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

Juan Rodriguez; Cuicui Xie; Tao Li; Yanyan Sun; Yafeng Wang; Yiran Xu; Kenan Li; Shan Zhang; Kai Zhou; Yong Wang; Carina Mallard; Henrik Hagberg; Nunzianna Doti; Xiaoyang Wang; Changlian Zhu

doi:10.1016/j.neuropharm.2020.108088

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

Neuropharmacology. 2020 Jul:171:108088. doi: 10.1016/j.neuropharm.2020.108088. Epub 2020 Apr 8.

Authors

Juan Rodriguez¹, Cuicui Xie¹, Tao Li², Yanyan Sun³, Yafeng Wang², Yiran Xu⁴, Kenan Li⁴, Shan Zhang⁴, Kai Zhou⁵, Yong Wang⁴, Carina Mallard⁶, Henrik Hagberg⁷, Nunzianna Doti⁸, Xiaoyang Wang⁶, Changlian Zhu⁹

Affiliations

¹ Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ Istituto di Biostrutture e Bioimmagini-CNR, Via Mezzocannone 16, Napoli, 80134, Italy.
⁹ 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. Electronic address: changlian.zhu@neuro.gu.se.

PMID: 32277944
DOI: 10.1016/j.neuropharm.2020.108088

Abstract

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.

Keywords: Apoptosis-inducing factor; Blocking peptide; Brain injury; Cyclophilin A; Hypoxia-ischemia; Immature brain.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Intranasal
Animals
Animals, Newborn
Apoptosis / drug effects
Apoptosis Inducing Factor / antagonists & inhibitors*
Apoptosis Inducing Factor / pharmacology*
CA1 Region, Hippocampal / drug effects
CA1 Region, Hippocampal / pathology
Caspases / physiology
Cell Death / drug effects
Cyclophilins / antagonists & inhibitors*
Female
Gray Matter / pathology
Hypoxia-Ischemia, Brain / pathology
Hypoxia-Ischemia, Brain / prevention & control*
Male
Mice
Mice, Inbred C57BL
Neuroprotective Agents / pharmacology*
Organelle Biogenesis
Sex Characteristics
White Matter / pathology

Substances

Apoptosis Inducing Factor
Neuroprotective Agents
Caspases
Cyclophilins