膜表面活性剂泊洛沙姆188抗脑外伤后神经细胞死亡作用及机制研究
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摘要
目的：细胞质膜完整性的破坏是导致脑外伤后继发性损伤的主要原因之一,我们的前期研究证实脑外伤可引起神经细胞凋亡及自噬激活等一些继发性事件。本研究主要以质膜完整性作为切入点,探索质膜修复剂泊洛沙姆188(P188)能否对脑外伤引起的细胞凋亡及自噬等产生影响,进而起到神经保护作用,并对其保护机制进行探讨。
方法：利用改良的自由落体装置建立小鼠定量脑外伤(traumatic brain injury, TBI)模型。脑外伤后P188通过鼠尾静脉立即给药,并按伤后时间不同分别于处死前1h用腹腔注射法将碘化丙啶(propidium iodide, PI)注入各组小鼠腹腔内,采用体视学显微镜观察损伤细胞并计数各组损伤中心区及周边区阳性细胞数,研究P188对TBI引起的神经细胞质膜完整性破坏的影响；为了探讨PI阳性细胞能否代表脑外伤引起的细胞丢失,用组织缺损体积(lesion volume, LV)评估TBI后脑组织缺损情况；应用行为学试验(Motor Test和Morris水迷宫试验)方法评估TBI后各组动物的运动和学习记忆功能,以探讨脑外伤引起的细胞丢失能否导致功能性损害。同时还检测了激活型的Caspase-3及凋亡相关蛋白表达水平,并对凋亡机制进行了深入的探讨；并检测了P188对脑外伤后细胞自噬信号途径的影响,并对其作用机制进行了探讨。
结果：(1)脑外伤后伤侧脑组织中均发现PI阳性细胞,其数量在24小时至48小时时间点达到高峰；与生理盐水组比较,P188组PI阳性细胞数量均在脑外伤后24小时和48小时时间点显著降低(P<0.05)。(2)与生理盐水组比较,P188能明显减少脑的缺损体积；与假手术组比较,小鼠脑外伤后寻找水迷宫平台有更长的潜伏期,提示脑外伤能引起学习和记忆功能障碍；与生理盐水组比较,P188处理后能明显加快其运动功能的恢复；P188处理组在脑外伤后表现出更短的潜伏期(P<0.05)。(3)脑外伤引起的caspase-3的激活、细胞色素c释放、Bcl-2蛋白表达水平下调以及Bax、P53蛋白表达水平表达上调,P188处理后能逆转这种改变；与盐水组比较,P188处理后使caspase-8和caspase-9的蛋白水平下调。(4)与盐水组比较,P188组脑外伤引起的的LC-3Ⅱ蛋白表达水平明显增高,P62明显降低,hVps34与Beclin-1蛋白水平大量增加。
结论：(1)P188处理后能减少脑外伤引起的细胞死亡和脑组织缺损,减轻运动及学习记忆功能障碍。(2)脑外伤后可引起神经细胞凋亡,P188通过抑制caspase-8和caspase-9以及细胞色素C的水平显著抑制TBI引起的神经细胞凋亡。(3)脑外伤后可激活自噬,P188通过调节Beclin-1/Bcl-2比值、促进hVps34表达来进一步促进自噬激活。
Objective:It has been reported that the loss in cell membrane integrity is a major contributor to the development of neuronal damage subsequent to traumatic brain injury (TBI). Our previous study has showed that TBI causes increasing of neural cell apoptosis and autophagy, and resealing of disrupted plasma membranes is a criticality therapeutic strategy for TBI. But the mechanism of rescue the subsequent damaged neuron in TBI after cell membrane integrity recovery remains elusive. Here, we utilized a copolymer membrane sealant, Poloxamer188(P188), to investigate whether the apoptosis and autophagy involve in the mechanism of rescuing cell death in our mice TBI model.
Methods:Mice TBI model was established by weight drop device in adult mice based on procedures previously reported. P188was administered with tail intravenous injection after TBI. Mice were pretreated with intraperitoneal injection of propidium iodide (PI)1h before sacrificed. PI-labeling was used to identify injured cells, and the amount of PI positive cells was counted. Furthermore, the cumulative loss of brain tissue was determined to explore whether PI-positive cells could represent TBI-induced cell lost. Finally, motor test and Morris water maze were performed for detecting whether TBI-induced cell loss would result in behavior deficits. We examined the levels of apoptosis associate proteins, and the protein levels of LC-3, beclin-1,P-Akt, hVps34were also detected.
Results:(1) PI-positive cells were found in all groups that surffered TBI. The number of PI-positive cells peaked in the24h time-point group, and P188treatment significantly decreased the number of PI-positive cells.(2) Compared with saline vehicle groups, P188treatment markedly reduced lesion volume and behavioral deficits which induced by TBI.(3) An elevated activated caspase-3, bax and P53protein levels were detected after TBI, but the elevation were suppressed by P188treatment. However, Bcl-2protein levels were up-regulated by P188. To further explore the mechanism of P188reduces apoptosis, cyt-c, caspase-8, caspase-9protein levels were also assessed by Western-bloting after TBI. The TBI induced up-regulation of cyt-c, caspase-8, and caspase-9protein levels were also reversed by P188.(4) Microtubule-associated protein light chain3(LC3Ⅱ) was up-regulated after TBI in P188treatment groups when compared with saline vehicle groups. To further investigate the mechanism of P188increases autophagy, P62, hVps34and Beclin-1protein levels were assessed. Compared with saline vehicle groups, P62level was significantly decreased vs. Vps34and Beclin-1remarkably increased in P188treatment groups.
Conclusion:(1) P188remarkably attenuated TBI-induced neural cell death, lesion volume, and motor and cognitive dysfunction.(2) P188reduced TBI induced apoptosis through both extrinsic and intrinsic pathway.(3) Autophagy is activated by P188treatment after TBI. P188promoted autophagy activation may rescue the subsequent damaged cells from death following TBI.
方法：利用改良的自由落体装置建立小鼠定量脑外伤(traumatic brain injury, TBI)模型。脑外伤后P188通过鼠尾静脉立即给药,并按伤后时间不同分别于处死前1h用腹腔注射法将碘化丙啶(propidium iodide, PI)注入各组小鼠腹腔内,采用体视学显微镜观察损伤细胞并计数各组损伤中心区及周边区阳性细胞数,研究P188对TBI引起的神经细胞质膜完整性破坏的影响；为了探讨PI阳性细胞能否代表脑外伤引起的细胞丢失,用组织缺损体积(lesion volume, LV)评估TBI后脑组织缺损情况；应用行为学试验(Motor Test和Morris水迷宫试验)方法评估TBI后各组动物的运动和学习记忆功能,以探讨脑外伤引起的细胞丢失能否导致功能性损害。同时还检测了激活型的Caspase-3及凋亡相关蛋白表达水平,并对凋亡机制进行了深入的探讨；并检测了P188对脑外伤后细胞自噬信号途径的影响,并对其作用机制进行了探讨。
结果：(1)脑外伤后伤侧脑组织中均发现PI阳性细胞,其数量在24小时至48小时时间点达到高峰；与生理盐水组比较,P188组PI阳性细胞数量均在脑外伤后24小时和48小时时间点显著降低(P<0.05)。(2)与生理盐水组比较,P188能明显减少脑的缺损体积；与假手术组比较,小鼠脑外伤后寻找水迷宫平台有更长的潜伏期,提示脑外伤能引起学习和记忆功能障碍；与生理盐水组比较,P188处理后能明显加快其运动功能的恢复；P188处理组在脑外伤后表现出更短的潜伏期(P<0.05)。(3)脑外伤引起的caspase-3的激活、细胞色素c释放、Bcl-2蛋白表达水平下调以及Bax、P53蛋白表达水平表达上调,P188处理后能逆转这种改变；与盐水组比较,P188处理后使caspase-8和caspase-9的蛋白水平下调。(4)与盐水组比较,P188组脑外伤引起的的LC-3Ⅱ蛋白表达水平明显增高,P62明显降低,hVps34与Beclin-1蛋白水平大量增加。
结论：(1)P188处理后能减少脑外伤引起的细胞死亡和脑组织缺损,减轻运动及学习记忆功能障碍。(2)脑外伤后可引起神经细胞凋亡,P188通过抑制caspase-8和caspase-9以及细胞色素C的水平显著抑制TBI引起的神经细胞凋亡。(3)脑外伤后可激活自噬,P188通过调节Beclin-1/Bcl-2比值、促进hVps34表达来进一步促进自噬激活。
Objective:It has been reported that the loss in cell membrane integrity is a major contributor to the development of neuronal damage subsequent to traumatic brain injury (TBI). Our previous study has showed that TBI causes increasing of neural cell apoptosis and autophagy, and resealing of disrupted plasma membranes is a criticality therapeutic strategy for TBI. But the mechanism of rescue the subsequent damaged neuron in TBI after cell membrane integrity recovery remains elusive. Here, we utilized a copolymer membrane sealant, Poloxamer188(P188), to investigate whether the apoptosis and autophagy involve in the mechanism of rescuing cell death in our mice TBI model.
Methods:Mice TBI model was established by weight drop device in adult mice based on procedures previously reported. P188was administered with tail intravenous injection after TBI. Mice were pretreated with intraperitoneal injection of propidium iodide (PI)1h before sacrificed. PI-labeling was used to identify injured cells, and the amount of PI positive cells was counted. Furthermore, the cumulative loss of brain tissue was determined to explore whether PI-positive cells could represent TBI-induced cell lost. Finally, motor test and Morris water maze were performed for detecting whether TBI-induced cell loss would result in behavior deficits. We examined the levels of apoptosis associate proteins, and the protein levels of LC-3, beclin-1,P-Akt, hVps34were also detected.
Results:(1) PI-positive cells were found in all groups that surffered TBI. The number of PI-positive cells peaked in the24h time-point group, and P188treatment significantly decreased the number of PI-positive cells.(2) Compared with saline vehicle groups, P188treatment markedly reduced lesion volume and behavioral deficits which induced by TBI.(3) An elevated activated caspase-3, bax and P53protein levels were detected after TBI, but the elevation were suppressed by P188treatment. However, Bcl-2protein levels were up-regulated by P188. To further explore the mechanism of P188reduces apoptosis, cyt-c, caspase-8, caspase-9protein levels were also assessed by Western-bloting after TBI. The TBI induced up-regulation of cyt-c, caspase-8, and caspase-9protein levels were also reversed by P188.(4) Microtubule-associated protein light chain3(LC3Ⅱ) was up-regulated after TBI in P188treatment groups when compared with saline vehicle groups. To further investigate the mechanism of P188increases autophagy, P62, hVps34and Beclin-1protein levels were assessed. Compared with saline vehicle groups, P62level was significantly decreased vs. Vps34and Beclin-1remarkably increased in P188treatment groups.
Conclusion:(1) P188remarkably attenuated TBI-induced neural cell death, lesion volume, and motor and cognitive dysfunction.(2) P188reduced TBI induced apoptosis through both extrinsic and intrinsic pathway.(3) Autophagy is activated by P188treatment after TBI. P188promoted autophagy activation may rescue the subsequent damaged cells from death following TBI.
引文
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