经鼻给予转化生长因子-β1对氯化锂—匹罗卡品诱导的癫痫持续状态大鼠海马神经元的保护作用
|
摘要
目的:运用无创、简便有效的鼻腔给药方法,将TGFβ1直接递送到癫痫持续状态(SE)大鼠中枢神经系统并避开血脑屏障(BBB)的阻隔,探讨TGFβ1对氯化锂-匹罗卡品所致癫痫持续状态大鼠海马神经元的保护作用及其潜在的机制。
方法:健康雄性SD大鼠60只,随机分为TGF组、Pilo组和正常对照组(Control)。建立氯化锂-匹罗卡品癫痫持续状态(Lithium-Pilocarpine induced status epilepticus)模型。SE后50 min,注射地西泮10 mg/kg终止SE。正常对照组大鼠采用等量的0.9%氯化钠溶液替代匹罗卡品。TGF组大鼠经鼻给予重组人TGFβ1,同时Pilo组和Control组经鼻给予相同容量的生理盐水。SE后6 h、24 h、48 h和72 h,开胸灌注取脑行冠状切片。应用HE染色、TUNEL染色、Fluoro-Jade B (FJB)荧光染色法分别观察各组大鼠海马神经元的形态结构变化、原位凋亡及变性死亡情况。并采用免疫组化方法检测凋亡相关基因Bcl-2、Bax及Caspase-3的蛋白表达。
结果:(1)正常对照组大鼠海马神经元排列整齐,胞浆透明,细胞核呈圆形或椭圆形,染色质分布均匀,核仁清晰;SE后6 h各组大鼠海马CA1、CA3及DG区部分细胞排列紊乱,胞体收缩呈三角形或极不规则,胞核固缩,结构不清;24 h后嗜伊红浓染显著,神经元坏死崩解逐渐增多;其中Pilo组SE后72 h达高峰。SE后24 h、48 h、72 h,TGF组海马神经元形态结构恶变数量、程度均较Pilo组减轻。(2)Fluoro-Jade B染色可特异性标记变性神经元,FJB阳性变性神经元呈亮黄绿色;Pilo组和TGF组大鼠海马均可见FJB阳性变性神经元,主要分布在海马DG和CA1区,CA3区亦可见少数FJB阳性细胞,FJB荧光染色可清晰地显示变性神经元的胞体和部分突起;正常对照组未见FJB阳性细胞。造模各组大鼠SE后6 h,DG和CA1区可见少量FJB阳性变性神经元,此后各组FJB阳性变性神经元明显增多,其中Pilo组72 h达高峰; SE后6 h,TGF组大鼠海马DG和CA1区FJB阳性变性神经元与Pilo组比较无统计学差异;SE后24 h、48 h、72 h,TGF组大鼠海马DG和CA1区FJB阳性变性神经元均较Pilo组显著减少(P < 0.05);其中72 h最为明显(P < 0.01)。(3)正常对照组大鼠海马未见TUNEL阳性细胞或仅有微量表达。Pilo组和TGF组大鼠海马均可见TUNEL阳性细胞,主要分布在海马CA1和CA3区; DG区亦可见少数TUNEL阳性细胞。SE后6 h各组大鼠海马可见少量TUNEL标记细胞,细胞核呈棕黄色~黄色(阴性细胞核蓝色),核固缩呈圆形或不规则形;高倍镜下可见染色质深染聚集成块或碎裂,核边聚等,符合凋亡细胞形态变化。此后各组TUNEL阳性细胞明显增多,其中Pilo组72 h达高峰; SE后6 h,TGF组大鼠海马CA1和CA3区TUNEL阳性细胞与Pilo组比较无统计学差异;SE后24 h、48 h、72 h,TGF组大鼠海马CA1和CA3区TUNEL阳性细胞均较Pilo组显著减少(P < 0.05);其中72 h最为明显(P < 0.01)。Pilo组和TGF组大鼠海马TUNEL阳性细胞数较正常对照组(Control)均有极显著性差异(P < 0.01)。(4)正常对照组大鼠海马未见Bcl-2阳性细胞或仅有微量的基础表达,主要为胞浆或核膜着色,呈棕黄色或棕褐色。Pilo组和TGF组大鼠海马均可见Bcl-2阳性细胞,主要分布在海马CA1和CA3区。SE后6 h各组大鼠海马Bcl-2阳性细胞有较明显的表达,此后各组Bcl-2阳性细胞逐渐增多;其中Pilo组48 h达高峰,SE后72 h较48 h下降; SE后6 h,TGF组大鼠海马CA1和CA3区Bcl-2阳性细胞与Pilo组比较无统计学差异;SE后24 h、48 h、72 h,TGF组大鼠海马CA1和CA3区Bcl-2阳性细胞均较Pilo组显著减少(P < 0.05);其中24 h最为明显(P < 0.01)。(P < 0.01)。Pilo组和TGF组大鼠海马Bcl-2阳性细胞数较正常对照组(Control)均有极显著性差异(P < 0.01)。(5)Caspase-3主要表达于细胞质或细胞核,呈棕黄色或棕褐色。正常对照组大鼠海马未见Caspase-3阳性细胞或仅有微量的基础表达; Pilo组和TGF组大鼠海马均可见Caspase-3阳性细胞,
主要分布在海马CA1和CA3区。各组大鼠海马Caspase-3阳性细胞的动态变化及实验结果与TUNEL染色的观察结果相一致。(6)正常对照组大鼠海马未见Bax阳性细胞或仅有微量的基础表达,主要为胞浆或核膜着色,呈棕褐色。各组大鼠海马Bax阳性细胞的动态变化及实验结果与TUNEL染色的观察结果相一致。
结论:经鼻(IN)给予TGFβ1可以显著抑制或减轻癫痫持续状态大鼠海马神经元的变性与凋亡,从而发挥神经保护作用。其潜在的神经保护机制可能涉及上调Bcl-2蛋白表达,下调Bax和Caspase-3蛋白表达。鼻腔给药是一种全新的可以避开血脑屏障阻隔的无创中枢给药途径,有希望为治疗癫痫、阿尔茨海默病或其它中枢神经系统疾病提供有实用前景的一条新思路。
Objective: Intranasal administration provides a noninvasive and effective method for bypassing blood-brain barrier (BBB) to deliver TGFβ1 to the central nervous system (CNS) of status epilepticus (SE) rats. To investigate the potential neuroprotectional role of intranasal TGFβ1 against hippocampal damage after lithium-pilocarpine induced status epilepticus, and to explore the underlying mechanisms.
Method: 60 Sprague-Dawley (SD) rats were randomly enrolled into the TGF group, Pilo group and the Control group. The lithium-pilocarpine induced SE was as the SE model. Diazepam (10 mg/kg i.p) was injected 50 min after the noset of SE to terminate seizue activity. Control animals were treated identically to the experimental group, but saline (0.9%) was given instead of pilocarpine. Recombinant human TGFβ1 was intranasally administered after SE cession immediately in TGF group. Meanwhile, rats in control group and pilocarpine group were treated identically with the same volume of saline. Rats were anesthetized and flush perfused transcardically 6 hours, 24 hours, 48 hours, and 72 hours after SE (n=5 for all time points). Then rats brains were carried out into sections in coronal. Morphological changes of hippocampal neurons were observed by hematoxylin-eosin (HE) staining. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method was applied to determine in situ apoptosis in the hippocampus. Fluoro-Jade B (FJB) stain dye was then used to visualize the dynamic changes of neuronal degeneration in the rat hippocampus in every group. Immunohistochemistry was conducted to detect the expression of Bcl-2, Bax and Caspase-3 in hippocampal neurons.
Results: (1) Normal neurons were regularly aligned and the structure was intact including transparent cytoplasm, round or oval nuclei, chromatin distribution and clear nucleoli. While HE staining showed that the cell bodies were irregularly aligned and became shrunken with the shape of irregular triangle, some nuclei were shrinkage and had the shape of crescent, and The structure of hippocampal neurons is unclear at 6 h after SE, which presenting mainly in CA1, CA3 and DG of hippocampus. Neurons in the hippocampus were more intensely stained and the extent of morphological changes became gradually severe, while peaked at 72 h after SE in Pilo group. The extent of these phological changes peaked at 48 h, while the morphology and staining of neurons close to normal increasing at 72 h after SE in TGF group. Morever, intranasal TGFβ1 in TGF group markedly attenuated these phological changes in Pilo group at the time point of 24 h、48 h and 72 h after SE. (2) FJB positive cell was observed in both Pilo group and TGF group, presenting mainly in DG and CA1 of hippocampus, which appeared bright yellow-green against a dark background. No FJB positive cell was observed in the control group. FJB positive cells appeared at 6 h after SE and then increased gradually, while peaking at 72 h after SE in Pilo group. Meanwhile, FJB positive cells were observed at 6 h after SE and peaked at 48 h, while decreasing at 72 h after SE in TGF group. Moreover, intranasal TGFβ1 in TGF group significantly reduced the number of FJB-positive cells in Pilo group at 24 h (P < 0.05), 48 h (P < 0.05) and 72 h (P < 0.01), with no significant difference at 6 h between Pilo and TGF groups. Both Pilo and TGF groups had significantly higher expression of FJB-positive cells compared to the control (P < 0.01). (3) TUNEL staining showed that nuclear condensation with the shape of irregularity, which appeared brownish yellow ~ yellow. Chromatin intensely stained and nuclear fragmentation were examined under a high power microscope, which were consistent with apoptotic morphological changes. TUNEL positive cell was observed in both Pilo group and TGF group, presenting mainly in CA1 and CA3 of hippocampus, while no or few TUNEL positive cell was observed in the control group. TUNEL positive cells appeared at 6 h after SE and then increased gradually, while peaking at 72 h after SE in Pilo group. Meanwhile, TUNEL positive cells were observed at 6 h after SE and peaked at 48 h, while decreasing at 72 h after SE in TGF group. Moreover, intranasal TGFβ1 in TGF group significantly reduced the number of TUNEL-positive cells in Pilo group at 24 h (P < 0.05), 48 h (P < 0.05) and at 72 h (P < 0.01), with no significant difference at 6 h between Pilo and TGF groups. Both Pilo and TGF groups had significantly higher expression of TUNEL-positive cells compared to the control (P < 0.01). (4) Bcl-2 positive cells mainly expressed in the cytoplasmic or nuclear membrane, which appeared brownish yellow ~ brown. Bcl-2 positive cell was observed in both Pilo group and TGF group, presenting mainly in CA1 and CA3 of hippocampus, while no or few Bcl-2 positive cell was observed in the control group. Bcl-2 positive cells were observed at 6 h after SE and peaked at 48 h, while decreasing at 72 h after SE in Pilo group. Meanwhile, Bcl-2 positive cells appeared at 6 h after SE and peaked at 24 h, while decreasing persistently until 72 h after SE in TGF group. Moreover, intranasal TGFβ1 in TGF group significantly increased the number of Bcl-2-positive cells in Pilo group at 24 h (P < 0.01), 48 h (P < 0.05) and 72 h (P < 0.05), with no significant difference at 6 h between Pilo and TGF groups. Both Pilo and TGF groups had significantly higher expression of Bcl-2-positive cells compared to the control (P < 0.01). (5) Caspase-3 was mainly expressed in the cytoplasm or nucleus, which appeared brownish yellow or brown. Caspase-3 positive cell was observed in both Pilo group and TGF group, presenting mainly in CA1 and CA3 of hippocampus, while no or few Caspase-3 positive cell was observed in the control group. It showed
essentially the same pattern as observed with the TUNEL labelling and a finding consistent with the results of the TUNEL assay. (6) Bax positive cells mainly expressed in the cytoplasmic or nuclear membrane, which appeared brown. Bax positive cell was observed in both Pilo group and TGF group, presenting mainly in CA1 and CA3 of hippocampus, while no or few Bax positive cell was observed in the control group. It showed essentially the same pattern as observed with the TUNEL labelling and a finding consistent with the results of the TUNEL assay.
Conclusion: Intranasal delivery of Transforming growth factor-beta1 can significantly decrease the neurons undergoing degeneration and apoptotic death in rats hippocampus after SE and exert potential neuroprotective effect. Its underlying neuroprotective machanisms were likely to relate to up-regulating Bcl-2 expression and down-regulating Bax and Caspase-3 expression. Intranasal administration is a noninvasive and practical method for bypassing blood-brain barrier (BBB) to deliver drugs to the central nervous system (CNS), which may offer a promising strategy for treating Epilepsy, Alzheimer’disease and other CNS disorders.
方法:健康雄性SD大鼠60只,随机分为TGF组、Pilo组和正常对照组(Control)。建立氯化锂-匹罗卡品癫痫持续状态(Lithium-Pilocarpine induced status epilepticus)模型。SE后50 min,注射地西泮10 mg/kg终止SE。正常对照组大鼠采用等量的0.9%氯化钠溶液替代匹罗卡品。TGF组大鼠经鼻给予重组人TGFβ1,同时Pilo组和Control组经鼻给予相同容量的生理盐水。SE后6 h、24 h、48 h和72 h,开胸灌注取脑行冠状切片。应用HE染色、TUNEL染色、Fluoro-Jade B (FJB)荧光染色法分别观察各组大鼠海马神经元的形态结构变化、原位凋亡及变性死亡情况。并采用免疫组化方法检测凋亡相关基因Bcl-2、Bax及Caspase-3的蛋白表达。
结果:(1)正常对照组大鼠海马神经元排列整齐,胞浆透明,细胞核呈圆形或椭圆形,染色质分布均匀,核仁清晰;SE后6 h各组大鼠海马CA1、CA3及DG区部分细胞排列紊乱,胞体收缩呈三角形或极不规则,胞核固缩,结构不清;24 h后嗜伊红浓染显著,神经元坏死崩解逐渐增多;其中Pilo组SE后72 h达高峰。SE后24 h、48 h、72 h,TGF组海马神经元形态结构恶变数量、程度均较Pilo组减轻。(2)Fluoro-Jade B染色可特异性标记变性神经元,FJB阳性变性神经元呈亮黄绿色;Pilo组和TGF组大鼠海马均可见FJB阳性变性神经元,主要分布在海马DG和CA1区,CA3区亦可见少数FJB阳性细胞,FJB荧光染色可清晰地显示变性神经元的胞体和部分突起;正常对照组未见FJB阳性细胞。造模各组大鼠SE后6 h,DG和CA1区可见少量FJB阳性变性神经元,此后各组FJB阳性变性神经元明显增多,其中Pilo组72 h达高峰; SE后6 h,TGF组大鼠海马DG和CA1区FJB阳性变性神经元与Pilo组比较无统计学差异;SE后24 h、48 h、72 h,TGF组大鼠海马DG和CA1区FJB阳性变性神经元均较Pilo组显著减少(P < 0.05);其中72 h最为明显(P < 0.01)。(3)正常对照组大鼠海马未见TUNEL阳性细胞或仅有微量表达。Pilo组和TGF组大鼠海马均可见TUNEL阳性细胞,主要分布在海马CA1和CA3区; DG区亦可见少数TUNEL阳性细胞。SE后6 h各组大鼠海马可见少量TUNEL标记细胞,细胞核呈棕黄色~黄色(阴性细胞核蓝色),核固缩呈圆形或不规则形;高倍镜下可见染色质深染聚集成块或碎裂,核边聚等,符合凋亡细胞形态变化。此后各组TUNEL阳性细胞明显增多,其中Pilo组72 h达高峰; SE后6 h,TGF组大鼠海马CA1和CA3区TUNEL阳性细胞与Pilo组比较无统计学差异;SE后24 h、48 h、72 h,TGF组大鼠海马CA1和CA3区TUNEL阳性细胞均较Pilo组显著减少(P < 0.05);其中72 h最为明显(P < 0.01)。Pilo组和TGF组大鼠海马TUNEL阳性细胞数较正常对照组(Control)均有极显著性差异(P < 0.01)。(4)正常对照组大鼠海马未见Bcl-2阳性细胞或仅有微量的基础表达,主要为胞浆或核膜着色,呈棕黄色或棕褐色。Pilo组和TGF组大鼠海马均可见Bcl-2阳性细胞,主要分布在海马CA1和CA3区。SE后6 h各组大鼠海马Bcl-2阳性细胞有较明显的表达,此后各组Bcl-2阳性细胞逐渐增多;其中Pilo组48 h达高峰,SE后72 h较48 h下降; SE后6 h,TGF组大鼠海马CA1和CA3区Bcl-2阳性细胞与Pilo组比较无统计学差异;SE后24 h、48 h、72 h,TGF组大鼠海马CA1和CA3区Bcl-2阳性细胞均较Pilo组显著减少(P < 0.05);其中24 h最为明显(P < 0.01)。(P < 0.01)。Pilo组和TGF组大鼠海马Bcl-2阳性细胞数较正常对照组(Control)均有极显著性差异(P < 0.01)。(5)Caspase-3主要表达于细胞质或细胞核,呈棕黄色或棕褐色。正常对照组大鼠海马未见Caspase-3阳性细胞或仅有微量的基础表达; Pilo组和TGF组大鼠海马均可见Caspase-3阳性细胞,
主要分布在海马CA1和CA3区。各组大鼠海马Caspase-3阳性细胞的动态变化及实验结果与TUNEL染色的观察结果相一致。(6)正常对照组大鼠海马未见Bax阳性细胞或仅有微量的基础表达,主要为胞浆或核膜着色,呈棕褐色。各组大鼠海马Bax阳性细胞的动态变化及实验结果与TUNEL染色的观察结果相一致。
结论:经鼻(IN)给予TGFβ1可以显著抑制或减轻癫痫持续状态大鼠海马神经元的变性与凋亡,从而发挥神经保护作用。其潜在的神经保护机制可能涉及上调Bcl-2蛋白表达,下调Bax和Caspase-3蛋白表达。鼻腔给药是一种全新的可以避开血脑屏障阻隔的无创中枢给药途径,有希望为治疗癫痫、阿尔茨海默病或其它中枢神经系统疾病提供有实用前景的一条新思路。
Objective: Intranasal administration provides a noninvasive and effective method for bypassing blood-brain barrier (BBB) to deliver TGFβ1 to the central nervous system (CNS) of status epilepticus (SE) rats. To investigate the potential neuroprotectional role of intranasal TGFβ1 against hippocampal damage after lithium-pilocarpine induced status epilepticus, and to explore the underlying mechanisms.
Method: 60 Sprague-Dawley (SD) rats were randomly enrolled into the TGF group, Pilo group and the Control group. The lithium-pilocarpine induced SE was as the SE model. Diazepam (10 mg/kg i.p) was injected 50 min after the noset of SE to terminate seizue activity. Control animals were treated identically to the experimental group, but saline (0.9%) was given instead of pilocarpine. Recombinant human TGFβ1 was intranasally administered after SE cession immediately in TGF group. Meanwhile, rats in control group and pilocarpine group were treated identically with the same volume of saline. Rats were anesthetized and flush perfused transcardically 6 hours, 24 hours, 48 hours, and 72 hours after SE (n=5 for all time points). Then rats brains were carried out into sections in coronal. Morphological changes of hippocampal neurons were observed by hematoxylin-eosin (HE) staining. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method was applied to determine in situ apoptosis in the hippocampus. Fluoro-Jade B (FJB) stain dye was then used to visualize the dynamic changes of neuronal degeneration in the rat hippocampus in every group. Immunohistochemistry was conducted to detect the expression of Bcl-2, Bax and Caspase-3 in hippocampal neurons.
Results: (1) Normal neurons were regularly aligned and the structure was intact including transparent cytoplasm, round or oval nuclei, chromatin distribution and clear nucleoli. While HE staining showed that the cell bodies were irregularly aligned and became shrunken with the shape of irregular triangle, some nuclei were shrinkage and had the shape of crescent, and The structure of hippocampal neurons is unclear at 6 h after SE, which presenting mainly in CA1, CA3 and DG of hippocampus. Neurons in the hippocampus were more intensely stained and the extent of morphological changes became gradually severe, while peaked at 72 h after SE in Pilo group. The extent of these phological changes peaked at 48 h, while the morphology and staining of neurons close to normal increasing at 72 h after SE in TGF group. Morever, intranasal TGFβ1 in TGF group markedly attenuated these phological changes in Pilo group at the time point of 24 h、48 h and 72 h after SE. (2) FJB positive cell was observed in both Pilo group and TGF group, presenting mainly in DG and CA1 of hippocampus, which appeared bright yellow-green against a dark background. No FJB positive cell was observed in the control group. FJB positive cells appeared at 6 h after SE and then increased gradually, while peaking at 72 h after SE in Pilo group. Meanwhile, FJB positive cells were observed at 6 h after SE and peaked at 48 h, while decreasing at 72 h after SE in TGF group. Moreover, intranasal TGFβ1 in TGF group significantly reduced the number of FJB-positive cells in Pilo group at 24 h (P < 0.05), 48 h (P < 0.05) and 72 h (P < 0.01), with no significant difference at 6 h between Pilo and TGF groups. Both Pilo and TGF groups had significantly higher expression of FJB-positive cells compared to the control (P < 0.01). (3) TUNEL staining showed that nuclear condensation with the shape of irregularity, which appeared brownish yellow ~ yellow. Chromatin intensely stained and nuclear fragmentation were examined under a high power microscope, which were consistent with apoptotic morphological changes. TUNEL positive cell was observed in both Pilo group and TGF group, presenting mainly in CA1 and CA3 of hippocampus, while no or few TUNEL positive cell was observed in the control group. TUNEL positive cells appeared at 6 h after SE and then increased gradually, while peaking at 72 h after SE in Pilo group. Meanwhile, TUNEL positive cells were observed at 6 h after SE and peaked at 48 h, while decreasing at 72 h after SE in TGF group. Moreover, intranasal TGFβ1 in TGF group significantly reduced the number of TUNEL-positive cells in Pilo group at 24 h (P < 0.05), 48 h (P < 0.05) and at 72 h (P < 0.01), with no significant difference at 6 h between Pilo and TGF groups. Both Pilo and TGF groups had significantly higher expression of TUNEL-positive cells compared to the control (P < 0.01). (4) Bcl-2 positive cells mainly expressed in the cytoplasmic or nuclear membrane, which appeared brownish yellow ~ brown. Bcl-2 positive cell was observed in both Pilo group and TGF group, presenting mainly in CA1 and CA3 of hippocampus, while no or few Bcl-2 positive cell was observed in the control group. Bcl-2 positive cells were observed at 6 h after SE and peaked at 48 h, while decreasing at 72 h after SE in Pilo group. Meanwhile, Bcl-2 positive cells appeared at 6 h after SE and peaked at 24 h, while decreasing persistently until 72 h after SE in TGF group. Moreover, intranasal TGFβ1 in TGF group significantly increased the number of Bcl-2-positive cells in Pilo group at 24 h (P < 0.01), 48 h (P < 0.05) and 72 h (P < 0.05), with no significant difference at 6 h between Pilo and TGF groups. Both Pilo and TGF groups had significantly higher expression of Bcl-2-positive cells compared to the control (P < 0.01). (5) Caspase-3 was mainly expressed in the cytoplasm or nucleus, which appeared brownish yellow or brown. Caspase-3 positive cell was observed in both Pilo group and TGF group, presenting mainly in CA1 and CA3 of hippocampus, while no or few Caspase-3 positive cell was observed in the control group. It showed
essentially the same pattern as observed with the TUNEL labelling and a finding consistent with the results of the TUNEL assay. (6) Bax positive cells mainly expressed in the cytoplasmic or nuclear membrane, which appeared brown. Bax positive cell was observed in both Pilo group and TGF group, presenting mainly in CA1 and CA3 of hippocampus, while no or few Bax positive cell was observed in the control group. It showed essentially the same pattern as observed with the TUNEL labelling and a finding consistent with the results of the TUNEL assay.
Conclusion: Intranasal delivery of Transforming growth factor-beta1 can significantly decrease the neurons undergoing degeneration and apoptotic death in rats hippocampus after SE and exert potential neuroprotective effect. Its underlying neuroprotective machanisms were likely to relate to up-regulating Bcl-2 expression and down-regulating Bax and Caspase-3 expression. Intranasal administration is a noninvasive and practical method for bypassing blood-brain barrier (BBB) to deliver drugs to the central nervous system (CNS), which may offer a promising strategy for treating Epilepsy, Alzheimer’disease and other CNS disorders.
引文
1. Raj, D., S. Gulati, and R. Lodha, Status epilepticus. Indian J Pediatr, 2011. 78(2): p. 219-26.
2. Henshall, D.C. and R.P. Simon, Epilepsy and apoptosis pathways. J Cereb Blood Flow Metab, 2005. 25(12): p. 1557-72.
3. Zhang, Y., et al., Granulocyte colony-stimulating factor treatment prevents cognitive impairment following status epilepticus in rats. Biol Pharm Bull, 2010.33(4): p. 572-9.
4. Gomes, F.C., O. Sousa Vde, and L. Romao, Emerging roles for TGF-beta1 in nervous system development. Int J Dev Neurosci, 2005. 23(5): p. 413-24.
5. Ma, M., et al., Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone. BMC Neurosci, 2008. 9: p. 117.
6. Zhang, H., et al., Small molecule tgf-beta mimetics as potential neuroprotective factors. Curr Alzheimer Res, 2005. 2(2): p. 183-6.
7. Mirshafiey, A. and M. Mohsenzadegan, TGF-beta as a promising option in the treatment of multiple sclerosis. Neuropharmacology, 2009. 56(6-7): p. 929-36.
8. Zhu, Y., et al., TGF-beta1 inhibits caspase-3 activation and neuronal apoptosis in rat hippocampal cultures. Neurochem Int, 2001. 38(3): p. 227-35.
9. Morgan, T.E., et al., TGF-beta 1 mRNA increases in macrophage/microglial cells of the hippocampus in response to deafferentation and kainic acid-induced neurodegeneration. Exp Neurol, 1993. 120(2): p. 291-301.
10. Brionne, T.C., et al., Loss of TGF-beta 1 leads to increased neuronal cell death and microgliosis in mouse brain. Neuron, 2003. 40(6): p. 1133-45.
11. Plata-Salaman, C.R., et al., Kindling modulates the IL-1beta system, TNF-alpha, TGF-beta1, and neuropeptide mRNAs in specific brain regions. Brain Res Mol Brain Res, 2000. 75(2): p. 248-58.
12. Ma, Y.P., et al., Intranasally delivered TGF-beta1 enters brain and regulates gene expressions of its receptors in rats. Brain Res Bull, 2007. 74(4): p. 271-7.
13. Hanson, L.R. and W.H. Frey, 2nd, Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci, 2008. 9 Suppl 3: p. S5.
14. Racine, R.J., Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol, 1972. 32(3): p. 281-94.
15. Engrand, N. and A. Crespel, [Pathophysiologic basis of status epilepticus]. Rev Neurol (Paris), 2009. 165(4): p. 315-9.
16. Knake, S., H.M. Hamer, and F. Rosenow, Status epilepticus: a critical review. Epilepsy Behav, 2009. 15(1): p. 10-4.
17. Curia, G., et al., The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods, 2008. 172(2): p. 143-57.
18. Garcia-Penas, J.J., [Neurocognitive dysfunction in electrical status epilepticus during slow-wave sleep syndrome: Can the natural course of the syndrome be modified with early pharmacological treatment?]. Rev Neurol, 2010. 50 Suppl 3: p. S37-47.
19. Magloczky, Z. and T.F. Freund, Delayed cell death in the contralateral hippocampus following kainate injection into the CA3 subfield. Neuroscience, 1995. 66(4): p. 847-60.
20. Narkilahti, S., et al., Expression and activation of caspase 3 following status epilepticus in the rat. Eur J Neurosci, 2003. 18(6): p. 1486-96.
21. Fujikawa, D.G., S.S. Shinmei, and B. Cai, Lithium-pilocarpine-induced status epilepticus produces necrotic neurons with internucleosomal DNA fragmentation in adult rats. Eur J Neurosci, 1999. 11(5): p. 1605-14.
22. Liou, A.K., et al., To die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: a review on the stress-activated signaling pathways and apoptotic pathways. Prog Neurobiol, 2003. 69(2): p. 103-42.
23. Gorter, J.A., et al., Neuronal cell death in a rat model for mesial temporal lobe epilepsy is induced by the initial status epilepticus and not by later repeated spontaneous seizures. Epilepsia, 2003. 44(5): p. 647-58.
24. Schmued, L.C. and K.J. Hopkins, Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res, 2000. 874(2): p. 123-30.
25. Kundrotiene, J., A. Wagner, and S. Liljequist, Fluoro-Jade and TUNEL staining as useful tools to identify ischemic brain damage following moderate extradural compression of sensorimotor cortex. Acta Neurobiol Exp (Wars), 2004. 64(2): p. 153-62.
26. Kubova, H., et al., Dynamic changes of status epilepticus-induced neuronal degeneration in the mediodorsal nucleus of the thalamus during postnatal development of the rat. Epilepsia, 2002. 43 Suppl 5: p. 54-60.
27. Butler, T.L., et al., Neurodegeneration in the rat hippocampus and striatum after middle cerebral artery occlusion. Brain Res, 2002. 929(2): p. 252-60.
28. Eyupoglu, I.Y., et al., Identification of neuronal cell death in a model of degeneration in the hippocampus. Brain Res Brain Res Protoc, 2003. 11(1): p. 1-8.
29. Zhu, Y., et al., The expression of transforming growth factor-beta1 (TGF-beta1) in hippocampal neurons: a temporary upregulated protein level after transient forebrain ischemia in the rat. Brain Res, 2000. 866(1-2): p. 286-98.
30. Caraci, F., et al., TGF-beta1 Pathway as a New Target for Neuroprotection in Alzheimer's Disease. CNS Neurosci Ther, 2009.
31. Sanchez-Capelo, A., Dual role for TGF-beta1 in apoptosis. Cytokine Growth Factor Rev, 2005. 16(1): p. 15-34.
32. Scorza, F.A., et al., The pilocarpine model of epilepsy: what have we learned? An Acad Bras Cienc, 2009. 81(3): p. 345-65.
33. Prehn, J.H., et al., Regulation of neuronal Bcl2 protein expression and calcium homeostasis by transforming growth factor type beta confers wide-ranging protection on rat hippocampal neurons. Proc Natl Acad Sci U S A, 1994. 91(26): p. 12599-603.
34. Prehn, J.H., C. Backhauss, and J. Krieglstein, Transforming growth factor-beta 1 prevents glutamate neurotoxicity in rat neocortical cultures and protects mouseneocortex from ischemic injury in vivo. J Cereb Blood Flow Metab, 1993. 13(3): p. 521-5.
35. Wetherington, J., G. Serrano, and R. Dingledine, Astrocytes in the epileptic brain. Neuron, 2008. 58(2): p. 168-78.
36. Lindholm, D., et al., Transforming growth factor-beta 1 in the rat brain: increase after injury and inhibition of astrocyte proliferation. J Cell Biol, 1992. 117(2): p. 395-400.
37. Buisson, A., et al., Transforming growth factor-beta and ischemic brain injury. Cell Mol Neurobiol, 2003. 23(4-5): p. 539-50.
38. Fabene, P.F., et al., Pilocarpine-induced status epilepticus in rats involves ischemic and excitotoxic mechanisms. PLoS One, 2007. 2(10): p. e1105.
39. Ivens, S., et al., TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain, 2007. 130(Pt 2): p. 535-47.
40. Cacheaux, L.P., et al., Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. J Neurosci, 2009. 29(28): p. 8927-35.
41. Konig, H.G., et al., TGF-{beta}1 activates two distinct type I receptors in neurons: implications for neuronal NF-{kappa}B signaling. J Cell Biol, 2005. 68(7): p. 1077-86.
42. Xiao, B.G., et al., Transforming growth factor-beta1 induces apoptosis of rat microglia without relation to bcl-2 oncoprotein expression. Neurosci Lett, 1997. 226(2): p. 71-4.
43. Sandoval, K.E. and K.A. Witt, Blood-brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis, 2008. 32(2): p. 200-19.
44. Pardridge, W.M., The blood-brain barrier: bottleneck in brain drug development. NeuroRx, 2005. 2(1): p. 3-14.
45. Kastin, A.J., V. Akerstrom, and W. Pan, Circulating TGF-beta1 does not cross the intact blood-brain barrier. J Mol Neurosci, 2003. 21(1): p. 43-8.
46. Wakefield, L.M., et al., Recombinant latent transforming growth factor beta 1 has a longer plasma half-life in rats than active transforming growth factor beta 1, and a different tissue distribution. J Clin Invest, 1990. 86(6): p. 1976-84.
47. Border, W.A. and N.A. Noble, Transforming growth factor beta in tissue fibrosis. N Engl J Med, 1994. 331(19): p. 1286-92.
48. Pathan, S.A., et al., CNS drug delivery systems: novel approaches. Recent Pat Drug Deliv Formul, 2009. 3(1): p. 71-89.
49. Merelli, A., et al., Recovery of Motor Spontaneous Activity After Intranasal Delivery of Human Recombinant Erythropoietin in a Focal Brain Hypoxia Model Induced by CoCl(2) in Rats. Neurotox Res, 2010.
50. Veronesi, M.C., D.J. Kubek, and M.J. Kubek, Intranasal delivery of a thyrotropin-releasing hormone analog attenuates seizures in the amygdala-kindled rat. Epilepsia, 2007. 48(12): p. 2280-6.
51. Liu, X.F., et al., Non-invasive intranasal insulin-like growth factor-I reduces infarct volume and improves neurologic function in rats following middle cerebral artery occlusion. Neurosci Lett, 2001. 308(2): p. 91-4.
52. Jogani, V., et al., Recent patents review on intranasal administration for CNS drug delivery. Recent Pat Drug Deliv Formul, 2008. 2(1): p. 25-40.
53. Yang, J., et al., Erythropoietin preconditioning suppresses neuronal death following status epilepticus in rats. Acta Neurobiol Exp (Wars), 2007. 67(2): p. 141-8.
54. Wen, X., Y. Huang, and J. Wang, Erythropoietin preconditioning on hippocampus neuronal apoptosis following status epilepticus induced by Li-pilocarpine in rats through anti-caspase-3 expression. Neurol India, 2006. 54(1): p. 58-63; discussion 63.
55. Jun, Y., et al., Erythropoietin pre-treatment prevents cognitive impairments following status epilepticus in rats. Brain Res, 2009. 1282: p. 57-66.
56. Sankar, R., et al., Patterns of status epilepticus-induced neuronal injury during development and long-term consequences. J Neurosci, 1998. 18(20): p. 8382-93.
57. Niquet, J. and C.G. Wasterlain, Bim, Bad, and Bax: a deadly combination in epileptic seizures. J Clin Invest, 2004. 113(7): p. 960-2.
58. Xu, J., et al., Ghrelin protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats. Neurosci Lett, 2009. 453(1): p. 58-61.
59. Xiang, J., et al., Chinese medicine Nao-Shuan-Tong attenuates cerebral ischemic injury by inhibiting apoptosis in a rat model of stroke. J Ethnopharmacol, 2010. 131(1): p. 174-81.
60. Weise, J., et al., Expression time course and spatial distribution of activated caspase-3 after experimental status epilepticus: contribution of delayed neuronal cell death to seizure-induced neuronal injury. Neurobiol Dis, 2005. 18(3): p. 582-90.
61. Ekdahl, C.T., et al., Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus. Eur J Neurosci, 2001. 14(6): p. 937-45.
1 Kerstin Krieglsteina, Jens Strelaub, Andreas Schoberb, et al. TGF-βand the regulation of neuron survival and death . Physiology -Paris, 96 (2002) 25-30.
2 Massague J. TGF-βsignal transduction[J]. Annu Rev Biochem,1998,67:753 -791.
3万赛英,顾卫,谭锋.转化生长因子β1与脑缺血[J].国际脑血管疾病分册. 2005, 13,No .8
4 T.E.Morgan, N.R.Nichols, G.M.Pasinetti, And C.E.Finch. TGF-β1mRNA increase in macrophage/microglial cell of the hippocampus in response to deafferentation and kainic acid-induced neurodegeneration[J]. Experimental Neurology,1993,120:291-301.
5 Thomas C. Brionne, Ina Tesseur, Eliezer Masliah, and Tony Wyss-Coray. Loss of TGF-β1 Leads to Increased Neuronal Cell Death and Microgliosis in Mouse Brain[J]. Neuron, 2003, 40, 1133–1145.
6 Carlos R. Plata-Salam′an, Sergey E. Ilyin , Nicolas P. Turrin , et al. Kindling modulates the IL-1βsystem, TNF-α, TGF-β1, and neuropeptide mRNAs in specific brain regions[J]. Molecular Brain Research.2000,75: 248–258.
7 FULVIO A. SCORZA, RICARDO M. ARIDA, MARIA DA GRA?A NAFFAH-MAZZACORATTI, et al. The pilocarpine model of epilepsy: what have we learned? [J]. Anais da Academia Brasileira de Ciências, 2009, 81(3): 345-365
8 JOCHEN H. M. PREHN, et al. Regulation of neuronal Bcl2 protein expression and calcium homeostasis by transforming growth factor typeβconfers wide-ranging protection on rat hippocampal neurons[J]. Neurobiology, 1994,91:12599-12603.
9 P rehn JH, Backhauss C, Krieg J, et al. Transforming growth factor betal prevents glutamate neurotoxicity in rat neoc rtical cultures and protects mouse neocortes from ischemic injury in vivo[J]. J Cereb Blood Flow Metab, 1993, 13 :521-525.
10 Wetherington, J., G. Serrano, and R. Dingledine. Astrocytes in the epileptic brain[J]. Neuron, 2008, 58(2): 168-78.
11 Dan Lindholm, et al. Transforming growth factor-β1 in rat brain:increase after injury and inhibition of astrocyte proliferation[J]. Cell Biology,1992,117,395-400.
12 Yuan Zhu , Barbara Ahlemeyer, Elke Bauerbach, et al. TGF-β1 inhibits caspase-3 activation and neuronal apoptosis in rat hippocampal cultures[J]. Neurochemistry International ,38 (2001) 227–235.
13 Alain Buisson, Sylvain Lesne, Fabian Docagne, et al. Transforming Growth Factor-βand Ischemic Brain Injury[J]. Cellular and Molecular Neurobiology,2003,13:539-550.
14 Fabene, P.F., et al. Pilocarpine-induced status epilepticus in rats involves ischemic and excitotoxic mechanisms[J]. PLoS One, 2007, 2(10): e1105.
15 Minmin Ma, Yuping Ma, Xueming Yi, et al. Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone[J]. BMC Neuroscience, 2008, 9(117): 1-10.
16 Sebastian Ivens, et al. TGF-βreceptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis[J]. Brain, 2007, 130:535–547.
17 Sebastian Ivens, et al. Transcriptome Profiling Reveals TGF-βSignaling Involvement in Epileptogenesis[J]. Neuroscience, 2009 ,29,:8927– 8935.
18 Hans-Georg K?nig, Donat K?gel,Abdelhaq Rami, et al. TGF-β1 activates two distinct type I receptors in neurons: implications for neuronal NF-?B signaling[J]. Cell Biology, 2005,168: 1077-1086.
19 Alon Friedman, Daniela Kaufer, Uwe Heinemann. Blood—brain barrier breakdown-inducing astrocytic transformation: Novel targets for the prevention of epilepsy[J]. Epilepsy Research,2009, 85:142—149.
20 Xuefeng WANG, et al. Increased expression of TGFβtype I receptor in brain tissues of patients with temporal lobe epilepsy[J]. Clinical Science,2009,117:17–22.
21 Peter ten Dijke, et al. Activin receptor-like kinase(ALK)1 is antagonistic mediator of lateral TGFβ/ALK5 signaling[J]. Molecular Cell,2003,12:817-828.
22 Xiao, B.G., et al. Transforming growth factor-beta1 induces apoptosis of rat microglia without relation to bcl-2 oncoprotein expression[J]. Neurosci Lett, 1997. 226(2): 71-4.
23 Sanchez-Capelo A., Dual role for TGF-beta1 in apoptosis[J]. Cytokine Growth Factor Rev, 2005. 16(1): 15-34.
1 Kerstin Krieglsteina, Jens Strelaub, Andreas Schoberb, et al. TGF-βand the regulation of neuron survival and death[J]. Physiology -Paris, 96 (2002) 25-30.
2 Massague J. TGF-βsignal transduction[J]. Annu Rev Biochem,1998,67:753 -791.
3万赛英,顾卫,谭锋.转化生长因子β1与脑缺血[J].国际脑血管疾病. 2005, 13, No .8
4 Amelia Sa′nchez-Capelo. Dual role for TGF-βin apoptosis[J]. Cytokine & Growth Factor ,16 (2005) 15-34.
5 Filippo Caraci, Giuseppe Battaglia, et al. TGF-β1 Pathway as a New Target for Neuroprotection in Alzheimer’s Disease[J]. Neuroscience & Therapeutics 00 (2009) 1-13.
6 Henshall DC,Simon RP.Epilepsy and apoptosis pathways [J].Cereb Blood Flow Metab,2005,25(12):1557-1572.
7陈旭东,赵文清,吴耀晨.中国老年学杂志,1999,19.
8 Bao-Gou Xiao, Xue-Feng Bai, Guang-Xian Zhang, et al. Transforming growth factor-β1 induces apoptosis of rat microglia without relation to bcl-2 oncoprotein expression[J]. Neuroscience Letters ,226 (1997) 71-74.
9 Bomi Jung, Mi-Ok Kim, Su-Jin Yun , et al. Down-regulation of the expression of rat inhibitor-of-apoptosis protein-1 and -3 during transforming growth factor-β1-mediated apoptosis in rat brain microglia[J]. Molecular Neuroscience,2003,14:857-860.
10 Cui Ping Chen, Peter Kuhn, Kirti Chaturvedi, et al. Ethanol Induces Apoptotic Deathof Developingβ-Endorphin Neurons via Suppression of Cyclic Adenosine Monophosphate Production and Activation of Transforming Growth Factor-β1-Linked Apoptotic Signaling[J]. Mol Pharmacol 2006,69:706–717.
11 Dipak K. Sarkar, Peter Kuhn, Jasson Marano, et al. Alcohol Exposure during the Developmental Period Inducesβ-Endorphin Neuronal Death and Causes Alteration in the Opioid Control of Stress Axis Function[J]. Endocrinology: 2007,148: 2828–2834.
12 Peter Kuhn and Dipak K. Sarkar. Ethanol Induces Apoptotic Death ofβ-Endorphin Neurons in the Rat Hypothalamus by a TGF-b1-Dependent Mechanism[J]. Alcoholism: Clinical and Experimental Research,2008,32:706-714.
13 Ariane de Luca, Michael Weller, Adriano Fontana. TGF-β-Induced Apoptosis of Cerebellar Granule Neurons Is Prevented by Depolarization[J]. Neuroscience, 1996, 16(13):4174–4185.
14 Marion S. Buckwalter, Makiko Yamane, Bronwen S. Coleman, et al. Chronically Increased Transforming Growth Factor-β1 Strongly Inhibits Hippocampal Neurogenesis in Aged Mice[J]. American Journal of Pathology,2006,169:154-164.
15 David M. Ashley, Feng M. Kong, Darell D. Bigner, et al. Endogenous Expression of Transforming Growth Factorβ1 Inhibits Growth and Tumorigenicity and Enhances Fas-mediated Apoptosis in a Murine High-Grade Glioma Model[J].Cancer Research ,1998,58:302-309.
16 Pradeep Salins, Yang He, Kelly Olson, et al. TGF-β1 is increased in a transgenic mouse model of familial Alzheimer’s disease and causes neuronal apoptosis[J]. Neuroscience Letters 430 (2008) 81–86.
17 Yuan Zhu , Barbara Ahlemeyer, Elke Bauerbach, et al. TGF-β1 inhibits caspase-3 activation and neuronal apoptosis in rat hippocampal cultures[J]. Neurochemistry International ,38 (2001) 227–235.
18 Yuan Zhu, Guo-Yuan Yang, Barbara Ahlemeyer, et al. Transforming Growth Factor-β1 Increases Bad Phosphorylation and Protects Neurons Against Damage[J].Neuroscience,2002, 22(10):3898–3909.
19 JOCHEN H. M. PREHN, VYTAUTAS P. BINDOKAS, CHARLES J. MARCUCCILLI, et al. Regulation of neuronal Bcl2 protein expression and calcium homeostasis by transforming growth factor typeβconfers wide-ranging protection on rat hippocampal neurons[J]. Neurobiology,1994,91:12599-12603.
20 Alain Buisson, Sylvain Lesne, Fabian Docagne, et al. Transforming Growth Factor-βand Ischemic Brain Injury[J]. Cellular and Molecular Neurobiology,2003,13:539-550.
21 Y. Zhua , S. Roth-Eichhorn, N. Braun, C. Culmsee,et al. The expression of transforming growth factor-beta1 (TGF-β1) in hippocampal neurons: a temporary upregulated protein level after transient forebrain ischemia in the rat[J]. Brain Research,866 (2000) 286–298.
22 Hans-Georg K?nig, Donat K?gel, Abdelhaq Rami, et al. TGF-β1 activates two distinct type I receptors in neurons: implications for neuronal NF-?B signaling[J]. Cell Biology, 2005,168: 1077-1086.
2. Henshall, D.C. and R.P. Simon, Epilepsy and apoptosis pathways. J Cereb Blood Flow Metab, 2005. 25(12): p. 1557-72.
3. Zhang, Y., et al., Granulocyte colony-stimulating factor treatment prevents cognitive impairment following status epilepticus in rats. Biol Pharm Bull, 2010.33(4): p. 572-9.
4. Gomes, F.C., O. Sousa Vde, and L. Romao, Emerging roles for TGF-beta1 in nervous system development. Int J Dev Neurosci, 2005. 23(5): p. 413-24.
5. Ma, M., et al., Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone. BMC Neurosci, 2008. 9: p. 117.
6. Zhang, H., et al., Small molecule tgf-beta mimetics as potential neuroprotective factors. Curr Alzheimer Res, 2005. 2(2): p. 183-6.
7. Mirshafiey, A. and M. Mohsenzadegan, TGF-beta as a promising option in the treatment of multiple sclerosis. Neuropharmacology, 2009. 56(6-7): p. 929-36.
8. Zhu, Y., et al., TGF-beta1 inhibits caspase-3 activation and neuronal apoptosis in rat hippocampal cultures. Neurochem Int, 2001. 38(3): p. 227-35.
9. Morgan, T.E., et al., TGF-beta 1 mRNA increases in macrophage/microglial cells of the hippocampus in response to deafferentation and kainic acid-induced neurodegeneration. Exp Neurol, 1993. 120(2): p. 291-301.
10. Brionne, T.C., et al., Loss of TGF-beta 1 leads to increased neuronal cell death and microgliosis in mouse brain. Neuron, 2003. 40(6): p. 1133-45.
11. Plata-Salaman, C.R., et al., Kindling modulates the IL-1beta system, TNF-alpha, TGF-beta1, and neuropeptide mRNAs in specific brain regions. Brain Res Mol Brain Res, 2000. 75(2): p. 248-58.
12. Ma, Y.P., et al., Intranasally delivered TGF-beta1 enters brain and regulates gene expressions of its receptors in rats. Brain Res Bull, 2007. 74(4): p. 271-7.
13. Hanson, L.R. and W.H. Frey, 2nd, Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci, 2008. 9 Suppl 3: p. S5.
14. Racine, R.J., Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol, 1972. 32(3): p. 281-94.
15. Engrand, N. and A. Crespel, [Pathophysiologic basis of status epilepticus]. Rev Neurol (Paris), 2009. 165(4): p. 315-9.
16. Knake, S., H.M. Hamer, and F. Rosenow, Status epilepticus: a critical review. Epilepsy Behav, 2009. 15(1): p. 10-4.
17. Curia, G., et al., The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods, 2008. 172(2): p. 143-57.
18. Garcia-Penas, J.J., [Neurocognitive dysfunction in electrical status epilepticus during slow-wave sleep syndrome: Can the natural course of the syndrome be modified with early pharmacological treatment?]. Rev Neurol, 2010. 50 Suppl 3: p. S37-47.
19. Magloczky, Z. and T.F. Freund, Delayed cell death in the contralateral hippocampus following kainate injection into the CA3 subfield. Neuroscience, 1995. 66(4): p. 847-60.
20. Narkilahti, S., et al., Expression and activation of caspase 3 following status epilepticus in the rat. Eur J Neurosci, 2003. 18(6): p. 1486-96.
21. Fujikawa, D.G., S.S. Shinmei, and B. Cai, Lithium-pilocarpine-induced status epilepticus produces necrotic neurons with internucleosomal DNA fragmentation in adult rats. Eur J Neurosci, 1999. 11(5): p. 1605-14.
22. Liou, A.K., et al., To die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: a review on the stress-activated signaling pathways and apoptotic pathways. Prog Neurobiol, 2003. 69(2): p. 103-42.
23. Gorter, J.A., et al., Neuronal cell death in a rat model for mesial temporal lobe epilepsy is induced by the initial status epilepticus and not by later repeated spontaneous seizures. Epilepsia, 2003. 44(5): p. 647-58.
24. Schmued, L.C. and K.J. Hopkins, Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res, 2000. 874(2): p. 123-30.
25. Kundrotiene, J., A. Wagner, and S. Liljequist, Fluoro-Jade and TUNEL staining as useful tools to identify ischemic brain damage following moderate extradural compression of sensorimotor cortex. Acta Neurobiol Exp (Wars), 2004. 64(2): p. 153-62.
26. Kubova, H., et al., Dynamic changes of status epilepticus-induced neuronal degeneration in the mediodorsal nucleus of the thalamus during postnatal development of the rat. Epilepsia, 2002. 43 Suppl 5: p. 54-60.
27. Butler, T.L., et al., Neurodegeneration in the rat hippocampus and striatum after middle cerebral artery occlusion. Brain Res, 2002. 929(2): p. 252-60.
28. Eyupoglu, I.Y., et al., Identification of neuronal cell death in a model of degeneration in the hippocampus. Brain Res Brain Res Protoc, 2003. 11(1): p. 1-8.
29. Zhu, Y., et al., The expression of transforming growth factor-beta1 (TGF-beta1) in hippocampal neurons: a temporary upregulated protein level after transient forebrain ischemia in the rat. Brain Res, 2000. 866(1-2): p. 286-98.
30. Caraci, F., et al., TGF-beta1 Pathway as a New Target for Neuroprotection in Alzheimer's Disease. CNS Neurosci Ther, 2009.
31. Sanchez-Capelo, A., Dual role for TGF-beta1 in apoptosis. Cytokine Growth Factor Rev, 2005. 16(1): p. 15-34.
32. Scorza, F.A., et al., The pilocarpine model of epilepsy: what have we learned? An Acad Bras Cienc, 2009. 81(3): p. 345-65.
33. Prehn, J.H., et al., Regulation of neuronal Bcl2 protein expression and calcium homeostasis by transforming growth factor type beta confers wide-ranging protection on rat hippocampal neurons. Proc Natl Acad Sci U S A, 1994. 91(26): p. 12599-603.
34. Prehn, J.H., C. Backhauss, and J. Krieglstein, Transforming growth factor-beta 1 prevents glutamate neurotoxicity in rat neocortical cultures and protects mouseneocortex from ischemic injury in vivo. J Cereb Blood Flow Metab, 1993. 13(3): p. 521-5.
35. Wetherington, J., G. Serrano, and R. Dingledine, Astrocytes in the epileptic brain. Neuron, 2008. 58(2): p. 168-78.
36. Lindholm, D., et al., Transforming growth factor-beta 1 in the rat brain: increase after injury and inhibition of astrocyte proliferation. J Cell Biol, 1992. 117(2): p. 395-400.
37. Buisson, A., et al., Transforming growth factor-beta and ischemic brain injury. Cell Mol Neurobiol, 2003. 23(4-5): p. 539-50.
38. Fabene, P.F., et al., Pilocarpine-induced status epilepticus in rats involves ischemic and excitotoxic mechanisms. PLoS One, 2007. 2(10): p. e1105.
39. Ivens, S., et al., TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain, 2007. 130(Pt 2): p. 535-47.
40. Cacheaux, L.P., et al., Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. J Neurosci, 2009. 29(28): p. 8927-35.
41. Konig, H.G., et al., TGF-{beta}1 activates two distinct type I receptors in neurons: implications for neuronal NF-{kappa}B signaling. J Cell Biol, 2005. 68(7): p. 1077-86.
42. Xiao, B.G., et al., Transforming growth factor-beta1 induces apoptosis of rat microglia without relation to bcl-2 oncoprotein expression. Neurosci Lett, 1997. 226(2): p. 71-4.
43. Sandoval, K.E. and K.A. Witt, Blood-brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis, 2008. 32(2): p. 200-19.
44. Pardridge, W.M., The blood-brain barrier: bottleneck in brain drug development. NeuroRx, 2005. 2(1): p. 3-14.
45. Kastin, A.J., V. Akerstrom, and W. Pan, Circulating TGF-beta1 does not cross the intact blood-brain barrier. J Mol Neurosci, 2003. 21(1): p. 43-8.
46. Wakefield, L.M., et al., Recombinant latent transforming growth factor beta 1 has a longer plasma half-life in rats than active transforming growth factor beta 1, and a different tissue distribution. J Clin Invest, 1990. 86(6): p. 1976-84.
47. Border, W.A. and N.A. Noble, Transforming growth factor beta in tissue fibrosis. N Engl J Med, 1994. 331(19): p. 1286-92.
48. Pathan, S.A., et al., CNS drug delivery systems: novel approaches. Recent Pat Drug Deliv Formul, 2009. 3(1): p. 71-89.
49. Merelli, A., et al., Recovery of Motor Spontaneous Activity After Intranasal Delivery of Human Recombinant Erythropoietin in a Focal Brain Hypoxia Model Induced by CoCl(2) in Rats. Neurotox Res, 2010.
50. Veronesi, M.C., D.J. Kubek, and M.J. Kubek, Intranasal delivery of a thyrotropin-releasing hormone analog attenuates seizures in the amygdala-kindled rat. Epilepsia, 2007. 48(12): p. 2280-6.
51. Liu, X.F., et al., Non-invasive intranasal insulin-like growth factor-I reduces infarct volume and improves neurologic function in rats following middle cerebral artery occlusion. Neurosci Lett, 2001. 308(2): p. 91-4.
52. Jogani, V., et al., Recent patents review on intranasal administration for CNS drug delivery. Recent Pat Drug Deliv Formul, 2008. 2(1): p. 25-40.
53. Yang, J., et al., Erythropoietin preconditioning suppresses neuronal death following status epilepticus in rats. Acta Neurobiol Exp (Wars), 2007. 67(2): p. 141-8.
54. Wen, X., Y. Huang, and J. Wang, Erythropoietin preconditioning on hippocampus neuronal apoptosis following status epilepticus induced by Li-pilocarpine in rats through anti-caspase-3 expression. Neurol India, 2006. 54(1): p. 58-63; discussion 63.
55. Jun, Y., et al., Erythropoietin pre-treatment prevents cognitive impairments following status epilepticus in rats. Brain Res, 2009. 1282: p. 57-66.
56. Sankar, R., et al., Patterns of status epilepticus-induced neuronal injury during development and long-term consequences. J Neurosci, 1998. 18(20): p. 8382-93.
57. Niquet, J. and C.G. Wasterlain, Bim, Bad, and Bax: a deadly combination in epileptic seizures. J Clin Invest, 2004. 113(7): p. 960-2.
58. Xu, J., et al., Ghrelin protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats. Neurosci Lett, 2009. 453(1): p. 58-61.
59. Xiang, J., et al., Chinese medicine Nao-Shuan-Tong attenuates cerebral ischemic injury by inhibiting apoptosis in a rat model of stroke. J Ethnopharmacol, 2010. 131(1): p. 174-81.
60. Weise, J., et al., Expression time course and spatial distribution of activated caspase-3 after experimental status epilepticus: contribution of delayed neuronal cell death to seizure-induced neuronal injury. Neurobiol Dis, 2005. 18(3): p. 582-90.
61. Ekdahl, C.T., et al., Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus. Eur J Neurosci, 2001. 14(6): p. 937-45.
1 Kerstin Krieglsteina, Jens Strelaub, Andreas Schoberb, et al. TGF-βand the regulation of neuron survival and death . Physiology -Paris, 96 (2002) 25-30.
2 Massague J. TGF-βsignal transduction[J]. Annu Rev Biochem,1998,67:753 -791.
3万赛英,顾卫,谭锋.转化生长因子β1与脑缺血[J].国际脑血管疾病分册. 2005, 13,No .8
4 T.E.Morgan, N.R.Nichols, G.M.Pasinetti, And C.E.Finch. TGF-β1mRNA increase in macrophage/microglial cell of the hippocampus in response to deafferentation and kainic acid-induced neurodegeneration[J]. Experimental Neurology,1993,120:291-301.
5 Thomas C. Brionne, Ina Tesseur, Eliezer Masliah, and Tony Wyss-Coray. Loss of TGF-β1 Leads to Increased Neuronal Cell Death and Microgliosis in Mouse Brain[J]. Neuron, 2003, 40, 1133–1145.
6 Carlos R. Plata-Salam′an, Sergey E. Ilyin , Nicolas P. Turrin , et al. Kindling modulates the IL-1βsystem, TNF-α, TGF-β1, and neuropeptide mRNAs in specific brain regions[J]. Molecular Brain Research.2000,75: 248–258.
7 FULVIO A. SCORZA, RICARDO M. ARIDA, MARIA DA GRA?A NAFFAH-MAZZACORATTI, et al. The pilocarpine model of epilepsy: what have we learned? [J]. Anais da Academia Brasileira de Ciências, 2009, 81(3): 345-365
8 JOCHEN H. M. PREHN, et al. Regulation of neuronal Bcl2 protein expression and calcium homeostasis by transforming growth factor typeβconfers wide-ranging protection on rat hippocampal neurons[J]. Neurobiology, 1994,91:12599-12603.
9 P rehn JH, Backhauss C, Krieg J, et al. Transforming growth factor betal prevents glutamate neurotoxicity in rat neoc rtical cultures and protects mouse neocortes from ischemic injury in vivo[J]. J Cereb Blood Flow Metab, 1993, 13 :521-525.
10 Wetherington, J., G. Serrano, and R. Dingledine. Astrocytes in the epileptic brain[J]. Neuron, 2008, 58(2): 168-78.
11 Dan Lindholm, et al. Transforming growth factor-β1 in rat brain:increase after injury and inhibition of astrocyte proliferation[J]. Cell Biology,1992,117,395-400.
12 Yuan Zhu , Barbara Ahlemeyer, Elke Bauerbach, et al. TGF-β1 inhibits caspase-3 activation and neuronal apoptosis in rat hippocampal cultures[J]. Neurochemistry International ,38 (2001) 227–235.
13 Alain Buisson, Sylvain Lesne, Fabian Docagne, et al. Transforming Growth Factor-βand Ischemic Brain Injury[J]. Cellular and Molecular Neurobiology,2003,13:539-550.
14 Fabene, P.F., et al. Pilocarpine-induced status epilepticus in rats involves ischemic and excitotoxic mechanisms[J]. PLoS One, 2007, 2(10): e1105.
15 Minmin Ma, Yuping Ma, Xueming Yi, et al. Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone[J]. BMC Neuroscience, 2008, 9(117): 1-10.
16 Sebastian Ivens, et al. TGF-βreceptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis[J]. Brain, 2007, 130:535–547.
17 Sebastian Ivens, et al. Transcriptome Profiling Reveals TGF-βSignaling Involvement in Epileptogenesis[J]. Neuroscience, 2009 ,29,:8927– 8935.
18 Hans-Georg K?nig, Donat K?gel,Abdelhaq Rami, et al. TGF-β1 activates two distinct type I receptors in neurons: implications for neuronal NF-?B signaling[J]. Cell Biology, 2005,168: 1077-1086.
19 Alon Friedman, Daniela Kaufer, Uwe Heinemann. Blood—brain barrier breakdown-inducing astrocytic transformation: Novel targets for the prevention of epilepsy[J]. Epilepsy Research,2009, 85:142—149.
20 Xuefeng WANG, et al. Increased expression of TGFβtype I receptor in brain tissues of patients with temporal lobe epilepsy[J]. Clinical Science,2009,117:17–22.
21 Peter ten Dijke, et al. Activin receptor-like kinase(ALK)1 is antagonistic mediator of lateral TGFβ/ALK5 signaling[J]. Molecular Cell,2003,12:817-828.
22 Xiao, B.G., et al. Transforming growth factor-beta1 induces apoptosis of rat microglia without relation to bcl-2 oncoprotein expression[J]. Neurosci Lett, 1997. 226(2): 71-4.
23 Sanchez-Capelo A., Dual role for TGF-beta1 in apoptosis[J]. Cytokine Growth Factor Rev, 2005. 16(1): 15-34.
1 Kerstin Krieglsteina, Jens Strelaub, Andreas Schoberb, et al. TGF-βand the regulation of neuron survival and death[J]. Physiology -Paris, 96 (2002) 25-30.
2 Massague J. TGF-βsignal transduction[J]. Annu Rev Biochem,1998,67:753 -791.
3万赛英,顾卫,谭锋.转化生长因子β1与脑缺血[J].国际脑血管疾病. 2005, 13, No .8
4 Amelia Sa′nchez-Capelo. Dual role for TGF-βin apoptosis[J]. Cytokine & Growth Factor ,16 (2005) 15-34.
5 Filippo Caraci, Giuseppe Battaglia, et al. TGF-β1 Pathway as a New Target for Neuroprotection in Alzheimer’s Disease[J]. Neuroscience & Therapeutics 00 (2009) 1-13.
6 Henshall DC,Simon RP.Epilepsy and apoptosis pathways [J].Cereb Blood Flow Metab,2005,25(12):1557-1572.
7陈旭东,赵文清,吴耀晨.中国老年学杂志,1999,19.
8 Bao-Gou Xiao, Xue-Feng Bai, Guang-Xian Zhang, et al. Transforming growth factor-β1 induces apoptosis of rat microglia without relation to bcl-2 oncoprotein expression[J]. Neuroscience Letters ,226 (1997) 71-74.
9 Bomi Jung, Mi-Ok Kim, Su-Jin Yun , et al. Down-regulation of the expression of rat inhibitor-of-apoptosis protein-1 and -3 during transforming growth factor-β1-mediated apoptosis in rat brain microglia[J]. Molecular Neuroscience,2003,14:857-860.
10 Cui Ping Chen, Peter Kuhn, Kirti Chaturvedi, et al. Ethanol Induces Apoptotic Deathof Developingβ-Endorphin Neurons via Suppression of Cyclic Adenosine Monophosphate Production and Activation of Transforming Growth Factor-β1-Linked Apoptotic Signaling[J]. Mol Pharmacol 2006,69:706–717.
11 Dipak K. Sarkar, Peter Kuhn, Jasson Marano, et al. Alcohol Exposure during the Developmental Period Inducesβ-Endorphin Neuronal Death and Causes Alteration in the Opioid Control of Stress Axis Function[J]. Endocrinology: 2007,148: 2828–2834.
12 Peter Kuhn and Dipak K. Sarkar. Ethanol Induces Apoptotic Death ofβ-Endorphin Neurons in the Rat Hypothalamus by a TGF-b1-Dependent Mechanism[J]. Alcoholism: Clinical and Experimental Research,2008,32:706-714.
13 Ariane de Luca, Michael Weller, Adriano Fontana. TGF-β-Induced Apoptosis of Cerebellar Granule Neurons Is Prevented by Depolarization[J]. Neuroscience, 1996, 16(13):4174–4185.
14 Marion S. Buckwalter, Makiko Yamane, Bronwen S. Coleman, et al. Chronically Increased Transforming Growth Factor-β1 Strongly Inhibits Hippocampal Neurogenesis in Aged Mice[J]. American Journal of Pathology,2006,169:154-164.
15 David M. Ashley, Feng M. Kong, Darell D. Bigner, et al. Endogenous Expression of Transforming Growth Factorβ1 Inhibits Growth and Tumorigenicity and Enhances Fas-mediated Apoptosis in a Murine High-Grade Glioma Model[J].Cancer Research ,1998,58:302-309.
16 Pradeep Salins, Yang He, Kelly Olson, et al. TGF-β1 is increased in a transgenic mouse model of familial Alzheimer’s disease and causes neuronal apoptosis[J]. Neuroscience Letters 430 (2008) 81–86.
17 Yuan Zhu , Barbara Ahlemeyer, Elke Bauerbach, et al. TGF-β1 inhibits caspase-3 activation and neuronal apoptosis in rat hippocampal cultures[J]. Neurochemistry International ,38 (2001) 227–235.
18 Yuan Zhu, Guo-Yuan Yang, Barbara Ahlemeyer, et al. Transforming Growth Factor-β1 Increases Bad Phosphorylation and Protects Neurons Against Damage[J].Neuroscience,2002, 22(10):3898–3909.
19 JOCHEN H. M. PREHN, VYTAUTAS P. BINDOKAS, CHARLES J. MARCUCCILLI, et al. Regulation of neuronal Bcl2 protein expression and calcium homeostasis by transforming growth factor typeβconfers wide-ranging protection on rat hippocampal neurons[J]. Neurobiology,1994,91:12599-12603.
20 Alain Buisson, Sylvain Lesne, Fabian Docagne, et al. Transforming Growth Factor-βand Ischemic Brain Injury[J]. Cellular and Molecular Neurobiology,2003,13:539-550.
21 Y. Zhua , S. Roth-Eichhorn, N. Braun, C. Culmsee,et al. The expression of transforming growth factor-beta1 (TGF-β1) in hippocampal neurons: a temporary upregulated protein level after transient forebrain ischemia in the rat[J]. Brain Research,866 (2000) 286–298.
22 Hans-Georg K?nig, Donat K?gel, Abdelhaq Rami, et al. TGF-β1 activates two distinct type I receptors in neurons: implications for neuronal NF-?B signaling[J]. Cell Biology, 2005,168: 1077-1086.