海马电刺激对耐药性癫痫大鼠脑组织GABA受体表达及钠通道电流的影响
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摘要
目的：建立多药耐药性颞叶癫痫模型,以海马细胞外液GABA浓度、海马细胞GABA(A)和GABA(B)受体表达以及海马CA1区锥体细胞钠通道电流的变化为观察指标,探讨海马电刺激治疗耐药性颞叶癫痫的可能机制。
方法：选用Wistar大鼠230只制作慢性杏仁核点燃癫痫模型,模型制作成功后用经典抗癫痫药苯妥英钠和苯巴比妥进行筛选,根据癫痫大鼠对药物的反应区别出耐药癫痫大鼠及药物敏感大鼠用于下列实验：1)用微透析方法收集脑组织细胞外液,采用高效液相色谱法检测海马电刺激后GABA含量的变化；2)用免疫组织化学方法观察海马电刺激后脑组织内GABA(A)和GABA(B)受体表达的变化；3)用荧光定量PCR方法观察海马电刺激后GABA(A)和GABA(B)受体mRNA表达的变化；4)用膜片钳全细胞记录模式观察海马电刺激后脑细胞钠通道电流的变化。
结果：1)在全部大鼠中成功点燃120只(点燃成功率52%),其中112只大鼠完成筛选过程,筛选出耐药性癫痫大鼠30只(癫痫耐药率26.8%)；2)脑细胞外液GABA浓度的变化：海马刺激组8-9AM和8-9PM两个时段的GABA浓度分别为32.69±7.80(μg/ml)和35.76±6.27(μg/ml),各时段的GABA浓度都明显高于对照组的26.58±6.87(μg/ml)和31.50±4.87 (μg/ml),差异具有显著性(P<0.05)；3)GABA(A)和GABA(B)受体表达的变化：与耐药对照组比较,海马刺激组GABA(A)受体阳性细胞数无明显变化,但其表达的灰度值降低,提示GABA(A)受体表达增强,GABA(B)受体阳性细胞数增多、灰度值降低,表明GABA(B)受体表达增强,差异具有显著性(P<0.05)；4)荧光定量PCR结果表明,海马刺激组GABA(A)和GABA(B)受体mRNA的ΔCt值和2(△△Ct)分别为4.180±0.386和1.120±0.324,与耐药对照组比较,其表达均明显增强(P<0.05)；5)膜片钳全细胞记录观察结果表明,海马刺激组钠通道电流峰值及激活曲线向去极化方向偏移,失活曲线向超极化方向偏移,钠通道失活后恢复时间延长。
结论：海马电刺激可以增加耐药性颞叶癫痫大鼠脑细胞外液GABA浓度,增加脑组织GABA(A)和GABA(B)受体的含量,增加GABA(A)和GABA(B)受体mRNA的表达,并可降低脑细胞兴奋性,减少癫痫性电活动的产生。
Objective:To establish a multi-drug resistant model of temporal lobe epilepsy, and the extracellular levels of GABA, the expression of GABA(A) and GABA(B) receptors, the mRNA expression of GABA(A) and GABA(B) receptors, the sodium current of pyramidal neurons in CA1 areas of the hippocampus were used as indexes to observe the effect of hippocampal stimulation on pharmacoresistant epileptic rats.
Methods:Two hundreds and thirty Wistar rats were selected to prepare the amygdaloid kindled model of epilepsy by chronic stimulation of amygaloid basal lateral nucleus. After the kindled model of epilepsy was prepared successfully, pharmacoresistant epileptic rats were selected according their response to phenobabital and phenytoin. The selected pharmacoresistant epileptic rats were divided into a hippocampal stimulation group and a pharmacoresistant control group, and the following experiments were performed.1) Extracellular fluid were collected by microdialysis and the samples were used to determine the levels of GABA by HPHC method after hippocampal stimulation;2) Immunohistochemical method was used to detect the expression of GABA(A) and GABA(B) receptors; 3) Real-time PCR were used to detect and quantitate the expression of GABA(A) and GABA(B) mRNA; 4) The whole-cell recording technique by patch-clamp was used to observe the changes of sodium current of hippocampal pyramidal neurons.
Results:A total of 120 rats were kindled successfully in all the 230 Wistar rats, the rate of kindling was 52%. Thirty pharmacoresistant epileptic rats were selected from the kindled model by their responses to phenobabital and phenytion. The pharmacoresistant epileptic rats in hippocampal stimulation group underwent stimulation with low frequency for two weeks and compared with the pharmacoresistant control group. The results were as follows:The extracellular level of GABA was increased in different stages as compared with the control group; The up-regulation of GABA(A) and GABA(B) receptors were observed, also the expression of GABA(A) and GABA(B) receptor mRNA, a significant difference was noted as compared with the pharmacoresistant control group; The sodium current of hippocampal pyramidal neurons in CA1 areas was inhibited by hippocampal stimulation.
Conclusions:Hippocampal stimulation might up-regulate the expression of GABA(A) and GABA(B) receptors, increase the extracellular levels of GABA in brain tissues, and inhibit the sodium channel current of pyramidal neurons in CA1 areas of hippocampus. The mechanism of hippocampal stimulation in the treatment of pharmacoresistant epilepsy might be achieved partly by increasing the function of GABA-ergic system and inhibiting the sodium channel current so as to decrease the excitability of hippocampal neurons.
方法：选用Wistar大鼠230只制作慢性杏仁核点燃癫痫模型,模型制作成功后用经典抗癫痫药苯妥英钠和苯巴比妥进行筛选,根据癫痫大鼠对药物的反应区别出耐药癫痫大鼠及药物敏感大鼠用于下列实验：1)用微透析方法收集脑组织细胞外液,采用高效液相色谱法检测海马电刺激后GABA含量的变化；2)用免疫组织化学方法观察海马电刺激后脑组织内GABA(A)和GABA(B)受体表达的变化；3)用荧光定量PCR方法观察海马电刺激后GABA(A)和GABA(B)受体mRNA表达的变化；4)用膜片钳全细胞记录模式观察海马电刺激后脑细胞钠通道电流的变化。
结果：1)在全部大鼠中成功点燃120只(点燃成功率52%),其中112只大鼠完成筛选过程,筛选出耐药性癫痫大鼠30只(癫痫耐药率26.8%)；2)脑细胞外液GABA浓度的变化：海马刺激组8-9AM和8-9PM两个时段的GABA浓度分别为32.69±7.80(μg/ml)和35.76±6.27(μg/ml),各时段的GABA浓度都明显高于对照组的26.58±6.87(μg/ml)和31.50±4.87 (μg/ml),差异具有显著性(P<0.05)；3)GABA(A)和GABA(B)受体表达的变化：与耐药对照组比较,海马刺激组GABA(A)受体阳性细胞数无明显变化,但其表达的灰度值降低,提示GABA(A)受体表达增强,GABA(B)受体阳性细胞数增多、灰度值降低,表明GABA(B)受体表达增强,差异具有显著性(P<0.05)；4)荧光定量PCR结果表明,海马刺激组GABA(A)和GABA(B)受体mRNA的ΔCt值和2(△△Ct)分别为4.180±0.386和1.120±0.324,与耐药对照组比较,其表达均明显增强(P<0.05)；5)膜片钳全细胞记录观察结果表明,海马刺激组钠通道电流峰值及激活曲线向去极化方向偏移,失活曲线向超极化方向偏移,钠通道失活后恢复时间延长。
结论：海马电刺激可以增加耐药性颞叶癫痫大鼠脑细胞外液GABA浓度,增加脑组织GABA(A)和GABA(B)受体的含量,增加GABA(A)和GABA(B)受体mRNA的表达,并可降低脑细胞兴奋性,减少癫痫性电活动的产生。
Objective:To establish a multi-drug resistant model of temporal lobe epilepsy, and the extracellular levels of GABA, the expression of GABA(A) and GABA(B) receptors, the mRNA expression of GABA(A) and GABA(B) receptors, the sodium current of pyramidal neurons in CA1 areas of the hippocampus were used as indexes to observe the effect of hippocampal stimulation on pharmacoresistant epileptic rats.
Methods:Two hundreds and thirty Wistar rats were selected to prepare the amygdaloid kindled model of epilepsy by chronic stimulation of amygaloid basal lateral nucleus. After the kindled model of epilepsy was prepared successfully, pharmacoresistant epileptic rats were selected according their response to phenobabital and phenytoin. The selected pharmacoresistant epileptic rats were divided into a hippocampal stimulation group and a pharmacoresistant control group, and the following experiments were performed.1) Extracellular fluid were collected by microdialysis and the samples were used to determine the levels of GABA by HPHC method after hippocampal stimulation;2) Immunohistochemical method was used to detect the expression of GABA(A) and GABA(B) receptors; 3) Real-time PCR were used to detect and quantitate the expression of GABA(A) and GABA(B) mRNA; 4) The whole-cell recording technique by patch-clamp was used to observe the changes of sodium current of hippocampal pyramidal neurons.
Results:A total of 120 rats were kindled successfully in all the 230 Wistar rats, the rate of kindling was 52%. Thirty pharmacoresistant epileptic rats were selected from the kindled model by their responses to phenobabital and phenytion. The pharmacoresistant epileptic rats in hippocampal stimulation group underwent stimulation with low frequency for two weeks and compared with the pharmacoresistant control group. The results were as follows:The extracellular level of GABA was increased in different stages as compared with the control group; The up-regulation of GABA(A) and GABA(B) receptors were observed, also the expression of GABA(A) and GABA(B) receptor mRNA, a significant difference was noted as compared with the pharmacoresistant control group; The sodium current of hippocampal pyramidal neurons in CA1 areas was inhibited by hippocampal stimulation.
Conclusions:Hippocampal stimulation might up-regulate the expression of GABA(A) and GABA(B) receptors, increase the extracellular levels of GABA in brain tissues, and inhibit the sodium channel current of pyramidal neurons in CA1 areas of hippocampus. The mechanism of hippocampal stimulation in the treatment of pharmacoresistant epilepsy might be achieved partly by increasing the function of GABA-ergic system and inhibiting the sodium channel current so as to decrease the excitability of hippocampal neurons.
引文
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[1]Blumenfeld H, Lampert A, Klein JP, et al. Role of hippocampal sodium channel Nav1.6 in kindling epileptogenesis[J]. Epilepsia,2009; 50(1):44-55.
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[3]Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs[J]. Nat Rev Neurosci, 2004; 5(7):553-564.
[4]Rudolph U, Mohler H. GABA-based therapeutic approaches:GABAA receptor subtype functions[J]. Curr Opin Pharmacol,2006; 6(1):18-23.
[5]Meldrum BS, Rogawski MA. Molecular targets for antiepileptic drug development[J]. Neurotherapeutics,2007; 4(1):18-61.
[6]Remy S, Gabriel S, Urban BW, et al. A novel mechanism underlying drug resistance in chronic epilepsy[J]. Ann Neurol,2003; 53(4):469-479.
[7]Jandova K, Pasler D, Antonio LL, et al. Carbamazepine-resistance in the epileptic dentate gyrus of human hippocampal slices[J]. Brain,2006; 129(Pt 12):3290-3306.
[8]Jeub M, Beck H, Siep E, et al. Effect of phenytoin on sodium and calcium currents in hippocampal CA1 neurons of phenytoin-resistant kindled rats[J]. Neuropharmacology,2002; 42(1):107-116.
[9]Schmidt D, Loscher W. Drug resistance in epilepsy:putative neurobiologic and clinical mechanisms[J]. Epilepsia,2005; 46(6):858-877.
[10]Pollo C, Villemure JG. Rationale, mechanisms of efficacy, anatomical targets and future prospects of electrical deep brain stimulation for epilepsy[J]. Acta Neurochir Suppl,2007; 97(Pt2):311-320.
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[13]Weiss SR, Eidsath A, Li XL, et al. Quenching revisited:low level direct current inhibits amygdala-kindled seizures[J].Exp Neurol,1998; 154(1):185-192.
[14]Weiss SR, Li XL, Rosen JB, et al. Quenching:inhibition of development and expression of amygdala kindled seizures with low frequency stimulation[J]. Neuroreport,1995; 6(16):2171-2176.
[15]Wyckhuys T, De Smedt T, Claeys P, et al. High frequency deep brain stimulation in the hippocampus modifies seizure characteristics in kindled rats[J]. Epilepsia,2007; 48(8):1543-1550.
[16]Wyckhuys T, Raedt R, Vonck K, et al. Comparison of hippocampal Deep Brain Stimulation with high (130Hz) and low frequency (5Hz) on afterdischarges in kindled rats[J]. Epilepsy Res; 88(2-3):239-246.
[17]Tellez-Zenteno JF, McLachlan RS, Parrent A, et al. Hippocampal electrical stimulation in mesial temporal lobe epilepsy[J]. Neurology,2006; 66(10):1490-1494.
[18]Yamamoto J, Ikeda A, Satow T, et al. Low-frequency electric cortical stimulation has an inhibitory effect on epileptic focus in mesial temporal lobe epilepsy[J]. Epilepsia,2002; 43(5):491-495.
[19]Yamamoto J, Ikeda A, Kinoshita M, et al. Low-frequency electric cortical stimulation decreases interictal and ictal activity in human epilepsy[J]. Seizure,2006; 15(7):520-527.
[20]Velasco M, Velasco F, Velasco AL, et al. Subacute electrical stimulation of the hippocampus blocks intractable temporal lobe seizures and paroxysmal EEG activities[J]. Epilepsia,2000; 41(2):158-169.
[21]Velasco F, Velasco M, Velasco AL, et al. Electrical stimulation for epilepsy:stimulation of hippocampal foci[J]. Stereotact Funct Neurosurg,2001; 77(1-4):223-227.
[22]Vonck K, Boon P, Goossens L, et al. Neurostimulation for refractory epilepsy[J]. Acta Neurol Belg,2003; 103(4):213-217.
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