Combined inhibition of cell death induced by apoptosis inducing factor and caspases provides additive neuroprotection in experimental traumatic brain injury

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• 作者：Chun-Shu Piao^a ; David J. Loane^a ; Bogdan A. Stoica^a ; Shihong Li^a ; Marie Hanscom^a ; Rainier Cabatbat^a ; Klas Blomgren^b ; ^c ; Alan I. Faden^a ; ^{afaden@anes.umm.edu}
• 关键词：AIF ; apoptosis inducing factor ; BAF ; boc-aspartyl(OMe)-fluoromethylketone ; CCI ; controlled cortical impact ; CypA ; Cyclophilin A ; Hq ; harlequin ; ICV ; intracerebroventricular ; PCD ; programmed cell death ; TBI ; traumatic brain injury
• 刊名：Neurobiology of Disease
• 出版年：2012
• 期刊代码：80_09699961
• 类别：neu
• 出版时间：June, 2012
• 卷：46
• 期：3
• 页码：745-758
• 文件大小：2426 K

摘要

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^{鈭?鈭?/sup>), 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鈭?鈭?/sup> mice. Each single intervention, (CypA鈭?鈭?/sup> or BAF-treated CypA+/+) reduced the number of apoptotic cells (TUNEL-positive) in the cortex and improved long-term sensorimotor function; CypA鈭?鈭?/sup> also attenuated microglial activation after injury. Importantly, BAF-treated CypA鈭?鈭?/sup> 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鈭?鈭?/sup> 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.}