不同抗癫痫药物对体外培养海马神经元存活率及其BDNF和p-CREB表达的影响
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摘要
目的观察不同剂量PB、VAP和LTG对体外培养海马神经元存活影响及细胞内BDNF、p-CREB的表达变化,探索不同抗癫痫药物所致脑损伤的机制。
方法取培养8天的成熟海马神经元,分为LTG组,PB组,VAP组和正常对照组(0.1% DMSO)。根据药物剂量,各组又分为高剂量组,中剂量组和低剂量组,分别为使用LTG12mg/L、8mg/L和4mg/L,PB26mg/L、13mg/L和6.5mg/L,VAP27mg/L、18mg/L和9mg/L。分别在加药后1天、4天、7天用MTT法检测细胞存活数量,免疫组化检测神经细胞BDNF和PCREB的表达变化。
结果(1)加药1d后,PB高剂量组神经元的神经网络连接稀疏,细胞立体感差,光晕稍模糊,其余各药物组变化不明显。(2)加药4d后,高、中剂量PB组细胞均出现退行性变化,轴突变细,培养板背景清晰度差,见部分细胞碎片,同时,加入不同剂量VAP的各组细胞也出现退行性变化,神经网络稀疏,光晕模糊,细胞折光性差,轴突变细,尤以VAP高剂量组变化明显,培养细胞胞体内出现明显气泡,背景见细胞碎片。加入不同剂量LTG的各组细胞也开始出现退化变性,胞内出现少量空泡,光晕模糊,轴突变细,且神经网络明显稀疏,以LTG中、高剂量组细胞变化尤其明显。(3)加药后7天,PB高剂量组神经元的神经网络连接稀疏更明显,在400倍光镜下观察发现,细胞胞体内出现气泡,轴突连续性差,胞体表面光滑性差。VAP高剂量组神经元在400倍光镜下可观察到胞体中出现气泡,PB低、中剂量组,VAP中、低剂量组和LTG各组细胞情况同加药后4天。(4)加药后1天,高剂量PB组存活率显著低于正常对照组(P<0.01);而低、中剂量PB处理组,以及不同剂量LTG处理组和不同剂量VAP处理组的细胞存活率与正常对照组比较无明显差异(P>0.05)。(5)加药后4天,除PB高剂量组外,PB中剂量组的海马神经元增殖率也显著低于对照组(P <0.05),且两组海马神经元增殖率也都显著低于PB低剂量组(P<0.05);不同浓度LTG处理组,VAP处理组存活率显著下降(P<0.05),而不同剂量组之间存活率没有差异(P>0.05)。(6)药物维持作用7天,与对照组比较,各种药物不同剂量对神经元存活率无明显差异(P>0.05)。(7)在不同时间,对同种药物同剂量组进行比较,不同剂量LTG组,中、低剂量PB组,高剂量VAP组细胞存活率随时间改变而下降(P<0.05)。(8)加药后1d,高剂量PB组神经细胞的p-CREB和BDNF表达显著低于对照组和中、低剂量组(P<0.05)。(9)加药4天,中、高剂量PB组细胞的BDNF和p-CREB表达都低于正常对照组(P <0.01)和低剂量PB组(P<0.05);高浓度VAP组细胞的BDNF的表达低于对照组,低、中剂量组(P<0.05),p-CREB的表达低于对照组,低、中剂量组(P<0.01);与对照组和中剂量组比较,BDNF的表达显著降低(P<0.01),同时也低于低剂量组(P<0.05),与对照组比较,高剂量LTG组细胞的p-CREB表达显著降低(P<0.05),同时也低于中、低剂量LTG组(P< 0.05),。(10)加药7天,各药物各浓度组BDNF和p-CREB的表达与对照组比较均无差异(P>0.05)。(11)不同时间,同种药物同剂量比较,中、高剂量PB组,高剂量VAP组和低、中、高剂量LTG组BDNF和p-CREB的表达下降。
结论(1)本试验所用的三种抗癫痫药物,除PB外,LTG、VAP均可造成体外培养的海马神经元死亡。(2)AEDs所致的神经元损伤与剂量存在相关性,尤以高剂量PB的损害最明显,可造成体外培养的海马神经元急性死亡,造成神经元BDNF和p-CREB的表达迅速显著下降。(3)药物持续作用后,不同剂量的丙戊酸、拉莫三嗪均可造成海马神经元死亡,影响神经元BDNF和p-CREB表达的改变,考虑与药物蓄积造成培养环境改变有关。(4)VAP、LTG的体外试验与临床观察存在差异,值得进一步研究差异出现的具体机制。
Objective: To explore the possible affections of neuron survival rate and the change of BDNF and p-CREB induced by different concentration of Lamotrigine, Valproic acid and Phenobarbital.
Methods: The hippocampus was harvested from newborn Sprague - Dawley rats. Primary hippocampal neuron cultures of 8 days in vitro were used and divided randomly into four groups: Valproic acid group, Phenobarbital group, lamotrigine group and 0.1%DMSO used as control group. Lamotrigine group was divided into low concentration (4 mg/ L) , middle concentration(8 mg/ L) ,high concentration(12 mg/ L). Valproic acid group was divided into low concentration (6.5mg/ L), middle concentration (13mg/ L), high concentration (26mg/ L). Phenobarbital group was divided into low concentration (6.5mg/ L), middle concentration (13mg/ L), high concentration (26mg/ L).The BDNF and p-CREB levels were determined by immunohistochemistry, and the cell survival rate was tested by MTT.
Results: (1) 1 day after the drug administration, the light ring of neuron of the high concentration PB group was not bright and the neuritic network began to reduce. Others were the same as the control group. (2) 4 days after the drugs administration,in the high and the middle PB group, all concentration of VAP group and the LTG group, neurons demonstrated degenerative change, the neurites were thin the and the neuritic network began to reduce. The debrises of the neurons as well as bubbles in the neurons were seen in the high and middle concentration PB group and high concentration VAP group. (3) 7 days after the drugs administration, the loss of the fine neuritic network was seen, the neurites were swollen in the PB of high concentration group and the bubble of the neuron cell in the VAP of high concentration group was seen. The other neurons of the other drug groups were the same as the control group. (4)1 day after the drug administration, comparing with the control group, the survival of the neuron of high concentration of PB group decreased significantly(P<0.01). (5)After 4 days adding the drugs, comparing with the control group, the survival of the neuron of all the VAP group, LTG group, the middle and the high concentration PB group decreased significantly (P<0.05). (6) After 7 days adding the drugs, comparing with the control group, the survival of the neuron of all the VAP group, LTG group and PB group did not change significantly.(7)The cell survival rate decreased as the culture time going on with high concentration VAP group , high and middle concentration phenobarbital group and all concentration LTG group (P<0.05).(8)After 1 days adding the drugs, BDNF and p-CREB expressing on the cell were significantly different in the high concentration PB group(P<0.01).(9)After 4 days adding the drugs,comparing with the control group, BDNF and p-CREB expressing on the cell are significantly different in the middle and the high concentration PB group(P<0.05); comparing with the control group,low concentration VAP group and the middle VAP concentration group, the express of the BDNF in the high concentration of VAP, decreaed (P<0.05) and the express of the p-CREB decreaed(P<0.01); comparing with the control group and the middle LTG concentration group, the express of the BDNF in the high concentration of lamotrigine group,decreaed(P<0.01), comparing with the low LTG concentration group, the express of the BDNF in the high concentration of lamotrigine group,decreaed(P<0.05) and comparing with the control group,low concentration LTG group and the middle LTG concentration group, the express of the p-CREB in the high concentration of lamotrigine group,decreaed (P<0.05).(10)After 7 days adding the drugs, comparing with the control group, the expression of the BDNF and p-CREB in all the drug groups did not change significantly(P>0.05).(11)As the time goes by, all the groups, except the low PB concentration, the low and middle concentration VAP group ,the BDNF and p-CREB expressing on the cell are different significantly.
Conclusion:(1)Except of PB, LTG and VAP can affect the cultured neurons’survival rate. (2)The damage caused by the AEDs has relationship with the drug concentration and the high concentration PB can affect the neuron survival rate soon after administration as well as the express of the BDNF and the p-CREB, significantly. (3) VAP and LTG can affect the neuron survival rate when keeping those drugs with the cultured neurons, but only high concentration can effect the BDNF and p-CREB express by changing the culture environment. (4) There is different between the clinical observing and the cell experiment but the mechanism should be discussed deeply further.
方法取培养8天的成熟海马神经元,分为LTG组,PB组,VAP组和正常对照组(0.1% DMSO)。根据药物剂量,各组又分为高剂量组,中剂量组和低剂量组,分别为使用LTG12mg/L、8mg/L和4mg/L,PB26mg/L、13mg/L和6.5mg/L,VAP27mg/L、18mg/L和9mg/L。分别在加药后1天、4天、7天用MTT法检测细胞存活数量,免疫组化检测神经细胞BDNF和PCREB的表达变化。
结果(1)加药1d后,PB高剂量组神经元的神经网络连接稀疏,细胞立体感差,光晕稍模糊,其余各药物组变化不明显。(2)加药4d后,高、中剂量PB组细胞均出现退行性变化,轴突变细,培养板背景清晰度差,见部分细胞碎片,同时,加入不同剂量VAP的各组细胞也出现退行性变化,神经网络稀疏,光晕模糊,细胞折光性差,轴突变细,尤以VAP高剂量组变化明显,培养细胞胞体内出现明显气泡,背景见细胞碎片。加入不同剂量LTG的各组细胞也开始出现退化变性,胞内出现少量空泡,光晕模糊,轴突变细,且神经网络明显稀疏,以LTG中、高剂量组细胞变化尤其明显。(3)加药后7天,PB高剂量组神经元的神经网络连接稀疏更明显,在400倍光镜下观察发现,细胞胞体内出现气泡,轴突连续性差,胞体表面光滑性差。VAP高剂量组神经元在400倍光镜下可观察到胞体中出现气泡,PB低、中剂量组,VAP中、低剂量组和LTG各组细胞情况同加药后4天。(4)加药后1天,高剂量PB组存活率显著低于正常对照组(P<0.01);而低、中剂量PB处理组,以及不同剂量LTG处理组和不同剂量VAP处理组的细胞存活率与正常对照组比较无明显差异(P>0.05)。(5)加药后4天,除PB高剂量组外,PB中剂量组的海马神经元增殖率也显著低于对照组(P <0.05),且两组海马神经元增殖率也都显著低于PB低剂量组(P<0.05);不同浓度LTG处理组,VAP处理组存活率显著下降(P<0.05),而不同剂量组之间存活率没有差异(P>0.05)。(6)药物维持作用7天,与对照组比较,各种药物不同剂量对神经元存活率无明显差异(P>0.05)。(7)在不同时间,对同种药物同剂量组进行比较,不同剂量LTG组,中、低剂量PB组,高剂量VAP组细胞存活率随时间改变而下降(P<0.05)。(8)加药后1d,高剂量PB组神经细胞的p-CREB和BDNF表达显著低于对照组和中、低剂量组(P<0.05)。(9)加药4天,中、高剂量PB组细胞的BDNF和p-CREB表达都低于正常对照组(P <0.01)和低剂量PB组(P<0.05);高浓度VAP组细胞的BDNF的表达低于对照组,低、中剂量组(P<0.05),p-CREB的表达低于对照组,低、中剂量组(P<0.01);与对照组和中剂量组比较,BDNF的表达显著降低(P<0.01),同时也低于低剂量组(P<0.05),与对照组比较,高剂量LTG组细胞的p-CREB表达显著降低(P<0.05),同时也低于中、低剂量LTG组(P< 0.05),。(10)加药7天,各药物各浓度组BDNF和p-CREB的表达与对照组比较均无差异(P>0.05)。(11)不同时间,同种药物同剂量比较,中、高剂量PB组,高剂量VAP组和低、中、高剂量LTG组BDNF和p-CREB的表达下降。
结论(1)本试验所用的三种抗癫痫药物,除PB外,LTG、VAP均可造成体外培养的海马神经元死亡。(2)AEDs所致的神经元损伤与剂量存在相关性,尤以高剂量PB的损害最明显,可造成体外培养的海马神经元急性死亡,造成神经元BDNF和p-CREB的表达迅速显著下降。(3)药物持续作用后,不同剂量的丙戊酸、拉莫三嗪均可造成海马神经元死亡,影响神经元BDNF和p-CREB表达的改变,考虑与药物蓄积造成培养环境改变有关。(4)VAP、LTG的体外试验与临床观察存在差异,值得进一步研究差异出现的具体机制。
Objective: To explore the possible affections of neuron survival rate and the change of BDNF and p-CREB induced by different concentration of Lamotrigine, Valproic acid and Phenobarbital.
Methods: The hippocampus was harvested from newborn Sprague - Dawley rats. Primary hippocampal neuron cultures of 8 days in vitro were used and divided randomly into four groups: Valproic acid group, Phenobarbital group, lamotrigine group and 0.1%DMSO used as control group. Lamotrigine group was divided into low concentration (4 mg/ L) , middle concentration(8 mg/ L) ,high concentration(12 mg/ L). Valproic acid group was divided into low concentration (6.5mg/ L), middle concentration (13mg/ L), high concentration (26mg/ L). Phenobarbital group was divided into low concentration (6.5mg/ L), middle concentration (13mg/ L), high concentration (26mg/ L).The BDNF and p-CREB levels were determined by immunohistochemistry, and the cell survival rate was tested by MTT.
Results: (1) 1 day after the drug administration, the light ring of neuron of the high concentration PB group was not bright and the neuritic network began to reduce. Others were the same as the control group. (2) 4 days after the drugs administration,in the high and the middle PB group, all concentration of VAP group and the LTG group, neurons demonstrated degenerative change, the neurites were thin the and the neuritic network began to reduce. The debrises of the neurons as well as bubbles in the neurons were seen in the high and middle concentration PB group and high concentration VAP group. (3) 7 days after the drugs administration, the loss of the fine neuritic network was seen, the neurites were swollen in the PB of high concentration group and the bubble of the neuron cell in the VAP of high concentration group was seen. The other neurons of the other drug groups were the same as the control group. (4)1 day after the drug administration, comparing with the control group, the survival of the neuron of high concentration of PB group decreased significantly(P<0.01). (5)After 4 days adding the drugs, comparing with the control group, the survival of the neuron of all the VAP group, LTG group, the middle and the high concentration PB group decreased significantly (P<0.05). (6) After 7 days adding the drugs, comparing with the control group, the survival of the neuron of all the VAP group, LTG group and PB group did not change significantly.(7)The cell survival rate decreased as the culture time going on with high concentration VAP group , high and middle concentration phenobarbital group and all concentration LTG group (P<0.05).(8)After 1 days adding the drugs, BDNF and p-CREB expressing on the cell were significantly different in the high concentration PB group(P<0.01).(9)After 4 days adding the drugs,comparing with the control group, BDNF and p-CREB expressing on the cell are significantly different in the middle and the high concentration PB group(P<0.05); comparing with the control group,low concentration VAP group and the middle VAP concentration group, the express of the BDNF in the high concentration of VAP, decreaed (P<0.05) and the express of the p-CREB decreaed(P<0.01); comparing with the control group and the middle LTG concentration group, the express of the BDNF in the high concentration of lamotrigine group,decreaed(P<0.01), comparing with the low LTG concentration group, the express of the BDNF in the high concentration of lamotrigine group,decreaed(P<0.05) and comparing with the control group,low concentration LTG group and the middle LTG concentration group, the express of the p-CREB in the high concentration of lamotrigine group,decreaed (P<0.05).(10)After 7 days adding the drugs, comparing with the control group, the expression of the BDNF and p-CREB in all the drug groups did not change significantly(P>0.05).(11)As the time goes by, all the groups, except the low PB concentration, the low and middle concentration VAP group ,the BDNF and p-CREB expressing on the cell are different significantly.
Conclusion:(1)Except of PB, LTG and VAP can affect the cultured neurons’survival rate. (2)The damage caused by the AEDs has relationship with the drug concentration and the high concentration PB can affect the neuron survival rate soon after administration as well as the express of the BDNF and the p-CREB, significantly. (3) VAP and LTG can affect the neuron survival rate when keeping those drugs with the cultured neurons, but only high concentration can effect the BDNF and p-CREB express by changing the culture environment. (4) There is different between the clinical observing and the cell experiment but the mechanism should be discussed deeply further.
引文
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[1] Deckers CL, Czuczwar SJ, Hekster YA et al. Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed [J]. Epilepsia. 2000:41(10):1364–1374
[2] Kockelmann E, Elger CE, Helmstaedter C et al. Cognitive profile of topiramate as compared with lamotrigine in epilepsy patients on antiepileptic drug polytherapy: relationships to blood serum levels and comedication[J].Epilepsy & Behavior. 2004;5(5):716–721
[3] Werza MA, Schoenberg MR,Meador KJ, et al. Subjective preference for lamotrigine or topiramate in healthy volunteers: Relationship to cognitive and behavioral functioning[J].Epilepsy & Behavior. 2006,8(1): 181–191
[4] Gates JR. Side effect profiles and behavioral consequences of antiepileptic medications [J]. Epilepsy & Behavior. 2000; 1(3):153–159
[5] Glier C, ZietkoM D,Bittigau P. Therapeutic doses of topiramate are not toxic to the developing rat brain[J].Exp Neurol. 2004; 187(2):403-405
[6] Aldenkamp AP,Baker G,Mulder OG. Effects of topiramate on cognition [J]. Neurol Neurosurg Psychiatry.2001, 71(3):134-135
[7] Castel-Branco M, Am?lcar VL,Falcao et al. Relationship between plasma and brain levels and the anticonvulsant effect of lamotrigine in rats [J]. European Journal of Pharmacology.2003, 482(1-3):163– 168
[8] Aldenkamy AP, Krom MD.Newer Antiepileptic Drug and Cognitive issue [J]. Epilepsia. 2003; 44(4):21-29
[9] McDonalda,Najama. The use of lamotrigine, vigabatrin and gabapentin as add-on therapy in intractable epilepsy of childhood [J]. Seizure. 2005; 14(2): 112-116
[10] 周波,周东.抗癫痫药对认知功能影响的研究进展[J].实用医院临床杂志. 2005;2(2):82-84
[11] Meador KJ, Loring DW, Hulihan JF et al. Differential cognitive and behavioral effects of topiramate and valprote [J].Neurology. 2003, 60 (9): 1481-1483
[12] Araujo IM, Ambrosio AF. Neuroxicity induced by antiepileptic drug in culturehippocampal neurons: A comparative study between carbamazapine oxcarbazepine and two new putativw antiepileptic drugs,BIA2-024 BIA2-093[J].Epilepsia. 2004, 45 (12): 1498-1505
[13]陈静,王薇薇,吴逊.奥卡西平?一种新型抗癫痫药物[J].临床神经病学杂志. 2004, 17(1):73
[14] Aldenkamp AP, Krom MC, Reijs R.Newer Antiepileptic Drugs and Cognitive Issues [J]. Epilepsia.2003 ,44 (4), 21–29.
[15] Ortinskia P, Meador KJ, Cognitive side effects of antiepileptic drugs[J]. Epilepsy & Behavior. 2004;5(1):60–65
[16] French JA.Vigabatrin [J]. Epilepsiu. 1999, 40 (5):11-16
[17] Monaco F. Cognitive effects of vigabatrin [J]. Neurology. 1996, 47 (1):6-l1
[18] Dodrill CB, Arnett JL, Sommerville KW, et a1. Effects of differing dosages of vigabatrin on cognitive abilities and quality of life in epilepsy [J]. Epilepsia. 1995, 36 (2):164 -173
[19] Aldenkamp AP, Baker G, Mulder OG, et al.A multicenter, randomized clinical study to evaluate the effect on cognitive function of topiramate compared with valproate as add on therapy to carbamazepine in patients with partial onset seizures [J]. Epilepsia. 2000, 41(9):116
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