细胞周期调控对慢性癫痫大鼠反应性星形胶质细胞增殖活化以及神经元凋亡的影响
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摘要
目的观察细胞周期素依赖性蛋白激酶(Cyclin-dependent protein kinases,CDK)的选择性抑制剂olomoucine对戊四氮点燃大鼠慢性癫痫模型反应性星形胶质细胞(Astrocyte,AST)增殖活化和凋亡的影响,以及对神经元凋亡的影响,探讨细胞周期调控与慢性癫痫反复发作的关系。
方法建立戊四氮(PTZ)点燃的大鼠慢性癫痫模型,随机分为生理盐水对照组,戊四氮组和olomoucine+戊四氮组,在完全点燃后1d、3d、7d、21d、30d、49d断头取脑行冰冻切片,利用共聚焦显微镜结合免疫荧光化学方法(immunofluores- cence staining)和原位末端标记法(TdT-mediated dUTP-biotin nick end labeling,TUNEL),观察戊四氮完全点燃后各组不同时期皮层及海马胶质细胞纤维酸性蛋白(glial fibrillary acidic protein ,GFAP)、神经元凋亡(neuronal apoptosis)、星形胶质细胞凋亡(astrocytic apoptosis)的动态变化。
结果1.慢性癫痫模型被完全点燃后大鼠海马及皮层星形胶质细胞(AST)增殖活化,选择性CDK抑制剂olomoucine干预后能抑制AST的增殖活化;2.慢性癫痫模型完全点燃后星形胶质细胞增殖活化的同时存在AST凋亡增加,选择性CDK抑制剂olomoucine部分减少AST凋亡;3.戊四氮完全点燃的慢性癫痫模型各时期神经元凋亡明显高于生理盐水对照组(p<0.05); PTZ+olo组与生理盐水相比,早期神经元凋亡(1d,3d,7d)显著增加(p<0.05),晚期无显著性差异(p>0.05); PTZ+olo组与PTZ组相比神经元凋亡明显减少(p<0.05),olomoucine明显减少了慢性癫痫大鼠海马及皮层脑区神经元凋亡,具有神经保护作用;4.选择性CDK抑制剂olomoucine并不能抑制慢性癫痫模型完全点燃,且早期有促痫性发作。
结论癫痫反复发作可促使神经细胞细胞周期(cell cycle)启动,AST反应性增殖活化,同时神经细胞凋亡增加。CDK选择性细胞周期抑制剂olomoucine可以调控细胞周期,抑制AST的反应性肥大、活化和增殖,减少神经元的凋亡,并能部分减少胶质细胞凋亡,为痫性发作的神经保护提供新靶点。
Abstract Object:To study the effect of Cyclin-dependent protein kinases selective inhibitor olomoucine on the activation and proliferation and of AST,and on astrocytic apoptosis and on neuronal apoptosis in pentylenetrazol induced chronic epileptic rats.to explore the effect of cell cycle regulation on chronic epilepsy.
Methods: The chronic epileptic model was induced by Pentylenetetrazol ( PTZ ) .Rats were randomly divided into 3 groups:sham-operated control groups(are treated by physiological saline);PTZ group and Olomoucine+PTZ group.The experimental rats were sacrificed on day 1,3,7,21,30,and 49 after complete kindling.The brain was taken, and then the apoptosis of neurons and astrocytes was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL).The expression of NeuN and GFAP were observed by immunofluorescence staining.To observed the dynamic change of GFAP、neuronal apoptosis、astrocytic apoptosis in cortical or hippocampus after treated with Olomoucine - a selective CDK inhibitor.
Result:1.After kindling, As a response to“brain injury”, AST in cortical and hippocampus area appeared hypertrophy、proliferation,the number Of the GFAP-positive cells increased. After treated with Olomoucine,the hypertrophy proliferation of AST mitigated;the number of the GFAP-positive cells decreased. 2.After kindling,the number of TUNEL-positive astrocytes in cortical or hippocampus significantly increased , After treated with Olomoucine , the number of TUNEL-positive astrocytes in cortical or hippocampus partly decreased.3.After kindling,in the PTZ groups,the number of TUNEL-positive neurons in cortex or hippocampus prominent increased compared with that of the control group(p<0.01). Compared with PTZ groups,the number of TUNEL-positive neurons decreased significantly in Olomoucine+PTZ groups(p<0.05).In Olomoucine+PTZ groups, the number of TUNEL-positive neurons increased significantly in the early period (1,3,7d), notablely on day 1(p<0.01) ,but shows little difference in the later phase( 21,30,49d,p>0.05),compared with that of the control group. 4.Cell cycle inhibitor olomoucine can not prevent the chronic epilepsia model was complete kindling.In the early period,the chronic epilepsia rats were easily kindled after treated with Olomoucine.
Conclusion:After kindling, AST entered cell cycle and appeared proliferation and activation, and astrocytic apoptosis increased, neuronal apoptosis increased prominently as well.Olomoucine, a selective CDK inhibitor could inhibit the hypertrophy, activation and proliferation of astrocytes effectively through regulating cell cycle. Our results also suggest that cell cycle regulation can reduce astrocytic and neuronal apoptosis after kindling . which might provide a new target for neuroprotection during chronic epilepsy.
方法建立戊四氮(PTZ)点燃的大鼠慢性癫痫模型,随机分为生理盐水对照组,戊四氮组和olomoucine+戊四氮组,在完全点燃后1d、3d、7d、21d、30d、49d断头取脑行冰冻切片,利用共聚焦显微镜结合免疫荧光化学方法(immunofluores- cence staining)和原位末端标记法(TdT-mediated dUTP-biotin nick end labeling,TUNEL),观察戊四氮完全点燃后各组不同时期皮层及海马胶质细胞纤维酸性蛋白(glial fibrillary acidic protein ,GFAP)、神经元凋亡(neuronal apoptosis)、星形胶质细胞凋亡(astrocytic apoptosis)的动态变化。
结果1.慢性癫痫模型被完全点燃后大鼠海马及皮层星形胶质细胞(AST)增殖活化,选择性CDK抑制剂olomoucine干预后能抑制AST的增殖活化;2.慢性癫痫模型完全点燃后星形胶质细胞增殖活化的同时存在AST凋亡增加,选择性CDK抑制剂olomoucine部分减少AST凋亡;3.戊四氮完全点燃的慢性癫痫模型各时期神经元凋亡明显高于生理盐水对照组(p<0.05); PTZ+olo组与生理盐水相比,早期神经元凋亡(1d,3d,7d)显著增加(p<0.05),晚期无显著性差异(p>0.05); PTZ+olo组与PTZ组相比神经元凋亡明显减少(p<0.05),olomoucine明显减少了慢性癫痫大鼠海马及皮层脑区神经元凋亡,具有神经保护作用;4.选择性CDK抑制剂olomoucine并不能抑制慢性癫痫模型完全点燃,且早期有促痫性发作。
结论癫痫反复发作可促使神经细胞细胞周期(cell cycle)启动,AST反应性增殖活化,同时神经细胞凋亡增加。CDK选择性细胞周期抑制剂olomoucine可以调控细胞周期,抑制AST的反应性肥大、活化和增殖,减少神经元的凋亡,并能部分减少胶质细胞凋亡,为痫性发作的神经保护提供新靶点。
Abstract Object:To study the effect of Cyclin-dependent protein kinases selective inhibitor olomoucine on the activation and proliferation and of AST,and on astrocytic apoptosis and on neuronal apoptosis in pentylenetrazol induced chronic epileptic rats.to explore the effect of cell cycle regulation on chronic epilepsy.
Methods: The chronic epileptic model was induced by Pentylenetetrazol ( PTZ ) .Rats were randomly divided into 3 groups:sham-operated control groups(are treated by physiological saline);PTZ group and Olomoucine+PTZ group.The experimental rats were sacrificed on day 1,3,7,21,30,and 49 after complete kindling.The brain was taken, and then the apoptosis of neurons and astrocytes was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL).The expression of NeuN and GFAP were observed by immunofluorescence staining.To observed the dynamic change of GFAP、neuronal apoptosis、astrocytic apoptosis in cortical or hippocampus after treated with Olomoucine - a selective CDK inhibitor.
Result:1.After kindling, As a response to“brain injury”, AST in cortical and hippocampus area appeared hypertrophy、proliferation,the number Of the GFAP-positive cells increased. After treated with Olomoucine,the hypertrophy proliferation of AST mitigated;the number of the GFAP-positive cells decreased. 2.After kindling,the number of TUNEL-positive astrocytes in cortical or hippocampus significantly increased , After treated with Olomoucine , the number of TUNEL-positive astrocytes in cortical or hippocampus partly decreased.3.After kindling,in the PTZ groups,the number of TUNEL-positive neurons in cortex or hippocampus prominent increased compared with that of the control group(p<0.01). Compared with PTZ groups,the number of TUNEL-positive neurons decreased significantly in Olomoucine+PTZ groups(p<0.05).In Olomoucine+PTZ groups, the number of TUNEL-positive neurons increased significantly in the early period (1,3,7d), notablely on day 1(p<0.01) ,but shows little difference in the later phase( 21,30,49d,p>0.05),compared with that of the control group. 4.Cell cycle inhibitor olomoucine can not prevent the chronic epilepsia model was complete kindling.In the early period,the chronic epilepsia rats were easily kindled after treated with Olomoucine.
Conclusion:After kindling, AST entered cell cycle and appeared proliferation and activation, and astrocytic apoptosis increased, neuronal apoptosis increased prominently as well.Olomoucine, a selective CDK inhibitor could inhibit the hypertrophy, activation and proliferation of astrocytes effectively through regulating cell cycle. Our results also suggest that cell cycle regulation can reduce astrocytic and neuronal apoptosis after kindling . which might provide a new target for neuroprotection during chronic epilepsy.
引文
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2.Norton WT,Aquino DA,et al.Quantitative aspects of reactive gliosis:a review.Neurochem Res;1992 Sep;17(9):877-885.
3.Rao SD,Weiss JH.Excitotoxic and oxidative cross-talk between motor neurons and glia in ALS pathogenesis. Trends Neurosci. 2004 Jan;27(1):17-23.
4.Goldman S. Glia as neural progenitor cells. Trends Neurosci.2003 Nov; 26(11) :590-6.
5. Horner PJ, Palmer TD.New roles for astrocytes: the nightlife of an 'astrocyte'. La vida loca! .Trends Neurosci.2003Nov;26(11):597-603.
6.Newman EA.New roles for astrocytes: regulation of synaptic transmission. Trends Neurosci.2003 Oct;26(10):536-42
7.Ransom B,Behar T,Nederqaard M.New roles for astrocytes (stars at last). Trends Neurosci.2003 Oct;26(10):520-2
8.Bennett MV,et al. New roles for astrocytes: gap junction hemichannels have something to communicate. Trends Neurosci.2003Nov;26(11):610-7
9.Nederqaard M,et al.New roles for astrocytes: redefining the functional archi- tecture of the brain. Trends Neurosci.2003 Oct;26(10):523-30
10.Slezak M,Dfrieqer FW. New roles for astrocytes: regulation of CNS synapto- genesis. Trends Neurosci.2003 Oct;26(10):531-5
11.Meijer L, Borgne A, Mulner O, et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem 1997, 243(1-2): 527-536.
12.Liu DX, Greene LA. Regulation of neuronal survival and death by E2F-dependent gene repression and derepression. Neuron, 2001, 32(3): 425-438.
13.王萍,王伟.神经元细胞周期再进入的研究进展,国际脑血管病杂志,2006,14(9):711-713.
14.Love S. Neuronal expression of cell cycle-related proteins after brain ischaemia in man. Neurosci Lett, 2003, 353(1): 29-32.
15.Husseman JW, Nochlin D, Vincent I. Mitotic activation: A convergent mechanism for a cohort of neurodegenerative diseases. Neurobiol Aging, 2000, 21(6): 815-828.
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