Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.
Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden; Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Department of Pediatrics, Children's Hospital of Zhengzhou University, Zhengzhou, China.
Neuropharmacology. 2020 Jul;171:108088. doi: 10.1016/j.neuropharm.2020.108088. Epub 2020 Apr 8.
The interaction between apoptosis-inducing factor (AIF) and cyclophilin A (CypA) has been shown to contribute to caspase-independent apoptosis. Blocking the AIF/CypA interaction protects against glutamate-induced neuronal cell death in vitro, and the purpose of this study was to determine the in vivo effect of an AIF/CypA interaction blocking peptide (AIF(370-394)-TAT) on neonatal mouse brain injury after hypoxia-ischemia (HI). The pups were treated with AIF (370-394)-TAT peptide intranasally prior to HI. Brain injury was significantly reduced at 72 h after HI in the AIF(370-394)-TAT peptide treatment group compared to vehicle-only treatment for both the gray matter and the subcortical white matter, and the neuroprotection was more pronounced in males than in females. Neuronal cell death was evaluated in males at 8 h and 24 h post-HI, and it was decreased significantly in the CA1 region of the hippocampus and the nucleus habenularis region after AIF(370-394)-TAT treatment. Caspase-independent apoptosis was decreased in the cortex, striatum, and nucleus habenularis after AIF(370-394)-TAT treatment, but no significant change was found on caspase-dependent apoptosis as indicated by the number of active caspase-3-labeled cells. Further analysis showed that both AIF and CypA nuclear accumulation were decreased after treatment with the AIF(370-394)-TAT peptide. These results suggest that AIF(370-394)-TAT inhibited AIF/CypA translocation to the nucleus and reduced HI-induced caspase-independent apoptosis and brain injury in young male mice, suggesting that blocking AIF/CypA might be a potential therapeutic target for neonatal brain injury.
凋亡诱导因子（AIF）与亲环素 A（CypA）的相互作用已被证明有助于 caspase 非依赖性细胞凋亡。阻断 AIF/CypA 相互作用可防止体外谷氨酸诱导的神经元细胞死亡，本研究旨在确定 AIF/CypA 相互作用阻断肽（AIF(370-394)-TAT）对缺氧缺血（HI）后新生小鼠脑损伤的体内作用。在 HI 前，通过鼻腔给予 AIF(370-394)-TAT 肽处理幼鼠。与单独使用载体相比，AIF(370-394)-TAT 肽治疗组在 HI 后 72 小时，灰质和皮质下白质的脑损伤明显减少，且雄性的神经保护作用强于雌性。在 HI 后 8 小时和 24 小时评估雄性的神经元细胞死亡，发现 AIF(370-394)-TAT 处理后海马 CA1 区和缰核区的神经元细胞死亡明显减少。AIF(370-394)-TAT 处理后，皮质、纹状体和缰核区的 caspase 非依赖性细胞凋亡减少，但活性 caspase-3 标记细胞数量无明显变化，表明 caspase 依赖性细胞凋亡无明显变化。进一步分析表明，AIF(370-394)-TAT 肽处理后 AIF 和 CypA 的核积累均减少。这些结果表明，AIF(370-394)-TAT 抑制了 AIF/CypA 向核内转移，并减少了 HI 诱导的 caspase 非依赖性细胞凋亡和年轻雄性小鼠的脑损伤，提示阻断 AIF/CypA 可能是新生儿脑损伤的潜在治疗靶点。
