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聚（ADP - 核糖）聚合酶 -1抑制在新生啮齿动物缺氧缺血性损伤模型中的作用

Effects of Poly(ADP-Ribose) Polymerase-1 Inhibition in a Neonatal Rodent Model of Hypoxic-Ischemic Injury.

作者信息

Klöfers Melanie, Kohaut Jules, Bendix Ivo, Herz Josephine, Boos Vinzenz, Felderhoff-Müser Ursula, Dzietko Mark

机构信息

Department of Pediatrics I, Neonatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Department of Neonatology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

出版信息

Biomed Res Int. 2017;2017:2924848. doi: 10.1155/2017/2924848. Epub 2017 Jun 15.

DOI:10.1155/2017/2924848
PMID:28698869
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5494065/
Abstract

BACKGROUND

Hypoxia ischemia (HI) to the developing brain occurs in 1-6 in 1000 live births. Large numbers of survivors have neurological long-term sequelae. However, mechanisms of recovery after HI are not understood and preventive measures or clinical treatments are not effective. Poly(ADP-ribose) polymerase-1 is overactivated in response to ischemia. In neonatal mice HI activates PARP-1 but its role in perinatal brain injury remains uncertain.

OBJECTIVE

Aim of this study was to explore the effect of TES448 (PARP-1-inhibitor) and hypothermia after an ischemic insult.

DESIGN AND METHODS

10-day-old Wistar rats underwent HI. TES448 was given 10 min, 3 hrs, and 6 hrs after hypoxia. Hypothermia was started 30 min after HI and brains were dissected at P12. Western blotting and histological staining were used to evaluate for degree of injury.

RESULTS

Protein expression of PARP-1 levels was diminished after TES448 treatment. Cresyl violet and TUNEL staining revealed decreased injury in male rat pups following TES448 and combined treatment. Female rats showed increased numbers of TUNEL-positive cells after combined therapy. TES448 inhibited microglia activation after hypoxic-ischemic injury. A cellular response including NeuN, Olig2, and MBP was not affected by PARP-1-inhibition.

CONCLUSIONS

Inhibition of PARP-1 and hypothermia lead to an alteration of injury but this effect is sexually dimorphic.

摘要

背景

发育中的大脑发生缺氧缺血（HI）的情况在每1000例活产中出现1 - 6例。大量幸存者有神经方面的长期后遗症。然而，HI后恢复的机制尚不清楚，预防措施或临床治疗也无效。聚（ADP - 核糖）聚合酶 - 1在缺血反应中过度激活。在新生小鼠中，HI激活PARP - 1，但其在围产期脑损伤中的作用仍不确定。

目的

本研究旨在探讨TES448（PARP - 1抑制剂）和低温对缺血性损伤后的影响。

设计与方法

10日龄的Wistar大鼠接受HI。在缺氧后10分钟、3小时和6小时给予TES448。HI后30分钟开始低温处理，并在出生后第12天解剖大脑。采用蛋白质印迹法和组织学染色评估损伤程度。

结果

TES448治疗后PARP - 1水平的蛋白质表达降低。甲酚紫和TUNEL染色显示，TES448及联合治疗后雄性幼鼠的损伤减少。联合治疗后雌性大鼠TUNEL阳性细胞数量增加。TES448抑制缺氧缺血性损伤后的小胶质细胞激活。包括NeuN、Olig2和MBP在内的细胞反应不受PARP - 1抑制的影响。

结论

抑制PARP - 1和低温导致损伤改变，但这种效应存在性别差异。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7585/5494065/c43cb999f7db/BMRI2017-2924848.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7585/5494065/23106f911cb5/BMRI2017-2924848.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7585/5494065/4c8ef7f661ee/BMRI2017-2924848.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7585/5494065/9064fbfe0cf2/BMRI2017-2924848.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7585/5494065/52ea6a2546cf/BMRI2017-2924848.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7585/5494065/c43cb999f7db/BMRI2017-2924848.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7585/5494065/23106f911cb5/BMRI2017-2924848.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7585/5494065/4c8ef7f661ee/BMRI2017-2924848.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7585/5494065/9064fbfe0cf2/BMRI2017-2924848.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7585/5494065/52ea6a2546cf/BMRI2017-2924848.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7585/5494065/c43cb999f7db/BMRI2017-2924848.005.jpg

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