Combined inhibition of cell death induced by apoptosis inducing factor and caspases provides additive neuroprotection in experimental traumatic brain injury.
Combined inhibition of cell death induced by apoptosis inducing factor and caspases provides additive neuroprotection in experimental traumatic brain injury.
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DOI：
10.1016/j.nbd.2012.03.018
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发表时间：
2012-06
影响因子：
6.1
通讯作者：
Faden AI
中科院分区：
文献类型：
--
作者：
Piao CS;Loane DJ;Stoica BA;Li S;Hanscom M;Cabatbat R;Blomgren K;Faden AI
神经细胞程序性死亡(PCD)是创伤性脑损伤(TBI)后迟发性组织损伤的重要原因。Caspase依赖的和非caspase依赖的机制都被涉及，后者包括凋亡诱导因子(AIF)。亲环素A(CypA)负责将AIF从胞浆转运到胞核，这是AIF依赖性细胞死亡的关键步骤。在小鼠控制的皮质撞击模型中，我们通过检测CypA基因敲除(CypA−/−)、半胱氨酸酶抑制剂(BOC-天门冬氨基(OME)-氟甲基酮)或联合调节的效果，比较了单独或联合抑制Caspase和AIF信号通路的效果。脑损伤后半胱氨酸天冬氨酸氨基转移酶激活，AIF移位至胞核。半胱氨酸天冬氨酸氨基转移酶激活的标志，包括caspase特异的fodrin裂解片段和Flo阳性细胞的数量在经生物活性因子处理的CypA+/+小鼠中减少，而在−/−小鼠中，包括AIF/H 2AX相互作用和AIF向细胞核移位的激活标志减弱。每一次干预(CypA−/−或经BAF处理的CypA+/+)均可减少皮质中凋亡细胞(TUNEL阳性)的数量，并改善长期感觉运动功能；CypA−/−也可减弱损伤后小胶质细胞的激活。重要的是，经曝气生物滤池处理的CypA−/−小鼠，在多项结果方面显示出比单独干预更大的效果，包括：减少TUNEL阳性细胞，减少神经炎症，改善运动和认知恢复，以及减轻海马区病变体积和神经元丢失。使用两种已知的诱导AIF介导的PCD的体外神经细胞死亡模型，我们还表明来自CypA−/−动物的神经元受到保护，并且这种作用与半胱氨酸天冬氨酸酶的激活无关。这些数据表明，AIF介导的通路和caspase依赖的通路在脑外伤后继发性损伤中起独立和平行的作用，提示针对多个PCD通路的联合治疗策略可能比针对单一机制的治疗策略提供更好的神经保护。
Neuronal programmed cell death (PCD) contributes to delayed tissue damage after traumatic brain injury (TBI). Both caspase-dependent and caspase-independent mechanisms have been implicated, with the latter including apoptosis inducing factor (AIF). The peptidyl-proplyl isomerase Cyclophilin A (CypA) transports AIF from the cytosol to the nucleus, a key step for AIF-dependent cell death. We compared the effects of single versus combined inhibition of caspase and AIF pathways in a mouse controlled cortical impact (CCI) model, by examining the effects of CypA gene knockout (CypA−/−), caspase inhibition with a pan-caspase inhibitor (boc-aspartyl(OMe)-fluoromethylketone, BAF), or combined modulation. TBI caused caspase activation as well as translocation of AIF to the nucleus. Markers of caspase activation including caspase-specific fodrin cleavage fragments and number of FLIVO positive cells were reduced in BAF-treated CypA+/+ mice, whereas markers of AIF activation including AIF/H2AX interaction and AIF translocation to the nucleus were attenuated in CypA−/− mice. Each single intervention, (CypA−/− or BAF-treated CypA+/+) reduced the number of apoptotic cells (TUNEL-positive) in the cortex and improved long-term sensorimotor function; CypA−/− also attenuated microglial activation after injury. Importantly, BAF-treated CypA−/− mice, showed greater effects than either intervention alone on multiple outcomes including: reduction in TUNEL-positive cells, decrease in neuroinflammation, improved motor and cognitive recovery, and attenuation of lesion volume and neuronal loss in the hippocampus. Using two in vitro neuronal cell death models known to induce AIF-mediated PCD, we also showed that neurons from CypA−/− animals were protected and that effects were unrelated to caspase activation. These data indicate that AIF-mediated and caspase-dependent pathways contribute independently and in parallel to secondary injury after TBI, and suggest that combined therapeutic strategies directed at multiple PCD pathways may provide superior neuroprotection than those directed at single mechanisms.
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影响因子：
4.2
作者：
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通讯作者：
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