L—NAME促进大鼠红藻氨酸诱导性发作

为证明癫痫发作早期一氧化氮（ＮＯ）抗发作效应，用ＮＯ合酶（ＮＯＳ）抑制剂Ｌ－硝基精氨酸甲酯（Ｌ－ＮＡＭＥ）对大鼠红藻氨酸（ＫＡ）诱导性发作进行干预，同时用分光光度法检测海马结构中ＮＯＳ活性的早期变化。发现ＫＡ发作１０ｍｉｎ、３０ｍｉｎ组海马结构中ＮＯＳ活性明显升高，而ＫＡ注射前３０ｍｉｎ给予Ｌ－ＮＡＭＥ可显著抑制ＮＯＳ活性的升高，这种抑制效应与大鼠ＫＡ发作中湿狗样摇动（ＷＤＳ）的提早出现和发生次数增多显著相关。结果提示在ＫＡ诱导大鼠发作早期内源性ＮＯ具有明显的抗发作效用。     

实验性过敏性脑脊髓炎豚鼠中枢神经系统一氧化氮合酶的表达

目的探讨诱导型一氧化氮合酶（ｉＮＯＳ）在中枢神经系统脱髓鞘疾病中的作用。方法采用硫辛胺脱氢酶染色和抗诱导型一氧化氮合酶（抗ｉＮＯＳ）抗体的免疫组化方法，对髓鞘碱性蛋白诱导豚鼠产生的实验性过敏性脑脊髓炎（ＥＡＥ）病程中，脑和脊髓的一氧化氮合酶（ＮＯＳ）和ｉＮＯＳ表达情况进行研究。结果在ＥＡＥ的急性期主要为血管、血管周围细胞、浸润细胞和小胶质细胞显示ｉＮＯＳ免疫反应阳性，在恢复期星形细胞则出现免疫反应阳性。结论提示一氧化氮是ＥＡＥ早期血脑屏障破坏以及进展期髓鞘和少突胶质细胞破坏的重要介导物质。     

脑缺血对cNOS、iNOS基因表达的影响

一氧化氮（ＮＯ）由一氧化氮合酶（ＮＯＳ）专一催化合成。ＮＯＳ有两种生化型：原生型（ｃＮＯＳ）和诱生型（ｉＮＯＳ）,它们各具有特殊作用。我们在自发性高血压大鼠（ＳＨＲ）局灶脑缺血模型（ＭＣＡＯ）的基础上,采用ＲＴＰＣＲ技术,观察ｃＮＯＳ、ｉＮＯＳ的表...     

实验性癫痫大鼠海马结构内一氧化氮-环磷酸鸟苷途径的研究

目的研究实验性癫痫发作大鼠海马结构内一氧化氮（ＮＯ）环磷酸鸟苷（ｃＧＭＰ）信使机制及其意义。方法雄性ＳＤ大鼠４１只，随机分为对照组（５只）、红藻氨酸（ＫＡ）１０、３０、６０分钟组（每组６只）和Ｌ硝基精氨酸甲酯（ＬＮＡＭＥ）＋ＫＡ１０、３０、６０分钟组（每组６只）。用放射免疫法测定ＫＡ诱导性癫痫发作中各时点海马结构内ｃＧＭＰ含量及ＬＮＡＭＥ的干预效应。结果ＫＡ注射引起大鼠海马结构内ｃＧＭＰ浓度升高，并加重大鼠癫痫发作（湿狗样摇动提早出现和发生次数增多）；ＫＡ注射前３０分钟给予ＬＮＡＭＥ可明显抑制ＫＡ１０、３０分钟组ｃＧＭＰ浓度的升高，但ＬＮＡＭＥ对ＫＡ６０分钟组ｃＧＭＰ的抑制作用不显著。结论在ＫＡ发作早期，ｃＧＭＰ浓度升高与内源性ＮＯ有关；ＮＯ的抗发作效应可能与ｃＧＭＰ信使机制存在某种联系。     

红藻氨酸诱导癫痫发作小鼠脑组织中 NO_2~- 与硫代巴比妥酸反应物浓度测定

了解活性介质一氧化氮（ＮＯ）与癫痫发作的关系。方法用比色法检测红藻氨酸（ＫＡ）诱导ＢＡＬＢ／ｃ小鼠癫痫发作后，不同时点脑匀浆上清液中亚硝酸根（ＮＯ２－）与硫代巴比妥酸（ＴＢＡ）反应物的含量。结果ＮＯ２－浓度与ＴＢＡ反应物含量的多少与ＫＡ诱导的癫痫发作时程有关。在发作初期，ＮＯ２－随发作持续而增多，但发作后期又迅速减少。ＮＯ２－浓度的升高与减低受Ｌ－精氨酸（Ｌ－Ａｒｇ）及其硝基衍生物ＮＧ位硝基左型精氨酸（Ｌ－ＮＮＡ）的影响。同时对ＮＯ２－检测标本做ＴＢＡ反应物检测，发现ＮＯ２－的减少与ＴＢＡ反应物增多相关，在癫痫发作初期ＴＢＡ反应物含量较低，但随着发作时间的延长明显增多，ＴＢＡ含量的变化同样可受Ｌ－Ａｒｇ与Ｌ－ＮＮＡ的影响。结论Ｌ－Ａｒｇ－ＮＯ途径可能参与了癫痫发作的起动、传播和继发性脑损害的全过程，在发作后期，过量生成的ＮＯ可能有神经兴奋毒性作用。     

大鼠急性局灶性脑缺血再灌注脑组织NO含量和NOS活性的变化

目的探讨一氧化氮（ＮＯ）和神经元型ＮＯ合酶（ｎＮＯＳ）是否参与急性局灶性脑缺血再灌注的发病机理。方法采用栓红法建立大鼠大脑中动脉阻塞（ＭＣＡＯ）模型,观察脑组织ＮＯ含量和一氧化氮合酶（ＮＯＳ）活性的变化及ｎＮＯＳ抑制剂７－硝基吲唑（７－ＮＩ）对再灌注期两者的影响。结果缺血３０分种ＮＯ含量和ＮＯＳ活性显著升高,缺血３小进两者下降;再灌注３０分种ＮＯＴ和ＮＯＳ再次升高,而再灌注３小时两者又下降。７－Ｎ     

iNOS抑制剂对海马缺血/再灌注损伤保护作用研究

目的：进一步证实诱导型一氧化氮合酶（ｉＮＯＳ）催化所形成的一氧化氮（ＮＯ）在脑缺血／再灌注损伤中具有毒性作用。方法：将Ｓ－Ｄ大鼠双侧颈总动脉短暂夹闭３分钟,然后分成应用药物组－氨基胍（ＡＧ）和非药物组．４８小时后取海马脑片,观察顺向群峰电位（ｏＰＳ）以及组织学改变。结果;给药组大部分可见ｏＰＳ发放．而对照组只见有突触前排放（ｐｖ）无ｏＰＳ（Ｐ＜０．０５）,两组超微结构也有明显差异。结论：本实验证明大鼠海马短暂缺血／再灌注后ｉＮＯＳ抑制剂可减轻神经元损害,即可抑制血由ｉＮＯＳ诱生表达所形成的ＮＯ在脑缺血／再灌注损伤中的毒性作用。     

海人酸致痫动物模型脑内一氧化氮,一氧化氮合酶的变化

目的探讨一氧化氮（ＮＯ）、一氧化氮合酶（ＮＯＳ）在癫痫发生中的作用及ＮＯＳ抑制剂的作用。方法采用海人酸致痫大鼠模型并应用ＮＯＳ抑制剂Ｌ－硝基精氨酸甲酯（Ｌ－ＮＡＭＥ）,分别在致痫后３０分钟、６０分钟取海马组织,匀浆后测定ＮＯ及ＮＯＳ水平。结果致痫３０分钟后海马ＮＯ含量显著升高,至６０分钟恢复正常;ＮＯＳ活性水平增高＞５０％;Ｌ－ＮＡＭＥ明显抑制大鼠的痫性发作,应用ＮＯＳ抑制剂组大鼠海马ＮＯ、ＮＯＳ含量明显下降。结论癫痫发作后脑内ＮＯ、ＮＯＳ活性增强,ＮＯＳ抑制剂通过抑制酶活性使ＮＯ生成降低,并完全抑制痫性发作。ＮＯＳ活性受抑制＞４８％即可产生明显效果。提示ＮＯ可能有内源性致痫作用。     

神经元型一氧化氮合酶在学习记忆过程中的变？…

目的 探讨神经元型一氧化氮合酶（ｎｅｕｒｏｎａｌ ｎｉｔｒｉｃ ｏｘｉｄｅ ｓｙｎｔｈａｓｅ,ｎＮＯＳ）及一氧化氮（ｎｉｔｒｉｃ ｏｘｉｄｅ,ＮＯ）在学习记忆机制中的相关作用。方法 采用免疫组化方法观察Ｙ迷宫空间辨别学习训练后大鼠不同脑区ｎＮＯＳ表达变化,并探讨特异性ｎＮＯＳ抑制剂７－ｎｉｔｒｏ ｉｎｄｏｚａｌ（７－ＮＩ）、钙拮抗剂尼莫通（ｎｉｍｏｔｏｐ）腹腔注射对大鼠学习获得和记忆再能能力的影响     

大鼠脑缺血和再灌流过程脑组织一氧化氮合成酶表达的变化

目的　探讨大鼠脑缺血再灌流海马及皮层一氧化氮合酶（ＮＯＳ） 的变化。方法　用线栓法建立大脑中动脉梗死（ＭＣＡＯ） 模型,用烟酰胺腺嘌呤二核苷酸磷酸黄递酶（ＮＡＤＰＨｄ） 染色法观察ＮＯＳ阳性细胞的变化。结果　海马及皮层ＮＯＳ阳性细胞在缺血１５ 分明显增多,１ 小时减少,６ 小时有所恢复;再灌流１５ 分又显著减少,１ 小时渐增多,２４ 小时皮层出现较多ＮＯＳ阳性的毛细血管和大量胶质细胞。结论　本实验结果符合ＮＯ 在缺血早期增加和再灌流后期大量增加的变化,支持ＮＯ参与脑缺血再灌流损害的观点。     

红藻氨酸致痫大鼠海马S100B、CGRP蛋白表达及病理改变

目的 研究红藻氨酸(KA)致痫大鼠海马S100B、降钙素基因相关肽(CGRP)的表达及病理改变.方法 雄性SD大鼠按照完全随机数字表法分成对照组(8只)和模型组(40只),模型组再根据处死时间分为造模后6 h、12 h、24 h、72 h、1周5个亚组,每组8只.模型组采用KA建立颞叶癫痫动物模型,对照组用等体积生理盐水代替KA注射.模型组造模后6 h、12 h、24 h、72 h、1周,对照组注射后24 h取大鼠海马组织行Nissl染色、Timm染色和免疫组化染色,观察S100B、CGRP蛋白的表达情况以及海马神经元和胶质细胞的病理变化.结果 Nissl染色结果显示,模型组大鼠1周后CA3区出现大量固缩的坏死神经元,胞体萎缩,尼氏体消失.Timm染色结果显示,模型组大鼠1周后CA3区始层出现条带状分布的棕色颗粒,齿状回内分子层亦可见少量棕色颗粒.免疫组化染色结果显示,模型组大鼠海马CGRP蛋白大量表达,72 h时达到高峰,同时伴随大量神经元丧失及胶质细胞增生.结论 KA致痫大鼠出现S100B、CGRP蛋白高表达,尼氏体消失,苔藓纤维发芽等一系列病理学改变,推测S100B、CGRP蛋白参与了癫痫发生.

Abstract：

Objective To investigate the expressions of S100B and calcitonin gene related peptide (CGRP) and the pathologic alterations of the hippocampus in kainic acid (KA)-induced epileptic rats. Methods Male SD rats were randomly divided into control group (n=8) and model group (n=40).Animal models of temporal lobe epilepsy were established by intracerebroventricular injection of KA; the same volume of saline was injected into the rats in the control group. Hippocampal tissues within various phases after seizures (6, 12, 24 and 72 h, and 24 h after the success of model making) were performed Nissl staining, Timm staining and immunohistochemical staining. The expressions of S100B and CGRP were observed, and the pathologic alterations of the hippocampal neurons and glial cells were studied.Results All rat models were successfully induced with epileptic seizures. Nissl staining showed that pyknotic neuronal necrosis appeared in the CA3 area of the hippocampus in the model group with cell body atrophy and disappearance of Nissl bodies 1 week after the injection. Timm staining showed that brown particles showed stripped distribution in the CA3 area of the hippocampus and some brown particles in the molecular layer of fascia dentate. Immunohistochemical staining indicated that significant neurons lost and gliosis appeared after seizures with abundant expressions of S100B and CGRP.Conclusion KA-induced epileptic rats express abundant S100B and CGRP and appear such pathological changes as disappearance of Nissl bodies and mossy fiber sprouting, indicating that both S100B and CGRP participate in the onset of epilepsy.     

MRS Metabolic Markers of Seizures and Seizure-Induced Neuronal Damage

Summary: Purpose: Proton magnetic resonance spectroscopy (MRS) was used to identify specific in situ metabolic markers for seizures and seizure-induced neuronal damage. Kainic acid (KA)-induced seizures lead to histopathologic changes in rat brain. The protective effect of cycloheximide treatment against neuronal damage caused by KA-induced seizures was studied, using in situ proton MRS imaging technique.
Methods: Rats were pretreated with placebo or cycloheximide 1 h before KA injection. Rat brains (n = 25) were scanned at the level of the hippocampus before, during, and 24 h after seizures. Spectra were recorded and the relative ratios of N-acetylaspartate (NAA), choline (cho), and lactate (Lac) to creatine (Cr) were calculated and compared between groups.
Results: A significant increase in Lac ratios was observed in KA-treated rats during and 24 h after seizure onset and this increase was prevented by cycloheximide pretreatment. NAA ratios were significantly higher during the ictal phase following KA treatment and this effect was not affected by cycloheximide pretreatment. Nissl staining confirmed previously reported prevention of KA-induced neuronal loss in CA1 and CA areas of the hippocampus by cycloheximide pretreatment.
Conclusions: Our results suggest that in situ Lac increase is a marker of seizure-induced neuronal damage, whereas N-acetylaspartate (NAA) changes during and after status epilepticus may be a reflection of neuronal activity and damage, respectively.     

N w‐Propyl‐l‐arginine (L‐NPA) reduces status epilepticus and early epileptogenic events in a mouse model of epilepsy: behavioural,EEG and immunohistochemical analyses

We investigated the anticonvulsant and neurobiological effects of a highly selective neuronal nitric oxide synthase (nNOS) inhibitor, N ^w‐propyl‐l ‐arginine (L‐NPA), on kainic acid (KA)‐induced status epilepticus (SE) and early epileptogenesis in C57BL/6J mice. SE was induced with 20 mg/kg KA (i.p.) and seizures terminated after 2 h with diazepam (10 mg/kg, i.p). L‐NPA (20 mg/kg, i.p.) or vehicle was administered 30 min before KA. Behavioural seizure severity was scored using a modified Racine score and electrographic seizure was recorded using an implantable telemetry device. Neuronal activity, activity‐dependent synaptogenesis and reactive gliosis were quantified immunohistochemically, using c‐Fos, synaptophysin and microglial and astrocytic markers. L‐NPA treatment reduced the severity and duration of convulsive motor seizures, the power of electroencephalogram in the gamma band, and the frequency of epileptiform spikes during SE. It also reduced c‐Fos expression in dentate granule cells at 2 h post‐KA, and reduced the overall rate of epileptiform spiking (by 2‐ to 2.5‐fold) in the first 7 days after KA administration. Furthermore, treatment with L‐NPA suppressed both hippocampal gliosis and activity‐dependent synaptogenesis in the outer and middle molecular layers of the dentate gyrus in the early phase of epileptogenesis (72 h post‐KA). These results suggest that nNOS facilitates seizure generation during SE and may be important for the neurobiological changes associated with the development of chronic epilepsy, especially in the early stages of epileptogenesis. As such, it might represent a novel target for disease modification in epilepsy.     

Neuronal and inducible nitric oxide synthase immunoreactivity following serotonin depletion

Serotonin (5HT) modulates the development and plasticity of its innervation areas in the central nervous system (CNS). Astrocytic 5HT(1A) receptors are involved in the plastic phenomena by releasing the astroglial-derived neurotrophic factor S-100beta. Several facts have demonstrated that nitric oxide (NO) and the nitric oxide synthase enzyme (NOS) may also be involved in this neuroglial interaction: (i) NO, S-100beta and 5HT are involved in CNS plasticity; (ii) micromolar S-100beta concentration stimulates inducible-NOS (iNOS) expression; (iii) neuronal NOS (nNOS) immunoreactive neurons are functionally and morphologically related to the serotoninergic neurons; (iv) monoamines level, including 5HT, can be modulated by NO release. We have already shown that 5HT depletion increases astroglial S-100beta immunoreactivity, induces neuronal cytoskeletal alterations and produces an astroglial reaction, while once 5HT level is recovered, a sprouting phenomenon occurs [Brain Res. 883 (2000) 1-14]. To further characterize the relationship among nNOS, iNOS and 5HT we have analyzed nNOS and iNOS expression in the CNS after 5HT depletion induced by parachlorophenylalanine (PCPA) treatment. Studies were performed immediately after ending the PCPA treatment and during a recovery period of 35 days. Areas densely innervated by 5HT fibers were studied by means of nNOS and iNOS immunoreactivity as well as NADPH diaphorase (NADPHd) staining. All parameters were quantified by computer-assisted image analysis. Increased nNOS immunoreactivity in striatum and hippocampus as well as increased NADPHd reactivity in the striatum, hippocampus and parietal cortex were found after PCPA treatment. The iNOS immunoreactivity in the corpus callosum increased 14 and 35 days after the end of PCPA treatment. These findings showed that nNOS immunoreactivity and NADPHd activity increased immediately after 5HT depletion evidencing a close functional interaction between nitrergic and serotoninergic systems. However, iNOS immunoreactivity increased when 5HT levels were normalized, which could indicate one of the biological responses to S-100beta release.     

Protective role of melatonin in domoic acid-induced neuronal damage in the hippocampus of adult rats

Domoic acid (DA), a kainite-receptor agonist and potent inducer of neurotoxicity, has been administered intravenously in adult rats in the present study (0.75 mg/kg body weight) to demonstrate neuronal degeneration followed by glial activation and their involvement with inducible nitric oxide synthase (iNOS) in the hippocampus. An equal volume of normal saline was administered in control rats. The pineal hormone melatonin, which protects the neurons efficiently against excitotoxicity mediated by sensitive glutamate receptor, was administered intraperitoneally (10 mg/kg body weight), 20 min before, immediately after, and 1 h and 2 h after the DA administration, to demonstrate its role in therapeutic strategy. Histopathological analysis (Nissl staining) demonstrated extensive neuronal damage in the pyramidal neurons of CA1, CA3 subfields and hilus of the dentate gyrus (DG) in the hippocampus at 5 days after DA administration. Sparsely distributed glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes were observed in the hippocampus at 4-24 h after DA administration and in the control rats. Astrogliosis was evidenced by increased GFAP immunoreactivity in the areas of severe neuronal degeneration at 5 days after DA administration. Along with this, microglial cells exhibited an intense immunoreaction with OX-42, indicating upregulation of complement type 3 receptors (CR3). Ultrastructural study revealed swollen or shrunken degenerating neurons in the CA1, CA3 subfields and hilus of the DG and hypertrophied astrocytes showing accumulation of intermediate filament bundles in the cytoplasm were observed after administration of DA. Although no significant change could be observed in the mRNA level of iNOS expression between the DA-treated rats and controls at 4-24 h and at 5-day time intervals, double immunofluorescense revealed co-expression of induced iNOS with GFAP immunoreactive astrocytes, but not in the microglial cells, and iNOS expression in the neurons of the hippocampal subfields at 5 days after DA administration. Expression of iNOS was not observed in the hippocampus of control rats. DA-induced neuronal death, glial activation, and iNOS protein expression were attenuated significantly by melatonin treatment and were comparable to the control groups. The results of the present study suggest that melatonin holds potential for the treatment of pathologies associated with DA-induced brain damage. It is speculated that astrogliosis and induction of iNOS protein expression in the neurons and astrocytes of the hippocampus may be in response to DA-induced neuronal degeneration.     

Involvement of nitric oxide in kainic acid-induced excitotoxicity in rat brain

The involvement of nitric oxide (NO) in kainic acid (KA)-induced excitotoxicity was studied in rat brain. With the onset of KA (15 mg kg(-1), s.c.)-induced seizures (convulsions) 30 min after injection, increases in NO, as measured by the formation of citrulline, were seen in cortex (302%), amygdala (171%) and hippocampus (203%). The highest increases were determined 90 min after onset of seizures (120 min after KA injection) with 633%, 314% and 365%, respectively. These changes in NO preceded significant decreases in ATP and phosphocreatine (PCr) ranging from 44 to 53% for ATP and from 40 to 52% for PCr in the respective brain areas. With the exception of the cortex, normal citrulline values were restored within 24 h. Pretreatment with the spin trapping agent N-tert-butyl-alpha-phenylnitrone (PBN, 200 mg kg(-1), i.p.) or the antioxidant vitamin E (Vit-E, 100 mg kg(-1) per day for 3 days) prevented the increase in citrulline and significantly attenuated the loss in ATP and PCr without affecting seizure activity. It is concluded that seizures induced by KA produced a marked increase in the free radical NO, causing oxidative stress and leading to depletion of energy stores. The prevention of the increase in NO and preservation of ATP and PCr levels by PBN and Vit-E suggests the involvement of NO and other related free radicals, such as peroxynitrite (ONOO(-)). The lack of effect of PBN and Vit-E on seizure activity, suggests that NO is not involved in mechanisms regulating KA seizure generation and propagation. PBN and Vit-E or similar compounds may be important protective agents against status epilepticus-induced neuronal degeneration.     

Seizure activity-induced changes in polyamine metabolism and neuronal pathology during the postnatal period in rat brain.

Systemic injection of kainic acid (KA) does not cause neuronal pathology in limbic structures in rat brain prior to postnatal day (PND) 21. The present study tested if the development of the pathogenic response is associated with the maturation of a link between seizure activity and polyamine metabolism. Pathology was assessed with histological techniques and with the binding of [3H]Ro5-4864, a ligand for the peripheral type benzodiazepine binding sites (PTBBS), a marker of glial cell proliferation. In agreement with previous results, peripherally administered kainate at doses sufficient to induce intense behavioral seizures produced a loss of Nissl staining in hippocampus after PND 21 but not at earlier ages. The pattern of neuronal damage observed after PND 21 resembled that found in adult animals: extensive losses of Nissl staining in area CA3 of hippocampus and in piriform cortex, more modest effects in CA1 and sparing of the granule cells of the dentate gyrus. Similarly, no increase in [3H]Ro5-4864 binding as a result of KA administration was observed in hippocampus and piriform cortex until PND 21. Ornithine decarboxylase (ODC) activity and putrescine levels were high in the neonatal brain and decreased to reach adult values by PND 21. KA-induced seizure activity did not significantly alter both variables until PND 21. After PND 21, ODC activity and putrescine levels markedly increased 16 h after KA-induced seizure activity in hippocampus and piriform cortex. The magnitude of the effects increased between PND 21 and PND 30, at which point the changes in both parameters were comparable to those found in adults. Polyamines stimulate the activity of the calcium-dependent proteases calpain in brain fractions and may increase calpain-mediated proteolysis in situ. In accord with this, kainate-induced breakdown of spectrin, a preferred substrate of calpain, measured 16 h after KA injection followed a developmental curve parallel to that for kainate-induced increases in putrescine levels. These results indicate that the onset of vulnerability to seizure activity triggered by kainic acid is correlated with the development of an ODC/polyamine response to the seizures and further support a critical role for the ODC/polyamine pathway in neuronal pathology following a variety of insults.     

Rapamycin has paradoxical effects on S6 phosphorylation in rats with and without seizures

Purpose: Accumulating data have demonstrated that seizures induced by kainate (KA) or pilocarpine activate the mammalian target of rapamycin (mTOR) pathway and that mTOR inhibitor rapamycin can inhibit mTOR activation, which subsequently has potential antiepileptic effects. However, a preliminary study showed a paradoxical exacerbation of increased mTOR pathway activity reflected by S6 phosphorylation when rapamycin was administrated within a short period before KA injection. In the present study, we examined this paradoxical effect of rapamycin in more detail, both in normal rats and KA‐injected animals. Methods: Normal rats or KA‐treated rats pretreated with rapamycin at different time intervals were sacrificed at various time points (1, 3, 6, 10, 15, and 24 h) after rapamycin administration or seizure onset for western blotting analysis. Phosphorylation of mTOR signaling target of Akt, mTOR, Rictor, Raptor, S6K, and S6 were analyzed. Seizure activity was monitored behaviorally and graded according to a modified Racine scale (n = 6 for each time point). Neuronal cell death was detected by Fluoro‐Jade B staining. Key Findings: In normal rats, we found that rapamycin showed the expected dose‐dependent inhibition of S6 phosphorylation 3–24 h after injection, whereas a paradoxical elevation of S6 phosphorylation was observed 1 h after rapamycin. Similarly, pretreatment with rapamycin over 10 h before KA inhibited the KA seizure–induced mTOR activation. In contrast, rapamycin administered 1–6 h before KA caused a paradoxical increase in the KA seizure–induced mTOR activation. Rats pretreated with rapamycin 1 h prior to KA exhibited an increase in severity and duration of seizures and more neuronal cell death as compared to vehicle‐treated groups. In contrast, rapamycin pretreated 10 h prior to KA had no effect on the seizures and decreased neuronal cell death. The paradoxical effect of rapamycin on S6 phosphorylation was correlated with upstream mTOR signaling and was reversed by pretreatment of perifosine, an Akt inhibitor. Significance: These data indicate the complexity of S6 regulation and its effect on epilepsy. Paradoxical effects of rapamycin need to be considered in clinical applications, such as for potential treatment for epilepsy and other neurologic disorders.