek L, Galanopoulou AS, Moshe SL. Age-dependent consequences of status epilepticus:animal models. Epilepsia. 2007,48(Suppl 2):75-82.
[20]Sheng JG, Boop FA, Mrak RE, Griffin WS.Increased neuronal beta-amyloid precursor protein expression in human temporal lobe epilepsy:association with interleukin-1 alpha immunoreactivity. J Neurochem.1994,63(5):1872-1879.
[21]Vezzani A, Moneta D, Richichi C, Aliprandi M, Burrows SJ, Ravizza T, Perego C, De Simoni MG. Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis. Epilepsia.2002,43(Suppl 5):30-35.
[22]Gahring LC, White HS, Skradski SL, Carlson NG, Rogers SW. Interleukin-1alpha in the brain is induced by audiogenic seizure. Neurobiol Dis.1997,3(4):263-269.
[23]Minami M, Kuraishi Y, Satoh M. Effects of kainic acid on messenger RNA levels of IL-1 beta, IL-6, TNF alpha and LIF in the rat brain. Biochem Biophys Res Commun. 1991,176(2):593-598.
[24]de Bock F, Dornand J, Rondouin G. Release of TNF alpha in the rat hippocampus following epileptic seizures and excitotoxic neuronal damage. Neuroreport.1996,7(6): 1125-1129.
[25]Ravizza T, Gagliardi B, Noe F, Boer K, Aronica E, Vezzani A. Innate and adaptive immunity during epileptogenesis and spontaneous seizures:evidence from experimental models and human temporal lobe epilepsy. Neurobiol Dis.2008,29(1):142-160.
[26]Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. Ⅳ. Th2 clones secrete a factor that inhibits cytokine production by Thl clones. Fiorentino DF, Bond MW, Mosmann TR. J Exp Med.1989,170(6):2081-2095.
[27]Conti P, Kempuraj D, Kandere K, Di Gioacchino M, Barbacane RC, Castellani ML, Felaco M, Boucher W, Letourneau R, Theoharides TC. IL-10, an inflammatory/inhibitory cytokine, but not always. Immunol Lett.2003,86(2):123-129.
[28]何大可,胡鸿文.癫痫患儿PBMC分泌IL-10、IFN-γ的研究.温州医学院学报.1999,29(4)：270-271.
[29]Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsberg FW, Mattson MP. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med.1996,2(7):788-794.
[1]Plata-Salaman CR. Immunoregulators in the nervous system. Neurosci Biobehav Rev.1991,15(2):185-215.
[2]Nistico G, De Sarro G. Is interleukin 2 a neuromodulator in the brain? Trends Neurosci.1991,14(4):146-150.
[3]Koh S, Storey TW, Santos TC, Mian AY, Cole AJ. Early-life seizures in rats increase susceptibility to seizure-induced brain injury in adulthood Neurology.1999,53(5): 915-921.
[4]Allan SM, Tyrrell PJ, Rothwell NJ.Interleukin-1 and neuronal injury. Nat Rev Immunol.2005,5(8):629-640.
[5]Miller LG, Galpern WR, Dunlap K, Dinarello CA, Turner TJ. Interleukin-1 augments gamma-aminobutyric acidA receptor function in brain. Mol Pharmacol.1991,39(2): 105-108.
[6]Sayyah M, Beheshti S, Shokrgozar MA, Eslami-far A, Deljoo Z, Khabiri AR, Haeri Rohani A. Antiepileptogenic and anticonvulsant activity of interleukin-1 beta in amygdala-kindled rats.Exp Neurol.2005,191(1):145-153.
[7]Yi PL, Tsai CH, Lin JG, Lee CC, Chang FC. Kindling stimuli delivered at different times in the sleep-wake cycle. Sleep.2004,27(2):203-212.
[8]Vezzani A, Conti M, De Luigi A, Ravizza T, Moneta D, Marchesi F, De Simoni MG Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application:functional evidence for enhancement of electrographic seizures. J Neurosci.1999,19:5054-5065.
[9]Eriksson C, Van Dam AM, Lucassen PJ, Bol JG, Winblad B, Schultzberg M. Immunohistochemical localization of interleukin-1beta, interleukin-1 receptor antagonist and interleukin-1beta converting enzyme/caspase-1 in the rat brain after peripheral administration of kainic acid. Neuroscience.1999,93(3):915-930.
[10]Dube C, Vezzani A, Behrens M, Bartfai T, Baram TZ. Interleukin-1beta contributes to the generation of experimental febrile seizures. Ann Neurol.2005,57(1):152-155.
[11]Panegyres PK, Hughes J. The neuroprotective effects of the recombinant interleukin-1 receptor antagonist rhIL-1ra after excitotoxic stimulation with kainic acid and its relationship to the amyloid precursor protein gene. J Neurol Sci.1998,154(2): 123-132.
[12]De Simoni MG, Perego C, Ravizza T, Moneta D, Conti M, Marchesi F, De Luigi A, Garattini S, Vezzani A. Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur J Neurosci.2000,12(7):2623-2633.
[13]Vezzani A, Moneta D, Conti M, Richichi C, Ravizza T, De Luigi A, De Simoni MQ Sperk G, Andell-Jonsson S, Lundkvist J, Iverfeldt K, Bartfai T. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci USA.2000,97(21):11534-11539.
[14]Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E, Di Luca M, Galli CL, Marino vich M. Interleukin-1 beta enhances NMD A receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci.2003,23(25):8692-8700.
[15]Vezzani A, Baram TZ. New roles for interleukin-1 Beta in the mechanisms of epilepsy. Epilepsy Curr.2007,7(2):45-50.
[16]Yang S, Liu ZW, Wen L, Qiao HF, Zhou WX, Zhang YX. Interleukin-1beta enhances NMDA receptor-mediated current but inhibits excitatory synaptic transmission. Brain Res.2005,1034(1-2):172-179.
[17]Zhang R, Yamada J, Hayashi Y, Wu Z, Koyama S, Nakanishi H. Inhibition of NMDA-induced outward currents by interleukin-1beta in hippocampal neurons. Biochem Biophys Res Commun.2008,372(4):816-820.
[18]Ye ZC, Sontheimer H. Cytokine modulation of glial glutamate uptake:a possible involvement of nitric oxide. Neuroreport.1996,7(13):2181-2185.
[19]Hu S, Sheng WS, Ehrlich LC, Peterson PK, Chao CC. Cytokine effects on glutamate uptake by human astrocytes. Neuroimmunomodulation.2000,7(3):153-159.
[20]Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, Vescovi A, Bagetta G, Kollias G, Meldolesi J, Volterra A. CXCR4-activated astrocyte glutamate release via TNFalpha:amplification by microglia triggers neurotoxicity. Nat Neurosci. 2001,4(7):702-710.
[21]Zeise ML, Espinoza J, Morales P, Nalli A. Interleukin-lbeta does not increase synaptic inhibition in hippocampal CA3 pyramidal and dentate gyrus granule cells of the rat in vitro. Brain Res.1997,768(1-2):341-344.
[22]Wang S, Cheng Q, Malik S, Yang J. Interleukin-lbeta inhibits gamma-aminobutyric acid type A (GABA(A)) receptor current in cultured hippocampal neurons. J Pharmacol Exp Ther.2000,292(2):497-504.
[23]Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, Feuerstein GZ. Tumor necrosis factor-alpha expression in ischemic neurons. Stroke.1994,25(7): 1481-1488.
[24]Mattson MP, Cheng B, Baldwin SA, Smith-Swintosky VL, Keller J, Geddes JW, Scheff SW, Christakos S. Brain injury and tumor necrosis factors induce calbindin D-28k in astrocytes:evidence for a cytoprotective response. J Neurosci Res.1995,42(3): 357-370.
[25]Feuerstein GZ, Wang X, Barone FC. Inflammatory gene expression in cerebral ischemia and trauma. Potential new therapeutic targets. Ann N Y Acad Sci.1997,825: 179-193.
[26]Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC. Control of synaptic strength by glial TNFalpha. Science.2002, 295(5563):2282-2285.
[27]Gary DS, Bruce-Keller AJ, Kindy MS, Mattson MP. Ischemic and excitotoxic brain injury is enhanced in mice lacking the p55 tumor necrosis factor receptor. J Cereb Blood Flow Metab.1998,18(12):1283-1287.
[28]Galasso JM, Wang P, Martin D, Silverstein FS. Inhibition of TNF-alpha can attenuate or exacerbate excitotoxic injury in neonatal rat brain. Neuroreport.2000,11(2): 231-235.
[29]Hallenbeck JM. The many faces of tumor necrosis factor in stroke. Nat Med.2002, 8(12):1363-1368.
[30]MacEwan DJ. TNF receptor subtype signalling:differences and cellular consequences. Cell Signal.2002,14(6):477-492.
[31]MacEwan DJ. TNF ligands and receptors--a matter of life and death. Br J Pharmacol.2002,135(4):855-875.
[32]Tartaglia LA, Pennica D, Goeddel DV. Ligand passing:the 75-kDa tumor necrosis factor (TNF) receptor recruits TNF for signaling by the 55-kDa TNF receptor. J Biol Chem.1993,268(25):18542-18548.
[33]Minami M, Kuraishi Y, Satoh M. Effects of kainic acid on messenger RNA levels of IL-1 beta, IL-6, TNF alpha and LIF in the rat brain. Biochem Biophys Res Commun. 1991,176(2):593-598.
[34]Plata-Salaman CR, Ilyin SE, Turrin NP, Gayle D, Flynn MC, Romanovitch AE, Kelly ME, Bureau Y, Anisman H, McIntyre DC. Kindling modulates the IL-1beta system, TNF-alpha, TGF-betal, and neuropeptide mRNAs in specific brain regions. Brain Res Mol Brain Res.2000,75(2):248-258.
[35]de Bock F, Dornand J, Rondouin G. Release of TNF alpha in the rat hippocampus following epileptic seizures and excitotoxic neuronal damage. Neuroreport.1996, (6): 1125-1129.
[36]Mittelman A, Puccio C, Gafhey E, Coombe N, Singh B, Wood D, Nadler P, Ahmed T, Arlin Z. A phase I pharmacokinetic study of recombinant human tumor necrosis factor administered by a 5-day continuous infusion. Invest New Drugs.1992,10(3):183-190.
[37]Probert L, Akassoglou K, Pasparakis M, Kontogeorgos G, Kollias G Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor alpha. Proc Natl Acad Sci U S A. 1995,92(24):11294-11298.
[38]Akassoglou K, Probert L, Kontogeorgos G, Kollias G. Astrocyte-specific but not neuron-specific transmembrane TNF triggers inflammation and degeneration in the central nervous system of transgenic mice. J Immunol.1997,158(1):438-445.
[39]Fontaine V, Mohand-Said S, Hanoteau N, Fuchs C, Pfizenmaier K, Eisel U. Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia:opposite roles of TNF receptor 1 and TNF receptor 2. J Neurosci.2002,22(7): RC216.
[40]Shen Y, Li R, Shiosaki K. Inhibition of p75 tumor necrosis factor receptor by antisense oligonucleotides increases hypoxic injury and beta-amyloid toxicity in human neuronal cell line. J Biol Chem.1997,272(6):3550-3553.
[41]Balosso S, Ravizza T, Perego C, Peschon J, Campbell IL, De Simoni MG, Vezzani A. Tumor necrosis factor-alpha inhibits seizures in mice via p75 receptors. Ann Neurol. 2005,57(6):804-812.
[42]Tancredi V, D'Arcangelo G, Grassi F, Tarroni P, Palmieri G, Santoni A, Eusebi F. Tumor necrosis factor alters synaptic transmission in rat hippocampal slices. Neurosci Lett.1992,146(2):176-178.
[43]Chao CC, Hu S. Tumor necrosis factor-alpha potentiates glutamate neurotoxicity in human fetal brain cell cultures. Dev Neurosci.1994,16(3-4):172-179.
[44]Liao SL, Chen CJ. Differential effects of cytokines and redox potential on glutamate uptake in rat cortical glial cultures. Neurosci Lett.2001,299(1-2):113-116.
[45]De Laurentiis A, Pisera D, Lasaga M, Diaz M, Theas S, Duvilanski B, Seilicovich A. Effect of interleukin-6 and tumor necrosis factor-alpha on GABA release from mediobasal hypothalamus and posterior pituitary. Neuroimmunomodulation.2000,7(2): 77-83.
[46]Barna BP, Estes ML, Jacobs BS, Hudson S, Ransohoff RM. Human astrocytes proliferate in response to tumor necrosis factor alpha. J Neuroimmunol.1990,30(2-3): 239-243.
[47]Howard M, O'Garra A, Ishida H, de Waal Malefyt R, de Vries J. Biological properties of interleukin 10. J Clin Immunol.1992,12(4):239-247.
[48]Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol.2001,19:683-765.
[49]Diab A, Zhu J, Xiao BG, Mustafa M, Link H. High IL-6 and low IL-10 in the central nervous system are associated with protracted relapsing EAE in DA rats. J Neuropathol Exp Neurol.1997,56(6):641-650.
[50]Grilli M, Barbieri I, Basudev H, Brusa R, Casati C, Lozza G, Ongini E. Interleukin-10 modulates neuronal threshold of vulnerability to ischaemic damage. Eur J Neurosci.2000,12(7):2265-2272.
[51]Oruckaptan HH, Ozisik P, Atilla P, Tuncel M, Kilinc K, Geyik PO, Basaran N, Yiiksel E, Ozcan OE. Systemic administration of interleukin-10 attenuates early ischemic response following spinal cord ischemia reperfusion injury in rats. J Surg Res. 2009,155(2):345-356.
[52]Koeberle PD, Gauldie J, Ball AK. Effects of adenoviral-mediated gene transfer of interleukin-10, interleukin-4, and transforming growth factor-beta on the survival of axotomized retinal ganglion cells. Neuroscience.2004,125(4):903-920.
[53]Zhou Z, Peng X, Insolera R, Fink DJ, Mata M. Interleukin-10 provides direct trophic support to neurons. J Neurochem.2009,110(5):1617-1627.
[54]Boyd ZS, Kriatchko A, Yang J, Agarwal N, Wax MB, Patil RV. Interleukin-10 receptor signaling through STAT-3 regulates the apoptosis of retinal ganglion cells in response to stress. Invest Ophthalmol Vis Sci.2003,44(12):5206-5211.
[55]Bachis A, Colangelo AM, Vicini S, Doe PP, De Bernardi MA, Brooker G, Mocchetti I. Interleukin-10 prevents glutamate-mediated cerebellar granule cell death by blocking caspase-3-like activity. J Neurosci.2001,21(9):3104-3112.
[56]Ishizaki Y, Kira R, Fukuda M, Torisu H, Sakai Y, Sanefuji M, Yukaya N, Hara T. Interleukin-10 is associated with resistance to febrile seizures:genetic association and experimental animal studies. Epilepsia.2009,50(4):761-767.
[57]Burkovetskaya ME, Levin SG, Godukhin OV. Neuroprotective effects of interleukin-10 and tumor necrosis factor-alpha against hypoxia-induced hyperexcitability in hippocampal slice neurons. Neurosci Lett.2007,416(3):236-240.
[1]Brown-Croyts LM, Caton PW, Radecki DT, McPherson SL. Phenobarbital pre-treatment prevents kainic acid-induced impairments in acquisition learning. Life Sci. 2000,67(6):643-650.
[2]Vizuete ML, Merino M, Cano J, Machado A. In vivo protection of striatal dopaminergic system against 1-methyl-4-phenylpyridinium neurotoxicity by phenobarbital. J Neurosci Res.1997,49(3):301-308.
[3]Bowyer JF, Holson RR, Miller DB, O'Callaghan JP. Phenobarbital and dizocilpine can block methamphetamine-induced neurotoxicity in mice by mechanisms that are independent of thermoregulation. Brain Res.2001,919(1):179-183.
[4]Frandsen A, Quistorff B, Schousboe A. Phenobarbital protects cerebral cortex neurones against toxicity induced by kainate but not by other excitatory amino acids. Neurosci Lett.1990 Mar,111(1-2):233-238.
[5]Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM. Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons:roles of glycogen synthase kinase-3 inhibition. J Neurosci.2008, 28(10):2576-2588.
[6]Jeong MR, Hashimoto R, Senatorov W, Fujimaki K, Ren M, Lee MS, Chuang DM. Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death:a role of histone deacetylase inhibition. FEBS Lett.2003, 542(1-3):74-78.
[7]Feng HL, Leng Y, Ma CH, Zhang J, Ren M, Chuang DM. Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience.2008,155(3): 567-572.
[8]Sinn DI, Kim SJ, Chu K, Jung KH, Lee ST, Song EC, Kim JM, Park DK, Kun Lee S, Kim M, Roh JK. Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation. Neurobiol Dis.2007 26(2):464-472.
[9]Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM. Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke:multiple mechanisms of action. J Pharmacol Exp Ther.2007, 321(3):892-901.
[10]Tsai LK, Tsai MS, Ting CH, Li H. Multiple therapeutic effects of valproic acid in spinal muscular atrophy model mice. J Mol Med.2008,86(11):1243-1254.
[11]Brandt C, Gastens AM, Sun M, Hausknecht M, Loscher W. Treatment with valproate after status epilepticus:effect on neuronal damage, epileptogenesis, and behavioral alterations in rats. Neuropharmacology.2006,51(4):789-804.
[12]Rigoulot MA, Koning E, Ferrandon A, Nehlig A. Neuroprotective properties of topiramate in the lithium-pilocarpine model of epilepsy. J Pharmacol Exp Ther.2004, 308(2):787-795.
[13]Yang Y, Shuaib A, Li Q, Siddiqui MM. Neuroprotection by delayed administration of topiramate in a rat model of middle cerebral artery embolization. Brain Res.1998, 804(2):169-176.
[14]Sfaello I, Baud O, Arzimanoglou A, Gressens P. Topiramate prevents excitotoxic damage in the newborn rodent brain. Neurobiol Dis.2005,20(3):837-848.
[15]Frisch C, Kudin AP, Elger CE, Kunz WS, Helmstaedter C. Amelioration of water maze performance deficits by topiramate applied during pilocarpine-induced status epilepticus is negatively dose-dependent. Epilepsy Res.2007,73(2):173-180
[16]Koh S, Tibayan FD, Simpson JN, Jensen FE. NBQX or topiramate treatment after perinatal hypoxia-induced seizures prevents later increases in seizure-induced neuronal injury. Epilepsia.2004,45(6):569-575.
[17]Schubert S, Brandl U, Brodhun M, Ulrich C, Spaltmann J, Fiedler N, Bauer R. Neuroprotective effects of topiramate after hypoxia-ischemia in newborn piglets. Brain Res.2005,1058(1-2):129-136.
[18]Kurul SH, Yis U, Kumral A, Tugyan K, Cilaker S, Kolatan E, Yilmaz O, Genc S. Protective effects of topiramate against hyperoxic brain injury in the developing brain. Neuropediatrics.2009,40(1):22-27.
[19]Conroy BP, Black D, Lin CY, Jenkins LW, Crumrine RC, DeWitt DS, Johnston WE. Lamotrigine attenuates cortical glutamate release during global cerebral ischemia in pigs on cardiopulmonary bypass. Anesthesiology.1999,90(3):844-854.
[20]Yi YH, Guo WC, Sun WW, Su T, Lin H, Chen SQ, Deng WY, Zhou W, Liao WP. Neuroprotection of lamotrigine on hypoxic-ischemic brain damage in neonatal rats: Relations to administration time and doses. Biologics.2008,2(2):339-344.
[21]Lagrue E, Chalon S, Bodard S, Saliba E, Gressens P, Castelnau P. Lamotrigine is neuroprotective in the energy deficiency model of MPTP intoxicated mice. Pediatr Res. 2007,62(1):14-19.
[22]Siniscalchi A, Zona C, Guatteo E, Mercuri NB, Bernardi G. An electrophysiological analysis of the protective effects of felbamate, lamotrigine, and lidocaine on the functional recovery from in vitro ischemia in rat neocortical slices. Synapse.1998, 30(4):371-379.
[23]Hanon E, Klitgaard H. Neuroprotective properties of the novel antiepileptic drug levetiracetam in the rat middle cerebral artery occlusion model of focal cerebral ischemia. Seizure.2001,10(4):287-293.
[24]Wang H, Gao J, Lassiter TF, McDonagh DL, Sheng H, Warner DS, Lynch JR, Laskowitz DT. Levetiracetam is neuroprotective in murine models of closed head injury and subarachnoid hemorrhage. Neurocrit Care.2006,5(1):71-78.
[25]Koh S, Storey TW, Santos TC, Mian AY, Cole AJ. Early-life seizures in rats increase susceptibility to seizure-induced brain injury in adulthood Neurology.1999,53(5): 915-921.
[26]Ichiyama T, Okada K, Lipton JM, Matsubara T, Hayashi T, Furukawa S. Sodium valproate inhibits production of TNF-alpha and IL-6 and activation of NF-kappaB. Brain Res.2000,857(1-2):246-251.
[27]Peng GS, Li G, Tzeng NS, Chen PS, Chuang DM, Hsu YD, Yang S, Hong JS. Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures:role of microglia. Brain Res Mol Brain Res.2005, 134(1):162-169.
[28]Chen PS, Wang CC, Bortner CD, Peng GS, Wu X, Pang H, Lu RB, Gean PW, Chuang DM, Hong JS. Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience.2007,149(1):203-212.
[29]Glauben R, Batra A, Fedke I, Zeitz M, Lehr HA, Leoni F, Mascagni P, Fantuzzi G, Dinarello CA, Siegmund B. Histone hyperacetylation is associated with amelioration of experimental colitis in mice. J Immunol.2006,176(8):5015-5022.
[30]Zhang Z, Zhang ZY, Fauser U, Schluesener HJ. Valproic acid attenuates inflammation in experimental autoimmune neuritis. Cell Mol Life Sci.2008,65(24): 4055-4065.
[31]Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem.2001,276(39):36734-36741.
[32]Shahbazian MD, Grunstein M. Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem.2007,76:75-100.
[33]Bhavsar P, Ahmad T, Adcock IM. The role of histone deacetylases in asthma and allergic diseases. J Allergy Clin Immunol.2008,121(3):580-584.
[34]Dinarello CA. Inhibitors of histone deacetylases as anti-inflammatory drugs. Ernst Schering Res Found Workshop.2006,56:45-60.
[35]Choo QY, Ho PC, Lin HS. Histone deacetylase inhibitors:new hope for rheumatoid arthritis? Curr Pharm Des.2008,14(8):803-820.
[36]Chen PS, Peng GS, Li G, Yang S, Wu X, Wang CC, Wilson B, Lu RB, Gean PW, Chuang DM, Hong JS. Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry.2006,11(12):1116-1125.
[37]Cross, J.H.,2004. Topiramate. In:Shorvan, S., Perucca, E., Fish, D., Dodson, E. (Eds.), The Treatment of Epilepsy, second ed. Blackwell Publications, Oxford, pp. 515-527.
[38]Alves OL, Doyle AJ, Clausen T, Gilman C, Bullock R. Evaluation of topiramate neuroprotective effect in severe TBI using microdialysis. Ann N Y Acad Sci.2003, 993:25-34; discussion 48-53.
[39]Poulsen CF, Schousboe I, Sarup A, White HS, Schousboe A. Effect of topiramate and dBcAMP on expression of the glutamate transporters GLAST and GLT-1 in astrocytes cultured separately, or together with neurons. Neurochem Int.2006,48(6-7): 657-661.
[40]Angehagen M, Ben-Menachem E, Ronnback L, Hansson ETopiramate protects against glutamate-and kainate-induced neurotoxicity in primary neuronal-astroglial cultures. Epilepsy Res.2003,54(1):63-71.
[41]Rigo JM, Hans G, Nguyen L, Rocher V, Belachew S, Malgrange B, Leprince P, Moonen G, Selak I, Matagne A, Klitgaard H. The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents. Br J Pharmacol.2002,136(5):659-672.
[42]Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, Fuks B. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A.2004,101(26):9861-9866.
[43]Marini H, Costa C, Passaniti M, Esposito M, Campo GM, Ientile R, Adamo EB, Marini R, Calabresi P, Altavilla D, Minutoli L, Pisani F, Squadrito F. Levetiracetam protects against kainic acid-induced toxicity. Life Sci.2004,74(10):1253-1264.
[44]Haghikia A, Ladage K, Hinkerohe D, Vollmar P, Heupel K, Dermietzel R, Faustmann PM. Implications of antiinflammatory properties of the anticonvulsant drug levetiracetam in astrocytes. J Neurosci Res.2008,86(8):1781-1788.
[45]Cardile V, Pavone A, Gulino R, Renis M, Scifo C, Perciavalle V. Expression of brain-derived neurotrophic factor (BDNF) and inducible nitric oxide synthase (iNOS) in rat astrocyte cultures treated with Levetiracetam. Brain Res.2003,976(2):227-233.
[46]Pavone A, Cardile V. An in vitro study of new antiepileptic drugs and astrocytes. Epilepsia.2003,44(Suppl 10):34-39.
[1]单英,秦炯,常杏芝,杨志仙.纳洛酮对反复热惊厥脑损伤的干预作用.中华儿科杂志.2004,42(4)：260-263.
[2]单英,秦炯,杨志仙,韩颖.纳洛酮对高热惊厥大鼠海马神经元c-fos表达的影响.实用儿科临床杂志.2005,20(1)：57-60.
[3]单英,秦炯,常杏芝,杨志仙.纳洛酮对幼年大鼠反复热惊厥后远期惊厥易感性的影响.北京大学学报·医学版.2004,36(1)：57-60.
[4]Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases:mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther. 2003,304(1):1-7.
[5]Koh S, Storey TW, Santos TC, Mian AY, Cole AJ. Early-life seizures in rats increase susceptibility to seizure-induced brain injury in adulthood Neurology.1999,53(5): 915-921.
[6]Dingledine R, Iversen LL, Breuker E. Naloxone as a GABA antagonist:evidence from iontophoretic, receptor binding and convulsant studies. Eur J Pharmacol.1978, 47(1):19-27.
[7]Hardy C, Panksepp J, Rossi J 3rd, Zolovick AJ. Naloxone facilitates amygdaloid kindling in rats. Brain Res.1980,194(1):293-297.
[8]Snyder EW, Dustman RE, Schlehuber C. Naloxone epileptogenesis in monkeys. J Pharmacol Exp Ther.1981,217(2):299-305.
[9]Turski L, Ikonomidou C, Cavalheiro EA, Kleinrok Z, Czuczwar SJ, Turski WA. Effects of morphine and naloxone on pilocarpine-induced convulsions in rats. Neuropeptides.1985,5(4-6):315-318.
[10]Puig MM, Miralles F, Laorden L. Naloxone prevents hyperthermia induced convulsions in the immature rat. Methods Find Exp Clin Pharmacol.1986,8(11): 649-653.
[11]Chen CS, Gates GR, Reynoldson JA. Effect of morphine and naloxone on priming-induced audiogenic seizures in BALB/c mice. Br J Pharmacol.1976,58(4): 517-520.
[12]Meldrum BS, Menini C, Stutzmann JM, Naquet R. Effects of opiate-like peptides, morphine, and naloxone in the photosensitive baboon, Papio papio. Brain Res.1979, 170(2):333-348.
[13]Liu B, Gao HM, Wang JY, Jeohn GH, Cooper CL, Hong JS. Role of nitric oxide in inflammation-mediated neurodegeneration. Ann N Y Acad Sci.2002,962:318-331.
[14]Das KP, McMillian MK, Bing G, Hong JS. Modulatory effects of [Met5]-enkephalin on interleukin-1 beta secretion from microglia in mixed brain cell cultures J Neuroimmunol.1995,62(1):9-17.
[15]Kong LY, McMillian MK, Hudson PM, Jin L, Hong JS. Inhibition of lipopolysaccharide-induced nitric oxide and cytokine production by ultralow concentrations of dynorphins in mixed glia cultures. J Pharmacol Exp Ther.1997, 280(1):61-66.
[16]Liu B, Du L, Hong JS. Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. J Pharmacol Exp Ther.2000,293(2):607-617.
[17]Liu B, Jiang JW, Wilson BC, Du L, Yang SN, Wang JY, Wu GC, Cao XD, Hong JS. Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide. J Pharmacol Exp Ther.2000,295(1):125-132.
[18]Lu X, Bing G, Hagg T. Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats. Neuroscience.2000,97(2): 285-291.
[19]Liu B, Du L, Kong LY, Hudson PM, Wilson BC, Chang RC, Abel HH, Hong JS. Reduction by naloxone of lipopolysaccharide-induced neurotoxicity in mouse cortical neuron-glia co-cultures. Neuroscience.2000,97(4):749-756.
[20]Qin L, Liu Y, Cooper C, Liu B, Wilson B, Hong JS. Microglia enhance beta-amyloid peptide-induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species. J Neurochem.2002,83(4):973-983.
[21]Prow NA, Irani DN. The opioid receptor antagonist, naloxone, protects spinal motor neurons in a murine model of alphavirus encephalomyelitis. Exp Neurol.2007,205(2): 461-470.
[22]Ni YQ, Xu GZ, Hu WZ, Shi L, Qin YW, Da CD. Neuroprotective effects of naloxone against light-induced photoreceptor degeneration through inhibiting retinal microglial activation. Invest Ophthalmol Vis Sci.2008,49(6):2589-2598.
[23]Somera-Molina KC, Robin B, Somera CA, Anderson C, Stine C, Koh S, Behanna HA, Van Eldik LJ, Watterson DM, Wainwright MS. Glial activation links early-life seizures and long-term neurologic dysfunction:evidence using a small molecule inhibitor of proinflammatory cytokine upregulation. Epilepsia.2007,48(9):1785-1800.
[24]Priller J, Haas CA, Reddington M, Kreutzberg GW. Calcitonin gene-related peptide and ATP induce immediate early gene expression in cultured rat microglial cells. Glia. 1995,15(4):447-457.
[25]Taniwaki Y, Kato M, Araki T, Kobayashi T. Microglial activation by epileptic activities through the propagation pathway of kainic acid-induced hippocampal seizures in the rat. Neurosci Lett.1996,217(1):29-32.
[26]Streit WJ, Walter SA, Pennell NA. Reactive microgliosis. Prog Neurobiol.1999, 57(6):563-581.
[27]Biber K, Neumann H, Inoue K, Boddeke HW. Neuronal 'On' and 'Off' signals control microglia. Trends Neurosci.2007,30(11):596-602.
[28]Oprica M, Eriksson C, Schultzberg M. Inflammatory mechanisms associated with brain damage induced by kainic acid with special reference to the interleukin-1 system. J Cell Mol Med.2003,7(2):127-140.
[29]Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E, Di Luca M, Galli CL, Marino vich M. Interleukin-1 beta enhances NMD A receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci.2003,23(25):8692-8700.
[30]Binder DK, Steinhauser C. Functional changes in astroglial cells in epilepsy. Glia. 2006,54(5):358-368.