腺苷A_(2A)受体阻断剂SCH58261对大鼠杏仁核点燃癫痫模型的影响及作用机制研究
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摘要
目的：目前临床上仍有20%-30%的癫痫患者药物治疗效果较差,不能很好的控制癫痫发作,这部分患者的发作类型主要是颞叶癫痫,因此仍需研究新的抗癫痫药物。杏仁核电点燃模型是模拟人类颞叶癫痫最好的癫痫模型,且对现有的大部分抗癫痫药物耐药。因此应用点燃模型在动物体内研究药物是否具有抗癫痫作用可以为以后的临床药物治疗提供理论基础。近年来研究发现,腺苷A2A受体阻断剂在很多慢性疾病模型中如帕金森病模型可以长时间发挥作用,但是它在不同的癫痫模型中的作用存在争议,在此基础上,本实验研究腺苷A2A受体阻断剂SCH58261对大鼠杏仁核点燃癫痫模型的作用及对点燃进程的影响。
方法：将电极植入Wistar大鼠右侧杏仁核,每天给予500肚的电流刺激,大鼠连续十天在刺激后达到5级发作视为点燃成功。点燃成功后的大鼠,通过腹腔给药的方法,观察SCH58261对模型成功后各发作参数的作用。除此之外,观察药物对杏仁核点燃进程的影响,每天刺激前30min给予SCH58261,记录大鼠每天发作级数及脑电变化。整个实验过程中,严密观察药物对大鼠行为学的影响。
结果：在成功点燃的癫痫模型中,SCH58261(0.005,0.05,0.5mg/kg)对全面性发作阈值(GST)没有影响。以GST(+4μA)为刺激强度,SCH58261(0.005,0.05mg/kg)可以降低杏仁核后放电时间(ADD),运动性发作持续时间(MSD),5级发作持续时问(S5D)和癫痫发作总的持续时间(SD); SCH58261(0.005,0.05mg/kg)对癫痫4级发作潜伏期(S4L)和癫痫发作状态(SS)没有影响；SCH58261(0.5mg/kg)对点燃模型各发作参数均无抑制作用。以2×GST为刺激强度,SCH58261(0.05mg/kg)对ADD和S5D均无明显抑制作用,但可以降低MSD和SD发作时间。SCH58261(0.005,0.05,0.5mg/kg)不影响杏仁核点燃癫痫模型进程。
结论：SCH58261在0.005-0.05mg/kg范围内不能影响杏仁核癫痫模型点燃进程,但可以抑制模型点燃成功后痫性发作。
目的：临床很多颞叶癫痫患者及颞叶癫痫动物模型中都发现海马神经元缺失,并与癫痫反复发作有相关性。减轻海马神经元损伤对治疗癫痫有一定作用。MAPK信号通路与癫痫的关系密切,并且参与细胞生长分化的很多过程,同时它也是腺苷A2A受体的下游信号转导通路之一。本部分实验在此基础上,研究杏仁核点燃癫痫模型海马损伤情况及腺苷A2A受体阻断剂SCH58261对其保护作用以及与MAPKs的关系。
方法：将电极植入Wistar大鼠右侧杏仁核,每天给予500μA的电流刺激,大鼠连续10天在刺激后达到5级发作视为点燃成功。SCH58261干预的大鼠,在每天刺激前30分钟腹腔注射0.05mg/kg药物。成功点燃的大鼠,在最后一次5级发作后2小时处死,尼氏染色法观察各组海马神经元损伤情况,Western blot检测海马JNK、p-JNK、p38、 p-p38、ERK、p-ERK的表达,免疫组化法观察p-JNK、p-p38的表达部位。
结果：尼氏染色结果显示杏仁核点燃大鼠刺激侧海马CA3区有神经元损伤,腹腔注射SCH58261对神经元损伤有保护作用。假手术组、点燃模型组及SCH58261组海马CA3区正常形态神经元计数分别为36.0±2.6,,22.2±1.9,31.2±1.9；各组间差别有统计学意义。Western blot及免疫组化方法显示刺激侧海马CA3区p-JNK、p-p38表达明显增多,SCH58261对其有抑制作用；杏仁核点燃不影响p-ERK的表达。
结论：腹腔注射SCH58261可以减轻杏仁核点燃模型海马CA3区神经元的损伤,其机制可能是通过抑制JNK、p38的活化实现的。
Objective:The current Antiepileptic drugs are not effective in20%-30%of epilepsy patients expecially in temporal lobe epilepsies. There is a need to develop new antiepileptic drugs. Amygdala kindling is one of the most commonly used experimental animal models of temporal lobe epilepsies which have the highest percentage of drug resistance. Experimental drug studies based on kindling model may provide good clues for clinical therapy for epilepsy. The brain neuroprotective effect of A2A receptor antagonists are maintained in chronic noxious brain conditions such as Parkinson's disease without observable peripheral effects. But the role of A2A receptor antagonists in different animal models of epilepsy is controversial. The purpose of this study was to evaluate the effect of adenosine A2A receptor antagonist SCH58261on amygdala-kindled seizures and its potential for epileptogenesis.
Methods:Electrodes were implanted into the right amygdala of adult male Wistar rats. Kindling was accomplished using stimulus strength of500μA applied daily to the amygdala until consecutive ten stage5were induced in rats. Then effect of SCH58261was studied in fully kindled rats after intraperitoneal injection. In addition, the effect on kindling development was evaluated through SCH58261injection30min before daily stimulation. In all experiments, behavioral changes in the rats in response to SCH58261were monitored closely.
Results:In fully amygdala-kindled rats SCH58261(0.005,0.05,0.5mg/kg) had no effect on generalized seizure threshold(GST). In the stimulus intensity of GST(+4μA) SCH58261(0.005,0.05mg/kg) decreased afterdischage duration (ADD), motor seizure duration (MSD), stage5duration (S5D)and seizure duration (SD); it had no influence on stage4latency (S4L) and seizure stage (SS). SCH58261(0.5mg/kg) had no effect on all seizure parameters. In the stimulus intensity of2×GST SCH58261(0.05mg/kg) decreased MSD and SD,but can not affect ADD and S5D. In contrast to the results in fully amygdala-kindled rats, SCH58261(0.005,0.05,0.5mg/kg) had few or no effects on the development of amygdala-kindled seizures.
Conclusion:although SCH58261had no influence on the development of amygdala-kindled seizures, it had potent anticonvulsant profile and little adverse effects at the dosage of0.005-0.05mg/kg, suggesting that the substance was effective against amygdala-kindled seizures.
Objective:Neuronal loss in hippocampus has been found in most patients with the temporal lobe epilepsy(TLE) and animal models simulating TLE;which is relative with recurrent seizures.The protective effect of hippocampus neuron is essential.The mitogen-activated protein kinase family(MAPKs) has been shown to be involved in cell cycle progression, proliferation and differentiation in all organisms including mammals,and considered to correlate with epilepsy.Meanwhile,the adenosine A2A receptors couple to the MAPKs. The purpose of this study was to evaluate the effect of adenosine A2A receptor antagonist SCH58261on hippocampus neuronal loss in amygdala-kindled models and its mechanisms.
Methods:Electrodes were implanted into the right amygdala of adult male Wistar rats. Kindling was accomplished using stimulus strength of500μA applied daily to the amygdala until consecutive10stage5were induced in rats.The animals was injected intraperitoneally SCH582610.05mg/kg30min before daily stimulation in SCH group.All kindled rats was decapitated2h after the tenth stage5seizure.Nissl staining was used to observe neuronal loss in hippocampus.Western blot and immunohistochemistry were performed to test the expression of JNK,p-JNK,p38,p-p38,ERK,p-ERK in hippocampus.
Results:Nissl staining revealed loss of neurons in the CA3of hippocampus in fully amygdala-kindled rats and intraperitoneal injection of SCH58261(0.05mg/kg) was protective.The normal neuron counting of hippocampus CA3was36.0±2.6,22.2±1.9,31.2±1.9in sham group,amygdala-kindled group and SCH group.The difference is statistical significant. Kindling increased the expression of p-JNK and p-p38and had no effect on activation of ERK.SCH58261was inhibitory to the activation of JNK and p38.
Conclusion:Intraperitoneal injection of SCH58261(0.05mg/kg) was protective to neuronal loss of hippocampus CA3in amygdala-kindled rats through inhibiting the activation of JNK and p38.
方法：将电极植入Wistar大鼠右侧杏仁核,每天给予500肚的电流刺激,大鼠连续十天在刺激后达到5级发作视为点燃成功。点燃成功后的大鼠,通过腹腔给药的方法,观察SCH58261对模型成功后各发作参数的作用。除此之外,观察药物对杏仁核点燃进程的影响,每天刺激前30min给予SCH58261,记录大鼠每天发作级数及脑电变化。整个实验过程中,严密观察药物对大鼠行为学的影响。
结果：在成功点燃的癫痫模型中,SCH58261(0.005,0.05,0.5mg/kg)对全面性发作阈值(GST)没有影响。以GST(+4μA)为刺激强度,SCH58261(0.005,0.05mg/kg)可以降低杏仁核后放电时间(ADD),运动性发作持续时间(MSD),5级发作持续时问(S5D)和癫痫发作总的持续时间(SD); SCH58261(0.005,0.05mg/kg)对癫痫4级发作潜伏期(S4L)和癫痫发作状态(SS)没有影响；SCH58261(0.5mg/kg)对点燃模型各发作参数均无抑制作用。以2×GST为刺激强度,SCH58261(0.05mg/kg)对ADD和S5D均无明显抑制作用,但可以降低MSD和SD发作时间。SCH58261(0.005,0.05,0.5mg/kg)不影响杏仁核点燃癫痫模型进程。
结论：SCH58261在0.005-0.05mg/kg范围内不能影响杏仁核癫痫模型点燃进程,但可以抑制模型点燃成功后痫性发作。
目的：临床很多颞叶癫痫患者及颞叶癫痫动物模型中都发现海马神经元缺失,并与癫痫反复发作有相关性。减轻海马神经元损伤对治疗癫痫有一定作用。MAPK信号通路与癫痫的关系密切,并且参与细胞生长分化的很多过程,同时它也是腺苷A2A受体的下游信号转导通路之一。本部分实验在此基础上,研究杏仁核点燃癫痫模型海马损伤情况及腺苷A2A受体阻断剂SCH58261对其保护作用以及与MAPKs的关系。
方法：将电极植入Wistar大鼠右侧杏仁核,每天给予500μA的电流刺激,大鼠连续10天在刺激后达到5级发作视为点燃成功。SCH58261干预的大鼠,在每天刺激前30分钟腹腔注射0.05mg/kg药物。成功点燃的大鼠,在最后一次5级发作后2小时处死,尼氏染色法观察各组海马神经元损伤情况,Western blot检测海马JNK、p-JNK、p38、 p-p38、ERK、p-ERK的表达,免疫组化法观察p-JNK、p-p38的表达部位。
结果：尼氏染色结果显示杏仁核点燃大鼠刺激侧海马CA3区有神经元损伤,腹腔注射SCH58261对神经元损伤有保护作用。假手术组、点燃模型组及SCH58261组海马CA3区正常形态神经元计数分别为36.0±2.6,,22.2±1.9,31.2±1.9；各组间差别有统计学意义。Western blot及免疫组化方法显示刺激侧海马CA3区p-JNK、p-p38表达明显增多,SCH58261对其有抑制作用；杏仁核点燃不影响p-ERK的表达。
结论：腹腔注射SCH58261可以减轻杏仁核点燃模型海马CA3区神经元的损伤,其机制可能是通过抑制JNK、p38的活化实现的。
Objective:The current Antiepileptic drugs are not effective in20%-30%of epilepsy patients expecially in temporal lobe epilepsies. There is a need to develop new antiepileptic drugs. Amygdala kindling is one of the most commonly used experimental animal models of temporal lobe epilepsies which have the highest percentage of drug resistance. Experimental drug studies based on kindling model may provide good clues for clinical therapy for epilepsy. The brain neuroprotective effect of A2A receptor antagonists are maintained in chronic noxious brain conditions such as Parkinson's disease without observable peripheral effects. But the role of A2A receptor antagonists in different animal models of epilepsy is controversial. The purpose of this study was to evaluate the effect of adenosine A2A receptor antagonist SCH58261on amygdala-kindled seizures and its potential for epileptogenesis.
Methods:Electrodes were implanted into the right amygdala of adult male Wistar rats. Kindling was accomplished using stimulus strength of500μA applied daily to the amygdala until consecutive ten stage5were induced in rats. Then effect of SCH58261was studied in fully kindled rats after intraperitoneal injection. In addition, the effect on kindling development was evaluated through SCH58261injection30min before daily stimulation. In all experiments, behavioral changes in the rats in response to SCH58261were monitored closely.
Results:In fully amygdala-kindled rats SCH58261(0.005,0.05,0.5mg/kg) had no effect on generalized seizure threshold(GST). In the stimulus intensity of GST(+4μA) SCH58261(0.005,0.05mg/kg) decreased afterdischage duration (ADD), motor seizure duration (MSD), stage5duration (S5D)and seizure duration (SD); it had no influence on stage4latency (S4L) and seizure stage (SS). SCH58261(0.5mg/kg) had no effect on all seizure parameters. In the stimulus intensity of2×GST SCH58261(0.05mg/kg) decreased MSD and SD,but can not affect ADD and S5D. In contrast to the results in fully amygdala-kindled rats, SCH58261(0.005,0.05,0.5mg/kg) had few or no effects on the development of amygdala-kindled seizures.
Conclusion:although SCH58261had no influence on the development of amygdala-kindled seizures, it had potent anticonvulsant profile and little adverse effects at the dosage of0.005-0.05mg/kg, suggesting that the substance was effective against amygdala-kindled seizures.
Objective:Neuronal loss in hippocampus has been found in most patients with the temporal lobe epilepsy(TLE) and animal models simulating TLE;which is relative with recurrent seizures.The protective effect of hippocampus neuron is essential.The mitogen-activated protein kinase family(MAPKs) has been shown to be involved in cell cycle progression, proliferation and differentiation in all organisms including mammals,and considered to correlate with epilepsy.Meanwhile,the adenosine A2A receptors couple to the MAPKs. The purpose of this study was to evaluate the effect of adenosine A2A receptor antagonist SCH58261on hippocampus neuronal loss in amygdala-kindled models and its mechanisms.
Methods:Electrodes were implanted into the right amygdala of adult male Wistar rats. Kindling was accomplished using stimulus strength of500μA applied daily to the amygdala until consecutive10stage5were induced in rats.The animals was injected intraperitoneally SCH582610.05mg/kg30min before daily stimulation in SCH group.All kindled rats was decapitated2h after the tenth stage5seizure.Nissl staining was used to observe neuronal loss in hippocampus.Western blot and immunohistochemistry were performed to test the expression of JNK,p-JNK,p38,p-p38,ERK,p-ERK in hippocampus.
Results:Nissl staining revealed loss of neurons in the CA3of hippocampus in fully amygdala-kindled rats and intraperitoneal injection of SCH58261(0.05mg/kg) was protective.The normal neuron counting of hippocampus CA3was36.0±2.6,22.2±1.9,31.2±1.9in sham group,amygdala-kindled group and SCH group.The difference is statistical significant. Kindling increased the expression of p-JNK and p-p38and had no effect on activation of ERK.SCH58261was inhibitory to the activation of JNK and p38.
Conclusion:Intraperitoneal injection of SCH58261(0.05mg/kg) was protective to neuronal loss of hippocampus CA3in amygdala-kindled rats through inhibiting the activation of JNK and p38.
引文
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