Comparative evaluation of rhFGF18 and rhGDF11 treatment in a transient ischemia stroke model.

IF 1.9 4区医学 Q4 NEUROSCIENCES

Restorative neurology and neuroscience Pub Date : 2023-01-01 DOI:10.3233/RNN-231347

Alex Goraltchouk, Svetlana Mankovskaya, Tatjana Kuznetsova, Zhanna Hladkova, Judith M Hollander, Francesco Luppino, Alexey Seregin

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引用次数: 0

Abstract

Background: Pharmacological treatments for ischemic stroke remain limited to thrombolysis, which is associated with increased risk of potentially fatal hemorrhage. Treatments with Recombinant Human Fibroblast Growth Factor 18 (rhFGF18) and Growth and Differentiation Factor 11 (rhGDF11) appear promising based on different preclinical models. The goal of this study was to compare the effects of rhFGF18 and rhGDF11 directly on survival, behavioral deficits, and histological fingerprint of cerebral ischemia in the Wistar rat middle cerebral artery occlusion (MCAO) model of stroke.

Methods: Ischemia-reperfusion injury was induced using a 2-hour transient MCAO. Animals were administered rhFGF18 (infusion), rhGDF11 (multi-injection), or Phosphate Buffered Saline (PBS) vehicle control and followed for 42 days. Motor-Cognitive deficits were evaluated using the Morris Water Maze at Days 0 (pre-MCAO), 7, 21, and 42. Histopathological assessments were performed on Days 21 and 42.

Results: Day 7 post-ischemia water maze performance times increased 38.3%, 2.1%, and 23.1% for PBS, rhFGF18, and rhGDF11-treated groups, respectively. Fraction of neurons with abnormal morphology (chromatolysis, pyknotic nuclei, somal degeneration) decreased in all groups toward Day 42 and was lowest for rhFGF18. AChE-positive fiber density and activity increased over time in the rhFGF18 group, remained unchanged in the rhGDF11 treatment arm, and declined in the PBS control. Metabolic increases were greatest in rhGDF11 treated animals, with both rhFGF18 and rhGDF11 achieving improvements over PBS, as evidenced by increased succinate dehydrogenase and lactate dehydrogenase activity. Finally, rhFGF18 treatment exhibited a trend for reduced mortality relative to PBS (5.6%, 95% CI [27.3%, 0.1% ] vs. 22.2%, 95% CI [47.6%, 6.4% ]).

Conclusions: rhFGF18 treatment appears promising in improving survival and promoting motor-cognitive recovery following cerebral ischemia-reperfusion injury.

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一过性脑缺血中风模型中 rhFGF18 和 rhGDF11 治疗的比较评估。

背景：缺血性脑卒中的药物治疗仍局限于溶栓，而溶栓会增加潜在致命性出血的风险。根据不同的临床前模型，使用重组人成纤维细胞生长因子 18（rhFGF18）和生长与分化因子 11（rhGDF11）进行治疗似乎很有前景。本研究的目的是比较 rhFGF18 和 rhGDF11 对 Wistar 大鼠大脑中动脉闭塞（MCAO）脑卒中模型的存活率、行为障碍和脑缺血组织学指纹的直接影响：方法：使用 2 小时瞬时 MCAO 诱导缺血再灌注损伤。给动物注射 rhFGF18（输注）、rhGDF11（多次注射）或磷酸盐缓冲盐水（PBS）药物对照，并随访 42 天。在第 0 天（MCAO 前）、第 7 天、第 21 天和第 42 天使用 Morris 水迷宫评估运动认知障碍。第21天和第42天进行组织病理学评估：结果：缺血后第 7 天，PBS、rhFGF18 和 rhGDF11 处理组的水迷宫表现时间分别增加了 38.3%、2.1% 和 23.1%。所有组中形态异常（色素溶解、细胞核萎缩、体细胞变性）的神经元比例在第 42 天时都有所下降，而 rhFGF18 的下降幅度最小。随着时间的推移，rhFGF18 组 AChE 阳性纤维密度和活性增加，rhGDF11 治疗组保持不变，而 PBS 对照组则有所下降。rhGDF11治疗组动物的代谢增加幅度最大，rhFGF18和rhGDF11均比PBS组有所改善，这体现在琥珀酸脱氢酶和乳酸脱氢酶活性的增加上。最后，与 PBS 相比，rhFGF18 治疗显示出死亡率降低的趋势（5.6%，95% CI [27.3%，0.1% ] 对比 22.2%，95% CI [47.6%，6.4% ]）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Restorative neurology and neuroscience 医学-神经科学

CiteScore

5.40

自引率

3.60%

发文量

审稿时长

>12 weeks

期刊介绍： This interdisciplinary journal publishes papers relating to the plasticity and response of the nervous system to accidental or experimental injuries and their interventions, transplantation, neurodegenerative disorders and experimental strategies to improve regeneration or functional recovery and rehabilitation. Experimental and clinical research papers adopting fresh conceptual approaches are encouraged. The overriding criteria for publication are novelty, significant experimental or clinical relevance and interest to a multidisciplinary audience. Experiments on un-anesthetized animals should conform with the standards for the use of laboratory animals as established by the Institute of Laboratory Animal Resources, US National Academy of Sciences. Experiments in which paralytic agents are used must be justified. Patient identity should be concealed. All manuscripts are sent out for blind peer review to editorial board members or outside reviewers. Restorative Neurology and Neuroscience is a member of Neuroscience Peer Review Consortium.