由CX32和CX43组成的缝隙连接在癫痫发病中的作用及调控机制的实验研究
摘要
癫痫是神经系统常见病，是多种病因导致的慢性脑疾患，其特点是大脑神经元反复地、过度地超同步化放电，引起一过性和发作性的脑功能障碍。癫痫患病率为0.46％，发病率为37/10万/年。癫痫是一种以药物治疗为主的疾病，随着医学科学的不断进步，药物治疗癫痫的总有效率已达65%以上，但仍有35%的癫痫对现有的药物治疗无效，成为难治性癫痫。目前，国内外许多实验都证实了癫痫与缝隙连接（GJ）有密切关联，但尚不弄清楚何种缝隙连接蛋白（CX）形成的GJ在癫痫活动中起主导作用。
目 的
本研究采用先进的实验手段，从分子水平探讨CX32和CX43在癫痫中变化，阐明何种CX形成的GJ在癫痫活动中起主要作用，为针对GJ发展新的抗癫痫药物确定靶点。合成特异性阻断GJ的连接蛋白拟似肽（CMP），并观察其作用, 以进一步针对该靶点的抗癫痫研究与治疗奠定基础。
方 法
雄性Wistar 大鼠250只， 正常对照组25只。手术对照组25只。KA致痫组200只，分别按3小时、6小时、12小时、24小时、72小时、7天、15天、30天时间点分为8组, 每组25只。以上各组又分三个小组，CMP组、甘珀酸(CAR)组、生理盐水组，每一个小组5只，进行脑电图描记（共150只）。剩余的100只按时间段分别进行Western blot及
免疫组化分析。
致痫方法 将大鼠固定于立体定位仪上，取头颅正中菱形切口，暴露颅骨及前卤、后卤。右侧杏仁核基底外侧核的坐标位置为前囟后3.5 mm，中线右侧旁开4.5mm，硬脑膜下7.5mm。按上述右侧杏仁核坐标，注入海人藻酸(KA)1μl，对照组为PBS注射液1μl。
脑电描记方法 将大鼠头部固定在立体定位仪上，身体用胶带固定。取头颅正中纵向切口，暴露颅骨及前卤、后卤。用小型牙科钻，以前囟后2.5mm, 中线左侧旁开2.5 mm 为中心, 去除颅骨3 mm×3mm 范围, 除去硬脑膜, 暴露皮层感觉运动区。被暴露的皮层面用3 mm ×3mm大小的干净滤纸片盖住以此保持体温和湿度。在此处局部浸润各种药物。用A g－A gCl 乏极化电极作为引导电极，分别牙科水泥固定在额顶部及顶枕部，即暴露皮层的前后两端，硬膜下0.25 cm。无关电极安置于鼻尖部。电极接到日本产EEG-7209型脑电记录仪上。 麻醉1～1.5小时后开始记录脑电，以尽量减少麻醉药对脑电的影响。
用药方法 先预防用药（多肽组用CMP, 浓度为500μΜ；CAR组用甘珀酸钠，浓度为10mM; 生理盐水对照组用生理盐水，滴入到盖在皮层上的滤纸片上）记录基础脑电30分钟, 再给致痫剂4－AP（将药物结晶体放到盖在皮层上的滤纸片上, 直到脑电描记结束，以将其充分融解、浸润到皮层脑组织）, 以引发痫性脑电的发放，连续描记1 小时。
3小时组的用药和脑电描记方法于其他时间段有所不同，此组描记脑电共一个小时，先未用任何药物的情况下记录基础脑电30分钟，而后用CMP、CAR及生理盐水（浓度同上），再描记脑电30分钟，其余同上。
主要观察潜伏期、出现第一个癫痫波开始15分钟内的癫痫波发放的总数、平均振幅和1小时内癫痫发作持续时间。
免疫组化方法 主要观察不同组别、不同脑区、不同时间段CX32和CX43阳性细胞的分布及表达数目。
Western blot方法 主要观察不同组别、不同脑区、不同时间段CX32和CX43的表达量的变化。
结 果
1．所建立的KA致痫模型成功率为96.4%，均出现Racine 分级Ⅳ级以上发作及相应的癫痫波发放。
2. KA致痫后脑组织病理形态学观察：
早期以神经元变性为主并有少许神经细胞坏死。中期KA注射组的颞顶叶皮层及海马区病变进一步加重，不同程度的神经元脱失及胶质细胞增生和毛细血管增多的改变。后期主要以神经细胞脱失，胶质细胞及毛细血管增生为主的病变。以上改变均以海马CA1和CA3区表现得最为严重，齿状回改变不明现。
3. KA致痫大鼠CX32表达的变化
免疫组化法 正常海马各区及皮层CX32阳性细胞稀少，胞浆与胞膜着色。KA致痫后大鼠的大脑皮层及海马均有CX32阳性表达。KA致痫后3小时大鼠的海马各区及皮层CX32的表达迅速增多，第3天达高峰，后逐渐下降。到第30天时阳性细胞数仍多于对照组。KA致痫后各时间组CX32阳性表达的细胞数与对照组相比，差异有极显著性，P＜0.01，手术对照组与正常对照组相比CX32阳性细胞数差异无显著性，P＞0.05。皮层与海马相比CX32阳性细胞数差异有显著性，P＜0.05。海马CA1、CA3及CA4区CX32阳性细胞数较多，其中CA3区表现明显，CA2和DG区变化不明现。
Western blot法 正常海马各区及皮层CX32表达量很少。KA致痫后大鼠的大脑皮层及海马均有CX32阳性表达。KA致痫后3小时大鼠的海马各区及皮层CX32的表达量迅速增多，第3天达高峰，后逐渐下降。到第30天时其表达量仍高于对照组。KA致痫后各时间组CX32表达量与对照组相比，差异有极显著性，P＜0.01，手术对照组与正常对照组相比CX32表达量差异无显著性，P＞0.05。皮层与海马相比CX32表达量差异有显著性，P＜0.05。
4. KA致痫大鼠CX43表达的变化
免疫组化法 正常海马各区及皮层CX43阳性细胞稀少，胞浆与胞膜着色。KA致痫后大鼠的大脑皮层及海马均有CX43阳性表达。KA致痫后3小时大鼠的海马各区及皮层CX43阳性细胞数逐渐增多，时程越长
阳性细胞数目越多。KA致痫后各时间组
Epilepsy is a kind of common disease in nervous system and it is a chronic disease induced by multi-etiological factors. It is characterized by brain neuron’s repeated and excessive super-synchronization discharging, which induces transitory and episodic dysencephalia. Prevalence rate of epilepsy is about 0.46％ and incidence rate is 37/100,000/ year. Drug treatment is a important method to epilepsy. 65% of epilepsy can be cured by drug treatment, however, still 35% of it is not effective to drug. At present, a lot of experiments indicate that epilepsy is related to GJ. However, it is not so clear. that which kind of connexin in forming GJ play important role in epilepsy activity.
AIM
Present study made use of advanced experimental method to observe the change of CX32 and CX43 in epilepsy on molecular level so that which kind of connexin in formting GJ play important role in epilepsy was clarified. The finding can define the target that new antiepileptic will act on. CMP, a kind of synthetic specific blocker of GJ, was used to study antiepileptic, which established the basis of the study and therapy of epileptic.
Method
Wistar rats of male were divided into several groups. There are 25 rats in normal matched control group and operation matched control group respectively and 200 rats in epileptic group induced by KA. Epileptic group was divided into 8 group on the order of 3
hours,6 hours,12 hourses,24 hourses,72 hourses,7 dayses,15 days and 30days. Above each was divided into three groups CMP group, CAR group and saline group, and each group has 5 rats. Above 150 rats were applied to tracing of EEG and surplus 100 rats were applied to Western blot and immunohistochemical analysis according to time course.
Method of making epileptic model
Rats was fixed on stereotaxic apparatus and take the rhombus slices from the skull center so that cranium, anterior fontanelle and posterior fontanelle was exposured .The position of basiolateral nuclear in right nucleus amygdalae is on the behind of the anterior fontanelle 3.5mm, on the right side of the centerline 4.5mm and under the dura 7.5mm. According to the coordinate of nucleus amygdalae ,KA was injiected into nucleus amygdalae and 1μl PBS was injected as control.
Tracing of Electro encephalogram
Rats was fixed on stereotaxic apparatus and their body were fixed with adhesive tape.Take the center and lengthways slice on the skull so that cranium , anterior fontanelle and posterior fontanelle was exposured. On the behind anterior fontanelle 2.5mm and on the left side of the centerline 2.5mm, take 3 mm×3mm skull slice away and remove the hard meninges with small dental drill so that cortex sensorimotor area was exposed. Keep the temperature and degree of wetness of the exposed cortex with 3 mm ×3mm filter paper. It is the position that various drugs were infiltrated on. Using Ag－AgCl non-polarizable electrode as channel electrode, the electrode was fixed on the frontal-parietal part and parietal- occipital part by dental cement，under dura mater 0.25 cm. Indifferent electrode was fixed on the tip of nose. All the electrodes were connected with brain electrographic recording. EEG will be recorded 1～1.5h after anesthesia in order to diminish the effect of anesthetic on brain electrographic.
Methods of adding drugs
After pretreated with some drugs(using 500μΜ CMP in CMP group, 10mM carbenoxolone sodium in CAR group and saline in control group), the basical EEG was recorded for half an hour. After that, 4-AP, a kind of inducing Epilepsy drug, was administrated so that EEG induced by Epilepsy was continuously recorded for an hour.
The Tracing of EEG in 3h group is different from it in other groups. In 3h group, after basical EEG was recorded for half an hour, the EEG induced CMP, CAR and saline was investigated for half an hour.
Main observing markers included in latent period, the amount of epilepsy waves within 15 minutes after the first epilepsy wave, average amplitude and lasting tempo of seizure.
The distribution
目 的
本研究采用先进的实验手段，从分子水平探讨CX32和CX43在癫痫中变化，阐明何种CX形成的GJ在癫痫活动中起主要作用，为针对GJ发展新的抗癫痫药物确定靶点。合成特异性阻断GJ的连接蛋白拟似肽（CMP），并观察其作用, 以进一步针对该靶点的抗癫痫研究与治疗奠定基础。
方 法
雄性Wistar 大鼠250只， 正常对照组25只。手术对照组25只。KA致痫组200只，分别按3小时、6小时、12小时、24小时、72小时、7天、15天、30天时间点分为8组, 每组25只。以上各组又分三个小组，CMP组、甘珀酸(CAR)组、生理盐水组，每一个小组5只，进行脑电图描记（共150只）。剩余的100只按时间段分别进行Western blot及
免疫组化分析。
致痫方法 将大鼠固定于立体定位仪上，取头颅正中菱形切口，暴露颅骨及前卤、后卤。右侧杏仁核基底外侧核的坐标位置为前囟后3.5 mm，中线右侧旁开4.5mm，硬脑膜下7.5mm。按上述右侧杏仁核坐标，注入海人藻酸(KA)1μl，对照组为PBS注射液1μl。
脑电描记方法 将大鼠头部固定在立体定位仪上，身体用胶带固定。取头颅正中纵向切口，暴露颅骨及前卤、后卤。用小型牙科钻，以前囟后2.5mm, 中线左侧旁开2.5 mm 为中心, 去除颅骨3 mm×3mm 范围, 除去硬脑膜, 暴露皮层感觉运动区。被暴露的皮层面用3 mm ×3mm大小的干净滤纸片盖住以此保持体温和湿度。在此处局部浸润各种药物。用A g－A gCl 乏极化电极作为引导电极，分别牙科水泥固定在额顶部及顶枕部，即暴露皮层的前后两端，硬膜下0.25 cm。无关电极安置于鼻尖部。电极接到日本产EEG-7209型脑电记录仪上。 麻醉1～1.5小时后开始记录脑电，以尽量减少麻醉药对脑电的影响。
用药方法 先预防用药（多肽组用CMP, 浓度为500μΜ；CAR组用甘珀酸钠，浓度为10mM; 生理盐水对照组用生理盐水，滴入到盖在皮层上的滤纸片上）记录基础脑电30分钟, 再给致痫剂4－AP（将药物结晶体放到盖在皮层上的滤纸片上, 直到脑电描记结束，以将其充分融解、浸润到皮层脑组织）, 以引发痫性脑电的发放，连续描记1 小时。
3小时组的用药和脑电描记方法于其他时间段有所不同，此组描记脑电共一个小时，先未用任何药物的情况下记录基础脑电30分钟，而后用CMP、CAR及生理盐水（浓度同上），再描记脑电30分钟，其余同上。
主要观察潜伏期、出现第一个癫痫波开始15分钟内的癫痫波发放的总数、平均振幅和1小时内癫痫发作持续时间。
免疫组化方法 主要观察不同组别、不同脑区、不同时间段CX32和CX43阳性细胞的分布及表达数目。
Western blot方法 主要观察不同组别、不同脑区、不同时间段CX32和CX43的表达量的变化。
结 果
1．所建立的KA致痫模型成功率为96.4%，均出现Racine 分级Ⅳ级以上发作及相应的癫痫波发放。
2. KA致痫后脑组织病理形态学观察：
早期以神经元变性为主并有少许神经细胞坏死。中期KA注射组的颞顶叶皮层及海马区病变进一步加重，不同程度的神经元脱失及胶质细胞增生和毛细血管增多的改变。后期主要以神经细胞脱失，胶质细胞及毛细血管增生为主的病变。以上改变均以海马CA1和CA3区表现得最为严重，齿状回改变不明现。
3. KA致痫大鼠CX32表达的变化
免疫组化法 正常海马各区及皮层CX32阳性细胞稀少，胞浆与胞膜着色。KA致痫后大鼠的大脑皮层及海马均有CX32阳性表达。KA致痫后3小时大鼠的海马各区及皮层CX32的表达迅速增多，第3天达高峰，后逐渐下降。到第30天时阳性细胞数仍多于对照组。KA致痫后各时间组CX32阳性表达的细胞数与对照组相比，差异有极显著性，P＜0.01，手术对照组与正常对照组相比CX32阳性细胞数差异无显著性，P＞0.05。皮层与海马相比CX32阳性细胞数差异有显著性，P＜0.05。海马CA1、CA3及CA4区CX32阳性细胞数较多，其中CA3区表现明显，CA2和DG区变化不明现。
Western blot法 正常海马各区及皮层CX32表达量很少。KA致痫后大鼠的大脑皮层及海马均有CX32阳性表达。KA致痫后3小时大鼠的海马各区及皮层CX32的表达量迅速增多，第3天达高峰，后逐渐下降。到第30天时其表达量仍高于对照组。KA致痫后各时间组CX32表达量与对照组相比，差异有极显著性，P＜0.01，手术对照组与正常对照组相比CX32表达量差异无显著性，P＞0.05。皮层与海马相比CX32表达量差异有显著性，P＜0.05。
4. KA致痫大鼠CX43表达的变化
免疫组化法 正常海马各区及皮层CX43阳性细胞稀少，胞浆与胞膜着色。KA致痫后大鼠的大脑皮层及海马均有CX43阳性表达。KA致痫后3小时大鼠的海马各区及皮层CX43阳性细胞数逐渐增多，时程越长
阳性细胞数目越多。KA致痫后各时间组
Epilepsy is a kind of common disease in nervous system and it is a chronic disease induced by multi-etiological factors. It is characterized by brain neuron’s repeated and excessive super-synchronization discharging, which induces transitory and episodic dysencephalia. Prevalence rate of epilepsy is about 0.46％ and incidence rate is 37/100,000/ year. Drug treatment is a important method to epilepsy. 65% of epilepsy can be cured by drug treatment, however, still 35% of it is not effective to drug. At present, a lot of experiments indicate that epilepsy is related to GJ. However, it is not so clear. that which kind of connexin in forming GJ play important role in epilepsy activity.
AIM
Present study made use of advanced experimental method to observe the change of CX32 and CX43 in epilepsy on molecular level so that which kind of connexin in formting GJ play important role in epilepsy was clarified. The finding can define the target that new antiepileptic will act on. CMP, a kind of synthetic specific blocker of GJ, was used to study antiepileptic, which established the basis of the study and therapy of epileptic.
Method
Wistar rats of male were divided into several groups. There are 25 rats in normal matched control group and operation matched control group respectively and 200 rats in epileptic group induced by KA. Epileptic group was divided into 8 group on the order of 3
hours,6 hours,12 hourses,24 hourses,72 hourses,7 dayses,15 days and 30days. Above each was divided into three groups CMP group, CAR group and saline group, and each group has 5 rats. Above 150 rats were applied to tracing of EEG and surplus 100 rats were applied to Western blot and immunohistochemical analysis according to time course.
Method of making epileptic model
Rats was fixed on stereotaxic apparatus and take the rhombus slices from the skull center so that cranium, anterior fontanelle and posterior fontanelle was exposured .The position of basiolateral nuclear in right nucleus amygdalae is on the behind of the anterior fontanelle 3.5mm, on the right side of the centerline 4.5mm and under the dura 7.5mm. According to the coordinate of nucleus amygdalae ,KA was injiected into nucleus amygdalae and 1μl PBS was injected as control.
Tracing of Electro encephalogram
Rats was fixed on stereotaxic apparatus and their body were fixed with adhesive tape.Take the center and lengthways slice on the skull so that cranium , anterior fontanelle and posterior fontanelle was exposured. On the behind anterior fontanelle 2.5mm and on the left side of the centerline 2.5mm, take 3 mm×3mm skull slice away and remove the hard meninges with small dental drill so that cortex sensorimotor area was exposed. Keep the temperature and degree of wetness of the exposed cortex with 3 mm ×3mm filter paper. It is the position that various drugs were infiltrated on. Using Ag－AgCl non-polarizable electrode as channel electrode, the electrode was fixed on the frontal-parietal part and parietal- occipital part by dental cement，under dura mater 0.25 cm. Indifferent electrode was fixed on the tip of nose. All the electrodes were connected with brain electrographic recording. EEG will be recorded 1～1.5h after anesthesia in order to diminish the effect of anesthetic on brain electrographic.
Methods of adding drugs
After pretreated with some drugs(using 500μΜ CMP in CMP group, 10mM carbenoxolone sodium in CAR group and saline in control group), the basical EEG was recorded for half an hour. After that, 4-AP, a kind of inducing Epilepsy drug, was administrated so that EEG induced by Epilepsy was continuously recorded for an hour.
The Tracing of EEG in 3h group is different from it in other groups. In 3h group, after basical EEG was recorded for half an hour, the EEG induced CMP, CAR and saline was investigated for half an hour.
Main observing markers included in latent period, the amount of epilepsy waves within 15 minutes after the first epilepsy wave, average amplitude and lasting tempo of seizure.
The distribution
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