FTY720抗癫癎发作及癫癎发生的实验研究
摘要
癫癎是一种常见病多发病，具有反复发作性，每次发作的不可预知性以及药物治疗的长期性等临床特点。发病年龄涵盖从新生儿至老年人各个年龄段，全球约5千万患者，严重影响患者身心健康，给社会和家庭带来沉重负担。尽管不断有新的抗癫癎药物问世，癫癎的治愈率并没有明显提高，约30%的患者抗癫癎药物治疗无效，称为难治性癫癎。在难治性癫癎中，一大部分是各种脑损伤后引起的症状性癫癎。脑损伤后通常经过一段时间的潜伏期，脑组织发生结构及功能的改变使得神经网络兴奋性升高，然后出现自发的癫癎发作。这种由“正常脑”转变为“癫癎脑”的过程称为癫癎发生。近年来，多项研究发现炎症在癫癎发作及癫癎发生过程中扮演了重要的角色，某些抗炎治疗在癫癎动物模型上显示出一定的抗癫癎发作及癫癎发生的作用，结合部分难治性癫癎患者加用抗炎治疗也能取得满意疗效，说明抗炎治疗是一条可能治疗癫癎的新途径。
芬戈莫德（FTY720）是一种已被临床批准使用的抗炎新药，在多发性硬化患者的治疗中取得良好的疗效。尽管目前机制尚不清，研究表明FTY720的作用主要是经过各种途径抑制病理状态下中枢神经系统炎症而实现的。因此在本研究中我们应用电生理技术、行为学及免疫组化等方法观察了FTY720抗癫癎发作及抗癫癎发生的作用，并探讨其潜在的机制，以期为临床治疗癫癎提供新的方法。
首先我们在离体脑片上验证了一种诱发脑内炎症的药物细菌脂多糖（Lipopolysaccharide，LPS）对癫癎样放电的影响，一方面从离体证实炎症在癫癎中的作用，另一方面探索炎症影响癫癎的电生理机制。结果如下：1、急性LPS暴露易化了海马CA1锥体细胞的癫癎样放电；2、急性LPS暴露增加了海马CA1锥体细胞的兴奋性突触后电流的强度，但对抑制性突触后电流无影响；3、急性LPS暴露增加了海马CA1锥体细胞的兴奋性，但未改变基强度下第一个动作电位的幅值和半波宽。提示急性炎症易化癫癎样放电的可能机制是增强兴奋性突触传递及细胞兴奋性，这可能是炎症诱发癫癎的电生理基础，并为下一步研究抗炎药物FTY720对癫癎的影响奠定了离体实验基础。
其次，我们观察了FTY720在MES、PTZ急性惊厥模型及匹罗卡品癫癎模型上抗癫癎发作的作用，并初步探讨了其潜在的机制。结果如下：1、FTY720在0.25mg/kg及1mg/kg剂量腹腔注射30min后对MES模型无效。2、FTY720在0.25mg/kg腹腔注射30min后对PTZ急性惊厥模型最小阵挛发作（Minimal clonic seizure，MCS）、全身强直阵挛性发作（Generalizedtonic-clonic seizure，GTCS）的潜伏期及动物死亡率均无影响，但可以减少GTCS的发作时间；1mg/kg腹腔注射能明显延长MCS和GTCS的潜伏期，减少GTCS的发作时间，提高动物存活率。3、FTY7201mg/kg腹腔注射30min后对匹罗卡品诱导大鼠癫癎持续状态的比例及死亡率无影响，但能延长SE潜伏期。4、离体脑片上，LPS增加了海马CA1区兴奋性突触后电位的幅值；0.1-10μM的FTY720-P对LPS导致的兴奋性突触后电位增加无影响而100μMFTY720-P明显降低了LPS诱导的兴奋性突触后电位；100μM FTY720-P对正常的兴奋性突触后电位无影响。以上结果说明FTY720有一定的抗癫癎发作的药理作用，这种作用有剂量依赖性。其潜在的机制可能是抑制了病理状态下兴奋性突触传递的增加。
既然FTY720有抗癫癎发作、减少异常兴奋性突触传递以及文献报道的抗炎作用，那么能否对症状性癫癎形成过程即癫癎发生期异常兴奋的神经环路产生抑制从而起到减少后期癫癎的自发发作呢？为证实这一假设，在最后一部分实验中我们在大鼠癫癎持续状态（Status epilepticus，SE）后24小时予以1mg/kg FTY720腹腔注射，每天1次，连续注射14天，观察了癫癎发生期海马神经环路兴奋性及慢性期大鼠癫癎自发发作的变化；同时观察了脑内海马的炎症反应程度如小胶质细胞、星型胶质细胞的激活程度，细胞因子IL-1β和TNFα含量的变化；还观察了导致癫癎发生的常见病理改变如海马神经元的变性丢失及苔藓纤维芽生的变化情况。结果发现：1、在SE后21-34天的视频检测中，FTY720明显降低了出现癫癎自发发作大鼠的数量，减轻了癫癎发作的频率、持续时间和严重程度。2、SE后第4天，大鼠海马IL-1β和TNFα的含量明显升高，但FTY720治疗组明显低于生理盐水治疗组；FTY720治疗组海马CA1、CA3和门区的星型胶质细胞和小胶质细胞数目也明显低于生理盐水治疗组； FTY720的治疗还减轻了海马各区神经元的变性。3、SE后第7天，FTY720治疗组大鼠海马神经环路兴奋性较生理盐水治疗组明显下降。4、SE后第35天， FTY720治疗显著减轻Timm染色标记的苔藓纤维芽生程度。结果说明抗炎药物FTY720能够改善SE后癫癎发生期海马的炎症反应程度，减少神经元变性，降低异常兴奋的神经环路形成，最终缓解了慢性期癫癎的自发发作。
综上所述，模拟急性炎症的LPS暴露可以通过增加兴奋性突触传递和神经元的兴奋性来易化离体诱导的癫癎样放电；FTY720抑制兴奋性突触的传递减轻了癫癎的发作；FTY720还有抗癫癎发生的作用，其机制与减轻癫癎发生期的炎症反应，降低异常神经环路形成有关。一系列实验揭示了炎症致癫癎的可能电生理基础，全面评价了抗炎药物FTY720抗癫癎发作及癫癎发生的特性及潜在的机制。
Epilepsy is a disorder of the brain clinically characterized by unexpectedrecurrent seizures and long-time treatment of antiepileptic drugs (AEDs). It is acommon human disease and affects the whole age range from neonates toelderly people. Approximately50million people around the world suffer fromepilepsy, which imposes a heavy burden on society and their families. Thoughthe new generation of AEDs is developed, there is no evidence that the efficacyof new AEDs is better than the old agents. About30%of epilepsy is intractableepilepsy which can not be cured by present AEDs. Majority of intractableepilepsy is the symptomatic epilepsy followed by brain injuries. An initial braininsult triggers a cascade of cellular events which, after a latent period,contributes “normal brain” to “epileptic brain” and leads to neural networkhyperexcitability and occurrence of spontaneous recurrent seizures. This processis termed epileptogenesis. Recently, emerging evidence has suggestedinflammatory processes play an important role in seizure and epileptogenesis.Several anti-neuroinflammatory agents have anticonvulsant and antiepileptogenic actions in animal models and some anti-inflammatory drugsare administered as adjunctive agents in patients with intractable epilepsy. All ofthese facts indicate that anti-inflammation is a new probable pathway fortreatment of epilepsy.
Fingolimod (FTY720) is a new anti-inflammatory drug approved for thetreatment of multiple sclerosis (MS) by the US Food and Drug Administration(FDA). Present data suggest that anti-neuroinflammatory effects of FTY720viavarious pathways are involved in its pharmacological properties. In our research,we studied FTY720′s anticonvulsant and antiepileptogenic actions in animalmodels and their underlying mechanisms through monitoring behavior,electrophysiological techniques and immunohistochemistry in vivo and vitro.We hope to provide a new pathway for treatment and prevention of epilepsy.
Firstly, to demonstrate the effects of acute inflammation on epileptiformdischarges in vitro and reveal its underlying mechanisms, we observed changesof epileptiform activity, synaptic strength and neuronal excitability after addingLPS (an extensively used agent to induce brain inflammatory processes inexperiments in vivo and in vitro) to hippocampal slices. The results were asfollowings:1. Acute administration of LPS facilitated epileptiform activity inhippocampal CA1pyramidal neurons in vitro;2. Acute LPS exposure enhancedevoked excitatory postsynaptic currents (eEPSCs) but did not modify evokedinhibitory postsynaptic currents (eIPSCs);3. Exposure to LPS increased theexcitability of CA1pyramidal neurons but did not change the amplitude orhalf-width of the first action potential evoked by rheobase current. These resultssuggest strengthened excitatory synaptic transmission and neuronal excitabilityare most likely attributable to this facilitation of acute inflammation induced byLPS. It provides a model to study the effects of FTY720on abnormal excitatorysynaptic strength in the following experiment.
Secondly, we evaluated anticonvulsant activity of FTY720in three animalmodels of epilepsy including MES model, s.c.PTZ model and pilocarpine model.In addition, we studied the underlying mechanisms in hippocampal slice in vitro.The results were as followings:1. At dosage of0.25mg/kg and1mg/kg,FTY720had not anticonvulsant activity in MES model.2. In s.c. PTZ model,0.25mg/kg FTY720had no effects on latency of minimal clonic seizure (MCS)or generalized tonic-clonic seizure (GTCS) or mortality of mice while reducedthe duration of GTCS.1mg/kg FTY720improved latency of MCS and GTCS,also decreased mortality and the duration of GTCS.3. In pilocarpine model,1mg/kg FTY720injection showed anticonvulsant activity demonstrated byreducing the latency to SE. However,1mg/kg FTY720did not decrease themortality and the number of rats developing SE.4. In vitro, LPS increasedamplitude of EPSP recorded in hippocampal CA1region. At100μM but not0.1-10μM concentration, FTY720-P suppressed increasing amplitude of EPSPinduced by LPS.100μM FTY720-P had no effect on normal EPSP in CA1region. These data indicate FTY720has anticonvulsant action and this action isdose-dependent. Ability of decreasing abnormal excitatory synaptic transmissionmay be one of underlying mechanisms.
Due to FTY720′s anticonvulsion, decreasing abnormal EPSP andanti-inflammation reported by others, we hypothesized that FTY720maysuppress epileptogenesis and reduce spontaneous recurrent seizures (SRS) inchronic epilepsy. In the third experiment, to test this hypothesis,1mg/kgFTY720was administrated24h after onset of status epilepticus (SE) for14consecutive days. We examined whether FTY720might attenuatehyperexcitability of hippocampal neuronal circuits and SRS following SE, andwhether FTY720might decrease inflammatory responses, such as glialactivation, expression of IL-1β and TNFα. Furthermore, we evaluated whether neuronal degeneration and aberrant mossy fiber sprouting (MFS) inhippocampus could be reversed by administration of FTY720. The results wereas followings:1. During21-34days post SE, FTY720decreased incidence ofSRS. The frequency, duration of SRS and severity of seizures were also reducedin this period.2. At four days post SE, FTY720alleviated the concentration ofIL-1β and TNFα in hippocampus. The number of micriglia and astrocytes inCA1、CA3and hilus were decreased in FTY720treated SE rats compared tosaline treated SE rats. At this time point, FTY720had a neuroprotective effectaganist neurodegeneration in hippocampus.3. At seven days post SE, FTY720decreased hyperexcitability of hippocampal neuronal circuits.4.35days afterSE, there were less Timm score in SE+FTY720group than SE+saline group.These observations suggest that FTY720has antiepileptogenic action in ratsfollowing SE induced by Li-pilocarpine. Anti-inflammatory and neuroprotectiveeffects and suppression of MFS may all involve in the underlying mechanisms.
In conclusion, mimic inflammatory environment by acute LPS exposurefacilitated epileptiform activity. Strengthened excitatory synaptic transmissionand neuronal excitability may contribute to this facilitation. FTY720exertsanticonvulsant action in animal epilepsy models and reducing abnormalexcitatory synaptic transmitter may be involved in its underlying mechanisms.In addition, FTY720plays an antiepileptic role in the Li-pilocarpine model inrats. This efficacy may result from anti-inflammation and suppression ofhyperexcitable circuit of FTY720. Our observations suggest inflammationaggravates epilepsy in electrophysiology and FTY720exerts anticonvulsant andantiepileptogenic actions in animal models of epilepsy.
芬戈莫德（FTY720）是一种已被临床批准使用的抗炎新药，在多发性硬化患者的治疗中取得良好的疗效。尽管目前机制尚不清，研究表明FTY720的作用主要是经过各种途径抑制病理状态下中枢神经系统炎症而实现的。因此在本研究中我们应用电生理技术、行为学及免疫组化等方法观察了FTY720抗癫癎发作及抗癫癎发生的作用，并探讨其潜在的机制，以期为临床治疗癫癎提供新的方法。
首先我们在离体脑片上验证了一种诱发脑内炎症的药物细菌脂多糖（Lipopolysaccharide，LPS）对癫癎样放电的影响，一方面从离体证实炎症在癫癎中的作用，另一方面探索炎症影响癫癎的电生理机制。结果如下：1、急性LPS暴露易化了海马CA1锥体细胞的癫癎样放电；2、急性LPS暴露增加了海马CA1锥体细胞的兴奋性突触后电流的强度，但对抑制性突触后电流无影响；3、急性LPS暴露增加了海马CA1锥体细胞的兴奋性，但未改变基强度下第一个动作电位的幅值和半波宽。提示急性炎症易化癫癎样放电的可能机制是增强兴奋性突触传递及细胞兴奋性，这可能是炎症诱发癫癎的电生理基础，并为下一步研究抗炎药物FTY720对癫癎的影响奠定了离体实验基础。
其次，我们观察了FTY720在MES、PTZ急性惊厥模型及匹罗卡品癫癎模型上抗癫癎发作的作用，并初步探讨了其潜在的机制。结果如下：1、FTY720在0.25mg/kg及1mg/kg剂量腹腔注射30min后对MES模型无效。2、FTY720在0.25mg/kg腹腔注射30min后对PTZ急性惊厥模型最小阵挛发作（Minimal clonic seizure，MCS）、全身强直阵挛性发作（Generalizedtonic-clonic seizure，GTCS）的潜伏期及动物死亡率均无影响，但可以减少GTCS的发作时间；1mg/kg腹腔注射能明显延长MCS和GTCS的潜伏期，减少GTCS的发作时间，提高动物存活率。3、FTY7201mg/kg腹腔注射30min后对匹罗卡品诱导大鼠癫癎持续状态的比例及死亡率无影响，但能延长SE潜伏期。4、离体脑片上，LPS增加了海马CA1区兴奋性突触后电位的幅值；0.1-10μM的FTY720-P对LPS导致的兴奋性突触后电位增加无影响而100μMFTY720-P明显降低了LPS诱导的兴奋性突触后电位；100μM FTY720-P对正常的兴奋性突触后电位无影响。以上结果说明FTY720有一定的抗癫癎发作的药理作用，这种作用有剂量依赖性。其潜在的机制可能是抑制了病理状态下兴奋性突触传递的增加。
既然FTY720有抗癫癎发作、减少异常兴奋性突触传递以及文献报道的抗炎作用，那么能否对症状性癫癎形成过程即癫癎发生期异常兴奋的神经环路产生抑制从而起到减少后期癫癎的自发发作呢？为证实这一假设，在最后一部分实验中我们在大鼠癫癎持续状态（Status epilepticus，SE）后24小时予以1mg/kg FTY720腹腔注射，每天1次，连续注射14天，观察了癫癎发生期海马神经环路兴奋性及慢性期大鼠癫癎自发发作的变化；同时观察了脑内海马的炎症反应程度如小胶质细胞、星型胶质细胞的激活程度，细胞因子IL-1β和TNFα含量的变化；还观察了导致癫癎发生的常见病理改变如海马神经元的变性丢失及苔藓纤维芽生的变化情况。结果发现：1、在SE后21-34天的视频检测中，FTY720明显降低了出现癫癎自发发作大鼠的数量，减轻了癫癎发作的频率、持续时间和严重程度。2、SE后第4天，大鼠海马IL-1β和TNFα的含量明显升高，但FTY720治疗组明显低于生理盐水治疗组；FTY720治疗组海马CA1、CA3和门区的星型胶质细胞和小胶质细胞数目也明显低于生理盐水治疗组； FTY720的治疗还减轻了海马各区神经元的变性。3、SE后第7天，FTY720治疗组大鼠海马神经环路兴奋性较生理盐水治疗组明显下降。4、SE后第35天， FTY720治疗显著减轻Timm染色标记的苔藓纤维芽生程度。结果说明抗炎药物FTY720能够改善SE后癫癎发生期海马的炎症反应程度，减少神经元变性，降低异常兴奋的神经环路形成，最终缓解了慢性期癫癎的自发发作。
综上所述，模拟急性炎症的LPS暴露可以通过增加兴奋性突触传递和神经元的兴奋性来易化离体诱导的癫癎样放电；FTY720抑制兴奋性突触的传递减轻了癫癎的发作；FTY720还有抗癫癎发生的作用，其机制与减轻癫癎发生期的炎症反应，降低异常神经环路形成有关。一系列实验揭示了炎症致癫癎的可能电生理基础，全面评价了抗炎药物FTY720抗癫癎发作及癫癎发生的特性及潜在的机制。
Epilepsy is a disorder of the brain clinically characterized by unexpectedrecurrent seizures and long-time treatment of antiepileptic drugs (AEDs). It is acommon human disease and affects the whole age range from neonates toelderly people. Approximately50million people around the world suffer fromepilepsy, which imposes a heavy burden on society and their families. Thoughthe new generation of AEDs is developed, there is no evidence that the efficacyof new AEDs is better than the old agents. About30%of epilepsy is intractableepilepsy which can not be cured by present AEDs. Majority of intractableepilepsy is the symptomatic epilepsy followed by brain injuries. An initial braininsult triggers a cascade of cellular events which, after a latent period,contributes “normal brain” to “epileptic brain” and leads to neural networkhyperexcitability and occurrence of spontaneous recurrent seizures. This processis termed epileptogenesis. Recently, emerging evidence has suggestedinflammatory processes play an important role in seizure and epileptogenesis.Several anti-neuroinflammatory agents have anticonvulsant and antiepileptogenic actions in animal models and some anti-inflammatory drugsare administered as adjunctive agents in patients with intractable epilepsy. All ofthese facts indicate that anti-inflammation is a new probable pathway fortreatment of epilepsy.
Fingolimod (FTY720) is a new anti-inflammatory drug approved for thetreatment of multiple sclerosis (MS) by the US Food and Drug Administration(FDA). Present data suggest that anti-neuroinflammatory effects of FTY720viavarious pathways are involved in its pharmacological properties. In our research,we studied FTY720′s anticonvulsant and antiepileptogenic actions in animalmodels and their underlying mechanisms through monitoring behavior,electrophysiological techniques and immunohistochemistry in vivo and vitro.We hope to provide a new pathway for treatment and prevention of epilepsy.
Firstly, to demonstrate the effects of acute inflammation on epileptiformdischarges in vitro and reveal its underlying mechanisms, we observed changesof epileptiform activity, synaptic strength and neuronal excitability after addingLPS (an extensively used agent to induce brain inflammatory processes inexperiments in vivo and in vitro) to hippocampal slices. The results were asfollowings:1. Acute administration of LPS facilitated epileptiform activity inhippocampal CA1pyramidal neurons in vitro;2. Acute LPS exposure enhancedevoked excitatory postsynaptic currents (eEPSCs) but did not modify evokedinhibitory postsynaptic currents (eIPSCs);3. Exposure to LPS increased theexcitability of CA1pyramidal neurons but did not change the amplitude orhalf-width of the first action potential evoked by rheobase current. These resultssuggest strengthened excitatory synaptic transmission and neuronal excitabilityare most likely attributable to this facilitation of acute inflammation induced byLPS. It provides a model to study the effects of FTY720on abnormal excitatorysynaptic strength in the following experiment.
Secondly, we evaluated anticonvulsant activity of FTY720in three animalmodels of epilepsy including MES model, s.c.PTZ model and pilocarpine model.In addition, we studied the underlying mechanisms in hippocampal slice in vitro.The results were as followings:1. At dosage of0.25mg/kg and1mg/kg,FTY720had not anticonvulsant activity in MES model.2. In s.c. PTZ model,0.25mg/kg FTY720had no effects on latency of minimal clonic seizure (MCS)or generalized tonic-clonic seizure (GTCS) or mortality of mice while reducedthe duration of GTCS.1mg/kg FTY720improved latency of MCS and GTCS,also decreased mortality and the duration of GTCS.3. In pilocarpine model,1mg/kg FTY720injection showed anticonvulsant activity demonstrated byreducing the latency to SE. However,1mg/kg FTY720did not decrease themortality and the number of rats developing SE.4. In vitro, LPS increasedamplitude of EPSP recorded in hippocampal CA1region. At100μM but not0.1-10μM concentration, FTY720-P suppressed increasing amplitude of EPSPinduced by LPS.100μM FTY720-P had no effect on normal EPSP in CA1region. These data indicate FTY720has anticonvulsant action and this action isdose-dependent. Ability of decreasing abnormal excitatory synaptic transmissionmay be one of underlying mechanisms.
Due to FTY720′s anticonvulsion, decreasing abnormal EPSP andanti-inflammation reported by others, we hypothesized that FTY720maysuppress epileptogenesis and reduce spontaneous recurrent seizures (SRS) inchronic epilepsy. In the third experiment, to test this hypothesis,1mg/kgFTY720was administrated24h after onset of status epilepticus (SE) for14consecutive days. We examined whether FTY720might attenuatehyperexcitability of hippocampal neuronal circuits and SRS following SE, andwhether FTY720might decrease inflammatory responses, such as glialactivation, expression of IL-1β and TNFα. Furthermore, we evaluated whether neuronal degeneration and aberrant mossy fiber sprouting (MFS) inhippocampus could be reversed by administration of FTY720. The results wereas followings:1. During21-34days post SE, FTY720decreased incidence ofSRS. The frequency, duration of SRS and severity of seizures were also reducedin this period.2. At four days post SE, FTY720alleviated the concentration ofIL-1β and TNFα in hippocampus. The number of micriglia and astrocytes inCA1、CA3and hilus were decreased in FTY720treated SE rats compared tosaline treated SE rats. At this time point, FTY720had a neuroprotective effectaganist neurodegeneration in hippocampus.3. At seven days post SE, FTY720decreased hyperexcitability of hippocampal neuronal circuits.4.35days afterSE, there were less Timm score in SE+FTY720group than SE+saline group.These observations suggest that FTY720has antiepileptogenic action in ratsfollowing SE induced by Li-pilocarpine. Anti-inflammatory and neuroprotectiveeffects and suppression of MFS may all involve in the underlying mechanisms.
In conclusion, mimic inflammatory environment by acute LPS exposurefacilitated epileptiform activity. Strengthened excitatory synaptic transmissionand neuronal excitability may contribute to this facilitation. FTY720exertsanticonvulsant action in animal epilepsy models and reducing abnormalexcitatory synaptic transmitter may be involved in its underlying mechanisms.In addition, FTY720plays an antiepileptic role in the Li-pilocarpine model inrats. This efficacy may result from anti-inflammation and suppression ofhyperexcitable circuit of FTY720. Our observations suggest inflammationaggravates epilepsy in electrophysiology and FTY720exerts anticonvulsant andantiepileptogenic actions in animal models of epilepsy.
引文
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