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

Abstract

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.

• Authors: 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
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 144 Pg. 112290 (Dec 2021) ISSN: 1950-6007 [Electronic] France
• PMID: 34673423 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier Masson SAS.

Chemical References

• Anti-Inflammatory Agents
• Antioxidants
• Delayed-Action Preparations
• Growth Differentiation Factors
• Inflammation Mediators
• Recombinant Proteins

Topics

• Administration, Topical
• Animals
• Anti-Inflammatory Agents (administration & dosage, chemistry)
• Antioxidants (administration & dosage, chemistry)
• Behavior, Animal (drug effects)
• Brain (drug effects, metabolism, pathology, physiopathology)
• Delayed-Action Preparations
• Disease Models, Animal
• Drug Compounding
• Gene Expression Regulation
• Growth Differentiation Factors (administration & dosage, chemistry)
• Hand Strength
• Infarction, Middle Cerebral Artery (drug therapy, metabolism, pathology, physiopathology)
• Inflammation Mediators (metabolism)
• Ischemic Stroke (drug therapy, metabolism, pathology, physiopathology)
• Mice, Inbred C57BL
• Motor Activity (drug effects)
• Neurogenesis (drug effects)
• Oxidative Stress (drug effects)
• Recombinant Proteins (pharmacology)
• Wnt Signaling Pathway