神经保护肽[Gly14]-Humanin对脑外伤的保护作用及其机制研究
摘要
目的：Humanin（HN）是2011年新鉴定出的一种神经保护肽，HN能抑制AD相关因子及疾病诱导的神经细胞死亡。HN的第14位的氨基酸丝氨酸被甘氨酸取代可形成HN衍生物[Gly14]-Humanin（HNG）。研究表明HNG减少缺血/再灌注诱导的脑梗死体积和改善其神经功能障碍。本研究中，我们将探索神经保护肽HNG对小鼠创伤性脑损伤（traumatic brain injury，TBI）是否具有保护作用，并探索HNG的神经保护作用与凋亡及自噬之间的关系。
方法：利用改良的自由落体装置建立小鼠TBI模型。TBI前15min小鼠侧脑室给予HNG，并于伤后47h腹腔注射碘化丙啶（propidium iodide，PI），TBI后48h（PI阳性细胞出现高峰时段）处死小鼠，采用体视学显微镜观察小鼠大脑损伤皮质及周边区，海马CA1，CA3及DG区PI阳性细胞数，研究HNG预处理对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）评估TBI后各组试验动物的运动和学习记忆功能，探讨TBI前15min侧脑室给予HNG及TBI后不同时间点腹腔给予HNG能否改善脑外伤后神经组织损伤及神经功能障碍。为了进一步探索HNG对TBI的神经保护机制，采用TBI前15min侧脑室给予HNG，检测TBI后不同时间点损伤皮质区及海马区激活型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；同时检测HNG对脑外伤后损伤皮质区及海马区神经细胞自噬激活的影响，并对其作用机制进行探讨。
结果：（1）与生理盐水组对比，HNG侧脑室预处理（0.1μg）能明显减少TBI后48h损伤皮质区及海马区（CA1，CA3和DG）PI阳性细胞。此外，在正常组，假手术组及损伤对侧半球的皮质区及海马区均没有发现PI阳性细胞。（2）与生理盐水组对比，侧脑室预给予HNG（0.1μg）在TBI后14d及28d均能明显减少脑缺损体积，而TBI后1h或2h腹腔给予HNG（1μg）仍能减少脑缺损体积，但TBI后4h腹腔给予同样剂量HNG不能减少脑缺损体积。（3）TBI前，HNG组与生理盐水组具有相同的运动能力。TBI后，与TBI+vehicle组比较，TBI+HNG侧脑室给药组（0.1μg）能加快运动功能的恢复（TBI后第1-5d）。然而，TBI后1h腹腔给予HNG（1μg）只能轻微的加快运动功能的恢复（TBI后第2-3d）。而伤后2h和4h并不能加快运动的恢复。（4）TBI前，各组小鼠在定向航行试验，可视平台试验及空间探索试验中表现正常的学习曲线。HNG侧脑室预给药组在TBI后10-12d寻找平台所需时间明显比生理盐水对照组缩短，并且在空间探索试验具有更好的表现。采用HNG腹腔脑外伤后1h，2h和4h单次给药，结果发现上述各个时间单次给药均不能改善小鼠的定向航行试验，伤后1h（伤后2h或4h均不能）给予HNG能增加小鼠在平台所在象限的搜索时间。（5）免疫印迹分析显示HNG能逆转TBI诱导的caspase-3和PARP的剪切，Bax的增加和Bcl-2的减少，免疫荧光检测表明HNG能减少损伤皮质区及海马CA1，CA3及DG的caspase-3阳性细胞（TBI后48h）。进一步研究HNG的抗凋亡机制发现，HNG能通过抑制内外源性两条凋亡途径而抑制TBI诱导的凋亡激活。（6）与生理盐水组对比，HNG能抑制TBI诱导的自噬的激活，即抑制LC3II，Beclin-1及Vps34等蛋白的激活，维持p62的蛋白水平。进一步免疫荧光检测表明HNG能减少损伤皮质区及海马CA1，CA3及DG的Beclin-1阳性细胞（TBI后24h）。
结论：（1）HNG能抑制TBI诱导的细胞质膜完整性的破坏，减少脑缺损体积，改善运动和记忆功能障碍。（2）HNG能抑制TBI诱导的凋亡和自噬的激活，这可能参与HNG对TBI的神经保护机制。
Objective: Humanin (HN) has been identified as an endogenous peptide thatinhibited AD-relevant neuronal cell death.[Gly14]-Humanin (HNG), a variant of HN inwhich the14th amino acid serine was replaced with glycine, can reduce infarct volumeand improve neurological deficits after ischemia/reperfusion injury. In this study, weaimed to exam the neuroprotective effect of HNG on traumatic brain injury (TBI) inmice and explored whether the protective effects were associated with regulatingapoptosis and autophagy.
Methods: Mice TBI model was established by weight drop device in adult micebased on procedures previously reported. Mice were pretreated with HNG (i.c.v.,0.1μgin5μL saline) or saline, and sacrificed at48h after TBI. Loss of plasmalemma integritywas evaluated by intraperitoneal injection of propidium iodide1h before sacrificing theanimal. The number of PI-positive cells in injured cortex, dentate gyrus, CA1and CA3regions was counted. Furthermore, the cumulative loss of brain tissue was determined toexplore whether PI-positive cells could represent TBI-induced cell lost. Moreover,motor test and Morris water maze were performed for detecting whether TBI-inducedcell loss would result in behavior deficits. We examined whether pretreatment (i.c.v.) orposttreatment (i.p.) with HNG at different time can reduce brain tissue damage, andimprove the recovery of motor and cognitive dysfunction. To explore theneuroprotective mechanism of HNG after TBI, mice was pretreated (i.c.v.) with HNGand brain tissues were obtained for specific protein analysis. We examined the levels ofapoptosis and autophagy related proteins.
Results:(1) Compared to vehicle-treated group, HNG pretreatment (i.c.v.)decreased the number of PI-positive cells in injured cortex, dentate gyrus, CA1and CA3regions (P <0.01)48h post TBI. In contrast to injured mice, PI-positive cells werenot detected in brain regions from naive or sham-injured mice, or in the contralateralhemisphere of injured mice.(2) Compared to vehicle-treated groups, mice administeredHNG (i.c.v.,0.1μg) prior to TBI had significantly reduced lesion volume byapproximately25-30%at14days after TBI (P <0.01) and even at28days after TBI (P<0.01), administration of HNG at1h or2h after TBI decreased lesion volume (P <0.05), but this effect was not significant when HNG was given4h after TBI.(3)Following TBI, pre-treatment with HNG (i.c.v.,0.1μg) improved the recovery of motorfunctional outcome on days1to5post TBI compared to vehicle (P <0.05). However,mice administered HNG (i.p.,1μg) at1h post TBI had minor amelioration in motorperformance (on days2to3post TBI) versus vehicle-treated mice, and there were noamelioration in motor performance when HNG was administered at2h and4h postinjury.(4) In Morris water maze experiments, mice showed normal acquisition curveson both hidden and visible platforms, and selective quadrant search on the probe trialbefore suffering TBI. Mice administered HNG before TBI had significantly decreasedescape latency to the hidden platform (on days10to12post TBI) and performedsignificantly better in probe trial test compared with vehicle-treated mice. Compared tovehicle-treated group, mice administered HNG (i.p.,1μg) at1h,2h and4h post injuryrespectively had similar performance in hidden platform trials. However, miceadministered HNG (i.p.,1μg) at1h, but not2h and4h post injury, had significantlyimproved probe trial performance versus vehicle-treated animals (P <0.05).(5)Immunoblotting results showed that HNG pretreatment (i.c.v.) reversed TBI-inducedcleavage of caspase-3and PARP, increase of Bax and decline of Bcl-2in injured cortexand hippocampus. Analyses of caspase-3expression by immunofluorescent staining at48h after traumatic brain injury shown HNG decreased the number of positive cells atthe cortical area near the site of injury and in the hippocampus (CA1, CA3and DG). Tofurther explore the anti-apoptosis mechanism of HNG, cyt-c, caspase-8and caspase-9protein levels were also assessed after TBI. The TBI induced up-regulation of cyt-c,caspase-8, and caspase-9were also reversed by HNG.(6) Compared withvehicle-treated group, HNG pretreatment (i.c.v.) suppressed activation of LC3II, Beclin-1and Vps34, and maintained p62level in injured cortex and hippocampus postTBI. In addition, immunofluorescent staining at24h after traumatic brain injury shownHNG decreased the number of Beclin-1positive cells at the cortical area near the site ofinjury and in the hippocampus (CA1, CA3and DG).
Conclusion:(1) HNG significantly suppressed TBI-induced cellular plasmalemmaintegrality disruption, reduced brain tissue damage, and improved the recovery of motorand cognitive dysfunction.(2) In addition, HNG was able to inhibit TBI-inducedapoptosis and autophagic activity, which may be involved in the neuroprotectivemechanism of HNG.
方法：利用改良的自由落体装置建立小鼠TBI模型。TBI前15min小鼠侧脑室给予HNG，并于伤后47h腹腔注射碘化丙啶（propidium iodide，PI），TBI后48h（PI阳性细胞出现高峰时段）处死小鼠，采用体视学显微镜观察小鼠大脑损伤皮质及周边区，海马CA1，CA3及DG区PI阳性细胞数，研究HNG预处理对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）评估TBI后各组试验动物的运动和学习记忆功能，探讨TBI前15min侧脑室给予HNG及TBI后不同时间点腹腔给予HNG能否改善脑外伤后神经组织损伤及神经功能障碍。为了进一步探索HNG对TBI的神经保护机制，采用TBI前15min侧脑室给予HNG，检测TBI后不同时间点损伤皮质区及海马区激活型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；同时检测HNG对脑外伤后损伤皮质区及海马区神经细胞自噬激活的影响，并对其作用机制进行探讨。
结果：（1）与生理盐水组对比，HNG侧脑室预处理（0.1μg）能明显减少TBI后48h损伤皮质区及海马区（CA1，CA3和DG）PI阳性细胞。此外，在正常组，假手术组及损伤对侧半球的皮质区及海马区均没有发现PI阳性细胞。（2）与生理盐水组对比，侧脑室预给予HNG（0.1μg）在TBI后14d及28d均能明显减少脑缺损体积，而TBI后1h或2h腹腔给予HNG（1μg）仍能减少脑缺损体积，但TBI后4h腹腔给予同样剂量HNG不能减少脑缺损体积。（3）TBI前，HNG组与生理盐水组具有相同的运动能力。TBI后，与TBI+vehicle组比较，TBI+HNG侧脑室给药组（0.1μg）能加快运动功能的恢复（TBI后第1-5d）。然而，TBI后1h腹腔给予HNG（1μg）只能轻微的加快运动功能的恢复（TBI后第2-3d）。而伤后2h和4h并不能加快运动的恢复。（4）TBI前，各组小鼠在定向航行试验，可视平台试验及空间探索试验中表现正常的学习曲线。HNG侧脑室预给药组在TBI后10-12d寻找平台所需时间明显比生理盐水对照组缩短，并且在空间探索试验具有更好的表现。采用HNG腹腔脑外伤后1h，2h和4h单次给药，结果发现上述各个时间单次给药均不能改善小鼠的定向航行试验，伤后1h（伤后2h或4h均不能）给予HNG能增加小鼠在平台所在象限的搜索时间。（5）免疫印迹分析显示HNG能逆转TBI诱导的caspase-3和PARP的剪切，Bax的增加和Bcl-2的减少，免疫荧光检测表明HNG能减少损伤皮质区及海马CA1，CA3及DG的caspase-3阳性细胞（TBI后48h）。进一步研究HNG的抗凋亡机制发现，HNG能通过抑制内外源性两条凋亡途径而抑制TBI诱导的凋亡激活。（6）与生理盐水组对比，HNG能抑制TBI诱导的自噬的激活，即抑制LC3II，Beclin-1及Vps34等蛋白的激活，维持p62的蛋白水平。进一步免疫荧光检测表明HNG能减少损伤皮质区及海马CA1，CA3及DG的Beclin-1阳性细胞（TBI后24h）。
结论：（1）HNG能抑制TBI诱导的细胞质膜完整性的破坏，减少脑缺损体积，改善运动和记忆功能障碍。（2）HNG能抑制TBI诱导的凋亡和自噬的激活，这可能参与HNG对TBI的神经保护机制。
Objective: Humanin (HN) has been identified as an endogenous peptide thatinhibited AD-relevant neuronal cell death.[Gly14]-Humanin (HNG), a variant of HN inwhich the14th amino acid serine was replaced with glycine, can reduce infarct volumeand improve neurological deficits after ischemia/reperfusion injury. In this study, weaimed to exam the neuroprotective effect of HNG on traumatic brain injury (TBI) inmice and explored whether the protective effects were associated with regulatingapoptosis and autophagy.
Methods: Mice TBI model was established by weight drop device in adult micebased on procedures previously reported. Mice were pretreated with HNG (i.c.v.,0.1μgin5μL saline) or saline, and sacrificed at48h after TBI. Loss of plasmalemma integritywas evaluated by intraperitoneal injection of propidium iodide1h before sacrificing theanimal. The number of PI-positive cells in injured cortex, dentate gyrus, CA1and CA3regions was counted. Furthermore, the cumulative loss of brain tissue was determined toexplore whether PI-positive cells could represent TBI-induced cell lost. Moreover,motor test and Morris water maze were performed for detecting whether TBI-inducedcell loss would result in behavior deficits. We examined whether pretreatment (i.c.v.) orposttreatment (i.p.) with HNG at different time can reduce brain tissue damage, andimprove the recovery of motor and cognitive dysfunction. To explore theneuroprotective mechanism of HNG after TBI, mice was pretreated (i.c.v.) with HNGand brain tissues were obtained for specific protein analysis. We examined the levels ofapoptosis and autophagy related proteins.
Results:(1) Compared to vehicle-treated group, HNG pretreatment (i.c.v.)decreased the number of PI-positive cells in injured cortex, dentate gyrus, CA1and CA3regions (P <0.01)48h post TBI. In contrast to injured mice, PI-positive cells werenot detected in brain regions from naive or sham-injured mice, or in the contralateralhemisphere of injured mice.(2) Compared to vehicle-treated groups, mice administeredHNG (i.c.v.,0.1μg) prior to TBI had significantly reduced lesion volume byapproximately25-30%at14days after TBI (P <0.01) and even at28days after TBI (P<0.01), administration of HNG at1h or2h after TBI decreased lesion volume (P <0.05), but this effect was not significant when HNG was given4h after TBI.(3)Following TBI, pre-treatment with HNG (i.c.v.,0.1μg) improved the recovery of motorfunctional outcome on days1to5post TBI compared to vehicle (P <0.05). However,mice administered HNG (i.p.,1μg) at1h post TBI had minor amelioration in motorperformance (on days2to3post TBI) versus vehicle-treated mice, and there were noamelioration in motor performance when HNG was administered at2h and4h postinjury.(4) In Morris water maze experiments, mice showed normal acquisition curveson both hidden and visible platforms, and selective quadrant search on the probe trialbefore suffering TBI. Mice administered HNG before TBI had significantly decreasedescape latency to the hidden platform (on days10to12post TBI) and performedsignificantly better in probe trial test compared with vehicle-treated mice. Compared tovehicle-treated group, mice administered HNG (i.p.,1μg) at1h,2h and4h post injuryrespectively had similar performance in hidden platform trials. However, miceadministered HNG (i.p.,1μg) at1h, but not2h and4h post injury, had significantlyimproved probe trial performance versus vehicle-treated animals (P <0.05).(5)Immunoblotting results showed that HNG pretreatment (i.c.v.) reversed TBI-inducedcleavage of caspase-3and PARP, increase of Bax and decline of Bcl-2in injured cortexand hippocampus. Analyses of caspase-3expression by immunofluorescent staining at48h after traumatic brain injury shown HNG decreased the number of positive cells atthe cortical area near the site of injury and in the hippocampus (CA1, CA3and DG). Tofurther explore the anti-apoptosis mechanism of HNG, cyt-c, caspase-8and caspase-9protein levels were also assessed after TBI. The TBI induced up-regulation of cyt-c,caspase-8, and caspase-9were also reversed by HNG.(6) Compared withvehicle-treated group, HNG pretreatment (i.c.v.) suppressed activation of LC3II, Beclin-1and Vps34, and maintained p62level in injured cortex and hippocampus postTBI. In addition, immunofluorescent staining at24h after traumatic brain injury shownHNG decreased the number of Beclin-1positive cells at the cortical area near the site ofinjury and in the hippocampus (CA1, CA3and DG).
Conclusion:(1) HNG significantly suppressed TBI-induced cellular plasmalemmaintegrality disruption, reduced brain tissue damage, and improved the recovery of motorand cognitive dysfunction.(2) In addition, HNG was able to inhibit TBI-inducedapoptosis and autophagic activity, which may be involved in the neuroprotectivemechanism of HNG.
引文
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