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白桦脂酸羟肟酸对未成熟大鼠脑室出血性脑损伤的神经保护作用。

Neuroprotective Effects of Betulinic Acid Hydroxamate in Intraventricular Hemorrhage-Induced Brain Damage in Immature Rats.

机构信息

Biomedical Research Foundation, Hospital Clínico San Carlos-IdISSC, 28040 Madrid, Spain.

Vivacell Biotechnology España S.L.U., 14014 Córdoba, Spain.

出版信息

Nutrients. 2022 Dec 12;14(24):5286. doi: 10.3390/nu14245286.

DOI:10.3390/nu14245286
PMID:36558445
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9786890/
Abstract

Intraventricular hemorrhage (IVH) is an important cause of long-term disability in extremely preterm infants, with no current treatment. We aimed to study in an IVH model in immature rats the neuroprotective effect of betulinic acid hydroxamate (BAH), a B55α/PP2A activator that inhibits the activity of the hypoxia-inducing factor prolyl-hydroxylase type 2. IVH was induced in 1-day-old (P1) Wistar rats by the left periventricular injection of Clostridial collagenase. Then, pups received i.p. vehicle or BAH 3 mg/kg single dose. At P6, P14 and P45, brain damage (area of damage, neurobehavioral deficits, Lactate/N-acetylaspartate ratio), white matter injury (WMI: corpus callosum atrophy and myelin basic protein signal reduction) and inflammation (TLR4, NF-κB and TNFα expression), excitotoxicity (Glutamate/N-acetylspartate) and oxidative stress (protein nitrosylation) were evaluated. BAH treatment did not reduce the volume of brain damage, but it did reduce perilesional tissue damage, preventing an IVH-induced increase in Lac/NAA. BAH restored neurobehavioral performance at P45 preventing WMI. BAH prevented an IVH-induced increase in inflammation, excitotoxicity and oxidative stress. In conclusion, in immature rats, BAH reduced IVH-induced brain damage and prevented its long-term functional consequences, preserving normal myelination in a manner related to the modulation of inflammation, excitotoxicity and oxidative stress.

摘要

脑室内出血（IVH）是极早产儿长期残疾的重要原因，目前尚无治疗方法。我们旨在研究不成熟大鼠 IVH 模型中桦木酸羟酰胺（BAH）的神经保护作用，BAH 是一种 B55α/PP2A 激活剂，可抑制缺氧诱导因子脯氨酰羟化酶 2 的活性。通过向 1 日龄（P1）Wistar 大鼠左室下注射梭菌胶原酶诱导 IVH。然后，给幼鼠腹腔内注射载体或 BAH 3mg/kg 单次剂量。在 P6、P14 和 P45 时，评估脑损伤（损伤面积、神经行为缺陷、乳酸/N-乙酰天冬氨酸比值）、白质损伤（WMI：胼胝体萎缩和髓鞘碱性蛋白信号减少）和炎症（TLR4、NF-κB 和 TNFα 表达）、兴奋性毒性（谷氨酸/N-乙酰天冬氨酸）和氧化应激（蛋白质硝基化）。BAH 治疗并未减少脑损伤体积，但减少了病变周围组织损伤，防止 IVH 引起的 Lac/NAA 增加。BAH 恢复了 P45 时的神经行为表现，防止了 WMI。BAH 防止了 IVH 引起的炎症、兴奋性毒性和氧化应激增加。总之，在不成熟的大鼠中，BAH 减少了 IVH 引起的脑损伤，并防止了其长期的功能后果，以一种与调节炎症、兴奋性毒性和氧化应激相关的方式保留了正常的髓鞘形成。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a9/9786890/3417af766ac0/nutrients-14-05286-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a9/9786890/da046f829ec5/nutrients-14-05286-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a9/9786890/d230f9e425d1/nutrients-14-05286-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a9/9786890/27d46811f0e9/nutrients-14-05286-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a9/9786890/3417af766ac0/nutrients-14-05286-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a9/9786890/da046f829ec5/nutrients-14-05286-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a9/9786890/d230f9e425d1/nutrients-14-05286-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a9/9786890/27d46811f0e9/nutrients-14-05286-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26a9/9786890/3417af766ac0/nutrients-14-05286-g004.jpg

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