Inhibiting the interaction between apoptosis-inducing factor and cyclophilin A prevents brain injury in neonatal mice after hypoxia-ischemia.,Neuropharmacology

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Inhibiting the interaction between apoptosis-inducing factor and cyclophilin A prevents brain injury in neonatal mice after hypoxia-ischemia.
Neuropharmacology ( IF 4.7 ) Pub Date : 2020-04-08 , DOI: 10.1016/j.neuropharm.2020.108088
Juan Rodriguez ₁ , Cuicui Xie ₁ , Tao Li ₂ , Yanyan Sun ₃ , Yafeng Wang ₂ , Yiran Xu ₄ , Kenan Li ₄ , Shan Zhang ₄ , Kai Zhou ₅ , Yong Wang ₄ , Carina Mallard ₆ , Henrik Hagberg ₇ , Nunzianna Doti ₈ , Xiaoyang Wang ₆ , Changlian Zhu ₉

Affiliation

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.
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 Anatomy, School of Basic Medical Science, Zhengzhou University, Zhengzhou, 450001, China.
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.
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 Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.
Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Dept of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden.
Istituto di Biostrutture e Bioimmagini-CNR, Via Mezzocannone 16, Napoli, 80134, Italy.
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 Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

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.

中文翻译：

抑制凋亡诱导因子与亲环蛋白A之间的相互作用可防止缺氧缺血后新生小鼠的脑损伤。

凋亡诱导因子（AIF）和亲环蛋白A（CypA）之间的相互作用已显示出不依赖caspase的凋亡。在体外，阻断AIF / CypA相互作用可防止谷氨酸诱导的神经元细胞死亡，本研究的目的是确定AIF / CypA相互作用阻断肽（AIF（370-394）-TAT）对新生儿的体内作用缺氧缺血（HI）后小鼠脑损伤。在HI之前，鼻内用AIF（370-394）-TAT肽处理幼犬。与单独使用赋形剂处理的灰质和皮层下白质相比，AIF（370-394）-TAT肽治疗组在HI后72 h的脑损伤显着减少，并且男性的神经保护作用比单纯的媒介物显着。女性。在HI后8小时和24小时评估了男性的神经元细胞死亡，AIF（370-394）-TAT处理后，海马CA1区和ha状核区CA1区明显减少。经AIF（370-394）-TAT处理后，大脑皮层，纹状体和羽状核中不依赖胱天蛋白酶的凋亡减少，但是通过激活胱天蛋白酶3标记的细胞数量表明，依赖胱天蛋白酶的凋亡没有显着变化。进一步的分析表明，用AIF（370-394）-TAT肽处理后，AIF和CypA核积累均减少。这些结果表明，AIF（370-394）-TAT可以抑制AIF / CypA易位至核内，并减少HI诱导的caspase独立凋亡和脑损伤，这表明，阻断AIF / CypA可能是潜在的治疗靶点新生儿脑损伤。

更新日期：2020-04-08

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