亚低温对癫痫持续状态脑损伤神经保护机制的实验研究
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摘要
目的：给幼鼠腹腔注射毛果云香碱诱发出SE,研究亚低温对幼鼠海马神经元细胞的保护作用。
方法：选择3周龄Wister雄性大鼠60只,随机分成生理盐水对照组、地西泮组和地西泮+亚低温干预2h组,每组20只。具体分组如下：地西泮组：SE后给予腹腔注射地西泮5mg/kg;地西泮+亚低温干预2h组：SE后给予地西泮的同时给予物理降温干预将深部体温控制在32-34℃之间,并维持2h；生理盐水对照组：腹腔注射生理盐水。各组幼鼠SE开始后3h、6h、24h和72h这4个时间点设定4个亚组。HE染色检测海马CA1和CA3区上高倍视野中正常神经元细胞和坏死神经元数目,定量观察海马神经元细胞坏死情况；TUNEL法检测海马CA1和CA3区相似部位单位面积TUNEL阳性细胞,定量观察海马神经元细胞凋亡情况
结果：1.海马CA1和CA3区的病理改变(HE染色)：生理盐水对照组：CA1和CA3区有3-5层神经元细胞且排列紧密且清晰,细胞形态基本正常,各时间段CA3区神经元形态无明显差别。地西泮组：CA1和CA3区出现明显神经元丢失。3h出现细胞坏死,6h和24h神经元坏死更加明显,72h正常神经元数目减少,神经元排列松散。海马神经元坏死程度为CA3区>CA1区。地西泮+亚低温干预2h组：CA1和CA3区神经元坏死明显减少,6h和24h细胞空泡坏死不明显,72h正常神经元数目未见明显减少,神经元排列尚紧密。自6h起CA1和CA3区神经元坏死百分比明显减少,与地西泮组相比,差异具有统计学意义P<0.05。2.海马CA1和CA3细胞凋亡的改变：生理盐水对照组：海马CA1和CA3区偶见个别细胞核呈棕黄色染色的TUNEL阳性细胞。地西泮组：海马CA1和CA3区6h起TUNEL阳性细胞增多,72hTUNEL阳性细胞明显增多,表现为染色质聚集,圆形或不规则的凋亡小体,染色不均,可见核固缩。自6h起与NS组相比,差异具有统计学意义P<0.05。海马神经元凋亡程度为CA1区>CA3区。地西泮+亚低温干预2h组：与地西泮组相比,CA1和CA3 TUNEL阳性细胞计数明显减少,自24h起与地西泮组相比,差异具有统计学意义P<0.05。
1.结论：1.SE后3h起海马神经元细胞坏死明显,细胞凋亡在SE后6h明显,随着时间的延长至72h,海马神经元细胞坏死和凋亡不断增加。2.在SE后,亚低温能够明显减少海马神经元细胞的坏死和凋亡。
目的：通过NMDAR1与C-JUN的表达变化,研究亚低温在脑损伤病变中起保护作用的机制,为儿童惊厥性脑损伤临床应用亚低温提供实验依据。
方法：选择3周龄Wister雄性大鼠60只,按第一部分分组方法分成3组并按SE后不同时间点分成4亚组。免疫组化检测海马CA1和CA3区NMDAR1与C-JUN蛋白表达水平；采用实时荧光定量PCR法检测海马NMDAR1和C-JUN基因表达水平。
结果：1.海马NMDAR1的改变：生理盐水对照组海马CA1和CA3区NMDAR1免疫阳性神经元细胞主要分布于锥体细胞层,在锥体细胞的树突也有表达,蛋白表达水平稳定；地西泮组：海马CA1和CA3区自6h起NMDAR1蛋白表达水平明显升高,持续性升高并维持至72h,与生理盐水对照组相比,差异具有统计学意义P<0.05；地西泮+亚低温干预2h组：海马CA1和CA3区自24h起NMDAR1蛋白表达水平明显降低,与地西泮组相比,差异具有统计学意义P<0.05。生理盐水对照组NMDAR1基因有稳定的基础水平;地西泮组NMDAR1mRNA在3h表达形成高峰,6h起开始略有下降并维持高水平至72h；地西泮+亚低温干预2h组NMDAR1mRNA在72h表达明显下调,与地西泮组相比,差异有显著意义P<0.05。2.海马C-JUN的改变：生理盐水对照组：海马CA1和CA3区见个别呈棕黄色染色的C-JUN免疫阳性细胞,C-JUN蛋白主要在细胞核和细胞浆中表达;地西泮组：海马CA1和CA3区6h起C-JUN阳性细胞有增多,表现为着色加深或密集浓染,24h阳性细胞明显增多,72hC-JUN阳性细胞较24h有较少。自6h起与NS组相比,差异均具有统计学意义P<0.05；地西泮+亚低温干预2h组：海马CA1和CA3区6h起C-JUN阳性细胞明显增多,与地西泮组相比,差异具有统计学意义P<0.05。24h起C-JUN阳性细胞明显减少,72h进一步减少,与地西泮组相比,差异具有统计学意义P<0.05。生理盐水对照组海马有C-JUN基因有稳定的基础水平：地西泮组C-JUNmRNA于3h上升,6h略有下降,24h又再次上升,72h略有下降并维持较高水平,形成双高峰；地西泮+亚低温干预2h组C-JUNmRNA3h显著上升,6h开始下降,24h显著下降,72h下降至更低水平,在这三个时间点(3h,24h和72h),与地西泮组相比,差异有显著意义P<0.05。
结论：NMDAR1和C-JUN共同参与SE后脑损伤形成,亚低温干预后,NMDAR1mRNA和蛋白表达下调,C-JUNmRNA和蛋白早期表达上调,晚期表达下调。
Objective Intraperitoneal injection of poliocarpine in young rats to induce ststus epilepticus, to study the neuro-protection of hypothermia on hippocampus neurons.
Methods Sixty 3 weeks old male Wister rats were randomly devided into 3 groups. Normal saline (NS) group, SE30min with diazepam (SE30minD)group, SE30min with diazepam+hypothermia(SE30minDH) group,20 rats each group. SE30minD group was given poliocarpine 380mg/kg by intraperitoneal injection to induce SE 30min and diazepam 5mg/kg by intraperitoneal injection to end SE. SE30minDH group was given diazepam 5mg/kg by intraperitoneal injection and core temperature was controlled between 32-34℃for 2 hours by hypothermy with physicalmeasure. NS group was given normal saline by intraperitoneal injection. According to hour 3, 6,24 and 72 after SE, each group was divided into 4 subgroups. The necrosis and apoptosis in hippocampal CA1 and CA3 regions were appraised by HE and TUNEL staining.
Results 1.Necrosis in hippocampal CA1 and CA3 regions (HE staining). Neurons in the NS group were arranged densely and clear,the neuron morphology of each time quantum was normal. In SE30minD group, cell necrosis was seen at 3h and become more obvious at 6h and 24h. At 72h, normal neuron decreased and the arrangement of neuron was loose.The nectotic neurons in CA3 region was more than that in in CA1 region. In SE30minDH group, cell necrosis was also seen at 3h but not become obvious at 6h and 24h. At 72h, the arrangement of neuron was slightly loose. from 6h,the percentage of necrotic neuron in CA1 and CA3 regions singanificantly decreased compared with that of SE30minDgroup. (2) Apoptosis in hippocampal CA1 and CA3 regions. The positive neurons in TUNEL staining sections were apoptotic neurons, in which the cell nucleus were presented brown-yellow fine particle shape, were occasionally found in in hippocampal CA1 and CA3 regions in NS group. From 6h in SE30minD group, TUNEL positive neurons started increasing, and at 72h obviously increased. It showed chromatin condensation,round or irregular apoptotic bodies, nuclear pkynosis. The apoptotic neurons in CA1 region was more than that in in CA3 region. From 6h, TUNEL positive neurons singanificantly increased compared with that of NS group P<0.05. In SE30minDH group, from 24h,TUNEL positive neurons singanificantly decreased compared with that of SE30minDgroup P<0.05.
Conclusions 1.After SE, necrotic neurons were obvious from 3h, and apoptotic neurons were obvious from 6h. With time going by, necrotic and apoptotic neurons increased gruadually.2. After SE, mild hypothermia could protect against cell necrosis and apoptosis.
Objective To study the mechanism of mild hypothermia protection on pathogenesis of brain injury,and to provide experimental data for clinical application of mild hypothermia for brain injury of following recurrent seizures in children. Methods A total of sixty 3 week old male Wister rats were randomly assigned into 3 groups according to different intervention methods and each group was divided into 4 subgroups according to different time point after SE. NMDAR1 and C-JUN protein expression were determined by immunohistochemistry,and NMDAR1 and C-JUN mRNA expressions were determined by real-time PCR.
Results 1.Change of NMDARl:In NS group, NMDAR1-immunoreactivity positive neurons were mainly located in CA1 and CA3 pyramidal layer, and NMDAR1 positive products were also found in Dendrites. The expression of NMDAR1 protein was stable. In SE30minD group, from 6h, the expression of NMDAR1 protein started increasing, and at 72h obviously increased which were significant (P<0.05) compared with NS group. In SE30minDH group, from 24h, the expression of NMDAR1 protein singanificantly decreased compared with that of SE30minDgroup P<0.05. The expression of NMDAR1 mRNA was also stable in NS group. In SE30minD group, it increased and peaked at 3h,and slightly declined since 6h and maintained high level till 72h. In SE30minDH group, it rapidly declined at 24h and fell down to lower level at 72h which was significant (P<0.05)compared with SE30minD group.2.Change of C-JUN:In NS group, C-JUN-immunoreactivity positive neurons,in which the cell nucleus and cytoplasm were presented brown-yellow particle shape, were occasionally found in in hippocampal CA1 and CA3 regions. In SE30minD group, from 6h, C-JUN positive neurons started increasing, at 24h obviously increased, and at 72h slightly declined. From 24h, C-JUN positive neurons singanificantly increased compared with that of NS group P<0.05. In SE30minDH group, at 6h,C-JUN positive neurons singanificantly increased compared with that of SE30minD group P<0.05. From 24h, C-JUN positive neurons singanificantly declined compared with that of SE30minD group P<0.05. The expression of C-JUNmRNA had a basic level in NS group. In SE30minD group, it increased since 3h, slightly declined at 6h, increased again at 24h, slightly declined and remained at higher level at 72h, forming double peaks. In SE30minDH group, it obviously increased at 3h, declined t 6h and further declined at 24h to a lower level at 72h. there was significant difference (P<0.05) compared with SE group at 3 time points(3h,24h and 72h).
Conclusions NMDARl and C-JUN were participated in of SE induced brain injury, mild hypothermia reduced neuron necrosis and apoptosis through down-regulateing expression of NMDAR1 gene and protein, up-regulateing early expression of C-JUN gene and protein, down-regulateing late expression of C-JUN gene and protein.
方法：选择3周龄Wister雄性大鼠60只,随机分成生理盐水对照组、地西泮组和地西泮+亚低温干预2h组,每组20只。具体分组如下：地西泮组：SE后给予腹腔注射地西泮5mg/kg;地西泮+亚低温干预2h组：SE后给予地西泮的同时给予物理降温干预将深部体温控制在32-34℃之间,并维持2h；生理盐水对照组：腹腔注射生理盐水。各组幼鼠SE开始后3h、6h、24h和72h这4个时间点设定4个亚组。HE染色检测海马CA1和CA3区上高倍视野中正常神经元细胞和坏死神经元数目,定量观察海马神经元细胞坏死情况；TUNEL法检测海马CA1和CA3区相似部位单位面积TUNEL阳性细胞,定量观察海马神经元细胞凋亡情况
结果：1.海马CA1和CA3区的病理改变(HE染色)：生理盐水对照组：CA1和CA3区有3-5层神经元细胞且排列紧密且清晰,细胞形态基本正常,各时间段CA3区神经元形态无明显差别。地西泮组：CA1和CA3区出现明显神经元丢失。3h出现细胞坏死,6h和24h神经元坏死更加明显,72h正常神经元数目减少,神经元排列松散。海马神经元坏死程度为CA3区>CA1区。地西泮+亚低温干预2h组：CA1和CA3区神经元坏死明显减少,6h和24h细胞空泡坏死不明显,72h正常神经元数目未见明显减少,神经元排列尚紧密。自6h起CA1和CA3区神经元坏死百分比明显减少,与地西泮组相比,差异具有统计学意义P<0.05。2.海马CA1和CA3细胞凋亡的改变：生理盐水对照组：海马CA1和CA3区偶见个别细胞核呈棕黄色染色的TUNEL阳性细胞。地西泮组：海马CA1和CA3区6h起TUNEL阳性细胞增多,72hTUNEL阳性细胞明显增多,表现为染色质聚集,圆形或不规则的凋亡小体,染色不均,可见核固缩。自6h起与NS组相比,差异具有统计学意义P<0.05。海马神经元凋亡程度为CA1区>CA3区。地西泮+亚低温干预2h组：与地西泮组相比,CA1和CA3 TUNEL阳性细胞计数明显减少,自24h起与地西泮组相比,差异具有统计学意义P<0.05。
1.结论：1.SE后3h起海马神经元细胞坏死明显,细胞凋亡在SE后6h明显,随着时间的延长至72h,海马神经元细胞坏死和凋亡不断增加。2.在SE后,亚低温能够明显减少海马神经元细胞的坏死和凋亡。
目的：通过NMDAR1与C-JUN的表达变化,研究亚低温在脑损伤病变中起保护作用的机制,为儿童惊厥性脑损伤临床应用亚低温提供实验依据。
方法：选择3周龄Wister雄性大鼠60只,按第一部分分组方法分成3组并按SE后不同时间点分成4亚组。免疫组化检测海马CA1和CA3区NMDAR1与C-JUN蛋白表达水平；采用实时荧光定量PCR法检测海马NMDAR1和C-JUN基因表达水平。
结果：1.海马NMDAR1的改变：生理盐水对照组海马CA1和CA3区NMDAR1免疫阳性神经元细胞主要分布于锥体细胞层,在锥体细胞的树突也有表达,蛋白表达水平稳定；地西泮组：海马CA1和CA3区自6h起NMDAR1蛋白表达水平明显升高,持续性升高并维持至72h,与生理盐水对照组相比,差异具有统计学意义P<0.05；地西泮+亚低温干预2h组：海马CA1和CA3区自24h起NMDAR1蛋白表达水平明显降低,与地西泮组相比,差异具有统计学意义P<0.05。生理盐水对照组NMDAR1基因有稳定的基础水平;地西泮组NMDAR1mRNA在3h表达形成高峰,6h起开始略有下降并维持高水平至72h；地西泮+亚低温干预2h组NMDAR1mRNA在72h表达明显下调,与地西泮组相比,差异有显著意义P<0.05。2.海马C-JUN的改变：生理盐水对照组：海马CA1和CA3区见个别呈棕黄色染色的C-JUN免疫阳性细胞,C-JUN蛋白主要在细胞核和细胞浆中表达;地西泮组：海马CA1和CA3区6h起C-JUN阳性细胞有增多,表现为着色加深或密集浓染,24h阳性细胞明显增多,72hC-JUN阳性细胞较24h有较少。自6h起与NS组相比,差异均具有统计学意义P<0.05；地西泮+亚低温干预2h组：海马CA1和CA3区6h起C-JUN阳性细胞明显增多,与地西泮组相比,差异具有统计学意义P<0.05。24h起C-JUN阳性细胞明显减少,72h进一步减少,与地西泮组相比,差异具有统计学意义P<0.05。生理盐水对照组海马有C-JUN基因有稳定的基础水平：地西泮组C-JUNmRNA于3h上升,6h略有下降,24h又再次上升,72h略有下降并维持较高水平,形成双高峰；地西泮+亚低温干预2h组C-JUNmRNA3h显著上升,6h开始下降,24h显著下降,72h下降至更低水平,在这三个时间点(3h,24h和72h),与地西泮组相比,差异有显著意义P<0.05。
结论：NMDAR1和C-JUN共同参与SE后脑损伤形成,亚低温干预后,NMDAR1mRNA和蛋白表达下调,C-JUNmRNA和蛋白早期表达上调,晚期表达下调。
Objective Intraperitoneal injection of poliocarpine in young rats to induce ststus epilepticus, to study the neuro-protection of hypothermia on hippocampus neurons.
Methods Sixty 3 weeks old male Wister rats were randomly devided into 3 groups. Normal saline (NS) group, SE30min with diazepam (SE30minD)group, SE30min with diazepam+hypothermia(SE30minDH) group,20 rats each group. SE30minD group was given poliocarpine 380mg/kg by intraperitoneal injection to induce SE 30min and diazepam 5mg/kg by intraperitoneal injection to end SE. SE30minDH group was given diazepam 5mg/kg by intraperitoneal injection and core temperature was controlled between 32-34℃for 2 hours by hypothermy with physicalmeasure. NS group was given normal saline by intraperitoneal injection. According to hour 3, 6,24 and 72 after SE, each group was divided into 4 subgroups. The necrosis and apoptosis in hippocampal CA1 and CA3 regions were appraised by HE and TUNEL staining.
Results 1.Necrosis in hippocampal CA1 and CA3 regions (HE staining). Neurons in the NS group were arranged densely and clear,the neuron morphology of each time quantum was normal. In SE30minD group, cell necrosis was seen at 3h and become more obvious at 6h and 24h. At 72h, normal neuron decreased and the arrangement of neuron was loose.The nectotic neurons in CA3 region was more than that in in CA1 region. In SE30minDH group, cell necrosis was also seen at 3h but not become obvious at 6h and 24h. At 72h, the arrangement of neuron was slightly loose. from 6h,the percentage of necrotic neuron in CA1 and CA3 regions singanificantly decreased compared with that of SE30minDgroup. (2) Apoptosis in hippocampal CA1 and CA3 regions. The positive neurons in TUNEL staining sections were apoptotic neurons, in which the cell nucleus were presented brown-yellow fine particle shape, were occasionally found in in hippocampal CA1 and CA3 regions in NS group. From 6h in SE30minD group, TUNEL positive neurons started increasing, and at 72h obviously increased. It showed chromatin condensation,round or irregular apoptotic bodies, nuclear pkynosis. The apoptotic neurons in CA1 region was more than that in in CA3 region. From 6h, TUNEL positive neurons singanificantly increased compared with that of NS group P<0.05. In SE30minDH group, from 24h,TUNEL positive neurons singanificantly decreased compared with that of SE30minDgroup P<0.05.
Conclusions 1.After SE, necrotic neurons were obvious from 3h, and apoptotic neurons were obvious from 6h. With time going by, necrotic and apoptotic neurons increased gruadually.2. After SE, mild hypothermia could protect against cell necrosis and apoptosis.
Objective To study the mechanism of mild hypothermia protection on pathogenesis of brain injury,and to provide experimental data for clinical application of mild hypothermia for brain injury of following recurrent seizures in children. Methods A total of sixty 3 week old male Wister rats were randomly assigned into 3 groups according to different intervention methods and each group was divided into 4 subgroups according to different time point after SE. NMDAR1 and C-JUN protein expression were determined by immunohistochemistry,and NMDAR1 and C-JUN mRNA expressions were determined by real-time PCR.
Results 1.Change of NMDARl:In NS group, NMDAR1-immunoreactivity positive neurons were mainly located in CA1 and CA3 pyramidal layer, and NMDAR1 positive products were also found in Dendrites. The expression of NMDAR1 protein was stable. In SE30minD group, from 6h, the expression of NMDAR1 protein started increasing, and at 72h obviously increased which were significant (P<0.05) compared with NS group. In SE30minDH group, from 24h, the expression of NMDAR1 protein singanificantly decreased compared with that of SE30minDgroup P<0.05. The expression of NMDAR1 mRNA was also stable in NS group. In SE30minD group, it increased and peaked at 3h,and slightly declined since 6h and maintained high level till 72h. In SE30minDH group, it rapidly declined at 24h and fell down to lower level at 72h which was significant (P<0.05)compared with SE30minD group.2.Change of C-JUN:In NS group, C-JUN-immunoreactivity positive neurons,in which the cell nucleus and cytoplasm were presented brown-yellow particle shape, were occasionally found in in hippocampal CA1 and CA3 regions. In SE30minD group, from 6h, C-JUN positive neurons started increasing, at 24h obviously increased, and at 72h slightly declined. From 24h, C-JUN positive neurons singanificantly increased compared with that of NS group P<0.05. In SE30minDH group, at 6h,C-JUN positive neurons singanificantly increased compared with that of SE30minD group P<0.05. From 24h, C-JUN positive neurons singanificantly declined compared with that of SE30minD group P<0.05. The expression of C-JUNmRNA had a basic level in NS group. In SE30minD group, it increased since 3h, slightly declined at 6h, increased again at 24h, slightly declined and remained at higher level at 72h, forming double peaks. In SE30minDH group, it obviously increased at 3h, declined t 6h and further declined at 24h to a lower level at 72h. there was significant difference (P<0.05) compared with SE group at 3 time points(3h,24h and 72h).
Conclusions NMDARl and C-JUN were participated in of SE induced brain injury, mild hypothermia reduced neuron necrosis and apoptosis through down-regulateing expression of NMDAR1 gene and protein, up-regulateing early expression of C-JUN gene and protein, down-regulateing late expression of C-JUN gene and protein.
引文
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