In situ slow-release recombinant growth differentiation factor 11 exhibits therapeutic efficacy in ischemic stroke

Systemic growth differentiation factor 11 (GDF11) treatment improves the vasculature in the hippocampus and cortex in mice in recent studies. However, systemic application of recombinant GDF11 (rGDF11) cannot cross the brain blood barrier (BBB). Thus, large doses and long-term administration are req...

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Autores principales:	Hsing-Hui Su, Jiin-Cherng Yen, Jiuan-Miaw Liao, Yi-Hsin Wang, Pei-Hsun Liu, Iona J. MacDonald, Chin-Feng Tsai, Yi-Hung Chen, Shiang-Suo Huang
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Stroke GDF11 Neurogenesis in situ Slow-release Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/fbae608d1ad34d7091790c7bc4032465
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spelling	oai:doaj.org-article:fbae608d1ad34d7091790c7bc40324652021-11-14T04:29:17ZIn situ slow-release recombinant growth differentiation factor 11 exhibits therapeutic efficacy in ischemic stroke0753-332210.1016/j.biopha.2021.112290https://doaj.org/article/fbae608d1ad34d7091790c7bc40324652021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S075333222101074Xhttps://doaj.org/toc/0753-3322Systemic growth differentiation factor 11 (GDF11) treatment improves the vasculature in the hippocampus and cortex in mice in recent studies. However, systemic application of recombinant GDF11 (rGDF11) cannot cross the brain blood barrier (BBB). Thus, large doses and long-term administration are required, while systemically applied high-dose rGDF11 is associated with deleterious effects, such as severe cachexia. This study tested whether in situ low dosage rGDF11 (1 μg/kg) protects the brain against ischemic stroke and it investigated the underlying mechanisms. Fibrin glue mixed with rGDF11 was applied to the surgical cortex for the slow release of rGDF11 in mice after permanent middle cerebral artery occlusion (MCAO). In situ rGDF11 improved cerebral infarction and sensorimotor function by upregulating Smad2/3 and downregulating FOXO3 expression. In situ rGDF11 was associated with reductions in protein and lipid oxidation, Wnt5a, iNOS and COX2 expression, at 24 h after injury. In situ rGDF11 protected hippocampal neurons and subventricular neural progenitor cells against MCAO injury, and increased newborn neurogenesis in the peri-infarct cortex. Systematic profiling and qPCR analysis revealed that Pax5, Sox3, Th, and Cdk5rap2, genes associated with neurogenesis, were increased by in situ rGDF11 treatment. In addition, greater numbers of newborn neurons in the peri-infarct cortex were observed with in situ rGDF11 than with systemic application. Our evidence indicates that in situ rGDF11 effectively decreases the extent of damage after ischemic stroke via antioxidative, anti-inflammatory and proneurogenic activities. We suggest that in situ slow-release rGDF11 with fibrin glue is a potential therapeutic approach against ischemic stroke.Hsing-Hui SuJiin-Cherng YenJiuan-Miaw LiaoYi-Hsin WangPei-Hsun LiuIona J. MacDonaldChin-Feng TsaiYi-Hung ChenShiang-Suo HuangElsevierarticleStrokeGDF11Neurogenesisin situSlow-releaseTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 144, Iss , Pp 112290- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Stroke GDF11 Neurogenesis in situ Slow-release Therapeutics. Pharmacology RM1-950
spellingShingle	Stroke GDF11 Neurogenesis in situ Slow-release Therapeutics. Pharmacology RM1-950 Hsing-Hui Su Jiin-Cherng Yen Jiuan-Miaw Liao Yi-Hsin Wang Pei-Hsun Liu Iona J. MacDonald Chin-Feng Tsai Yi-Hung Chen Shiang-Suo Huang In situ slow-release recombinant growth differentiation factor 11 exhibits therapeutic efficacy in ischemic stroke
description	Systemic growth differentiation factor 11 (GDF11) treatment improves the vasculature in the hippocampus and cortex in mice in recent studies. However, systemic application of recombinant GDF11 (rGDF11) cannot cross the brain blood barrier (BBB). Thus, large doses and long-term administration are required, while systemically applied high-dose rGDF11 is associated with deleterious effects, such as severe cachexia. This study tested whether in situ low dosage rGDF11 (1 μg/kg) protects the brain against ischemic stroke and it investigated the underlying mechanisms. Fibrin glue mixed with rGDF11 was applied to the surgical cortex for the slow release of rGDF11 in mice after permanent middle cerebral artery occlusion (MCAO). In situ rGDF11 improved cerebral infarction and sensorimotor function by upregulating Smad2/3 and downregulating FOXO3 expression. In situ rGDF11 was associated with reductions in protein and lipid oxidation, Wnt5a, iNOS and COX2 expression, at 24 h after injury. In situ rGDF11 protected hippocampal neurons and subventricular neural progenitor cells against MCAO injury, and increased newborn neurogenesis in the peri-infarct cortex. Systematic profiling and qPCR analysis revealed that Pax5, Sox3, Th, and Cdk5rap2, genes associated with neurogenesis, were increased by in situ rGDF11 treatment. In addition, greater numbers of newborn neurons in the peri-infarct cortex were observed with in situ rGDF11 than with systemic application. Our evidence indicates that in situ rGDF11 effectively decreases the extent of damage after ischemic stroke via antioxidative, anti-inflammatory and proneurogenic activities. We suggest that in situ slow-release rGDF11 with fibrin glue is a potential therapeutic approach against ischemic stroke.
format	article
author	Hsing-Hui Su Jiin-Cherng Yen Jiuan-Miaw Liao Yi-Hsin Wang Pei-Hsun Liu Iona J. MacDonald Chin-Feng Tsai Yi-Hung Chen Shiang-Suo Huang
author_facet	Hsing-Hui Su Jiin-Cherng Yen Jiuan-Miaw Liao Yi-Hsin Wang Pei-Hsun Liu Iona J. MacDonald Chin-Feng Tsai Yi-Hung Chen Shiang-Suo Huang
author_sort	Hsing-Hui Su
title	In situ slow-release recombinant growth differentiation factor 11 exhibits therapeutic efficacy in ischemic stroke
title_short	In situ slow-release recombinant growth differentiation factor 11 exhibits therapeutic efficacy in ischemic stroke
title_full	In situ slow-release recombinant growth differentiation factor 11 exhibits therapeutic efficacy in ischemic stroke
title_fullStr	In situ slow-release recombinant growth differentiation factor 11 exhibits therapeutic efficacy in ischemic stroke
title_full_unstemmed	In situ slow-release recombinant growth differentiation factor 11 exhibits therapeutic efficacy in ischemic stroke
title_sort	in situ slow-release recombinant growth differentiation factor 11 exhibits therapeutic efficacy in ischemic stroke
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/fbae608d1ad34d7091790c7bc4032465
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In situ slow-release recombinant growth differentiation factor 11 exhibits therapeutic efficacy in ischemic stroke

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