Abstract
Objective: Inflammation plays a key role in the pathophysiological processes after intracerebral hemorrhage (ICH). Post-ICH macrophages infiltrate the brain and release pro-inflammatory factors (tumor necrosis factor-α), amplifying microglial activation and neutrophil infiltration. Platelet-derived growth factor receptor-β (PDGFR-β) is expressed on macrophages and it's activation induces the recruitment of macrophages. Platelet-derived growth factor-D (PDGF-D) is an agonist with a significantly higher affinity to the PDGFR-β compared to another isoform of the receptor. In this study, we investigated the role of PDGF-D in the pro-inflammatory response after ICH in mice. Methods: A blood injection model of ICH was used in eight-week old male CD1 mice (weight 30 g). Some mice received an injection of plasmin or PDGF-D. Gleevec, a PDGFR inhibitor, was administered at 1, 3 or 6 h post-ICH. Plasmin was administered with or without PDGF-D siRNAs mixture or scramble siRNA. A plasmin-antagonist, ε-Aminocaproic acid (EACA), was co-administrated with the blood. The effects of ICH and treatment on the brain injury and post-ICH inflammation were investigated. Results: ICH resulted in the overexpression of PDGF-D, associated with the infiltration of macrophages. PDGFR-inhibition decreased ICH-induced brain injury, attenuating macrophage and neutrophil infiltration, reducing microglial activation and TNF-α production. Administration of recombinant PDGF-D induced TNF-α production, and PDGFR-inhibition attenuated it. A plasmin-antagonist suppressed PDGFR-β activation and microglial activation. Plasmin increased PDGF-D expression, and PDGF-D inhibition reduced neutrophil infiltration. Conclusion: ICH-induced PDGF-D accumulation contributed to post-ICH inflammation via PDGFR activation and enhanced macrophage infiltration. The inhibition of PDGFR had an anti-inflammatory effect. Plasmin is a possible upstream effector of PDGF-D. The targeting of PDGF-D may provide a novel way to decrease brain injury after ICH.
Original language | English |
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Pages (from-to) | 157-164 |
Number of pages | 8 |
Journal | Experimental Neurology |
Volume | 283 |
Issue number | Pt A |
DOIs | |
State | Published - Sep 1 2016 |
ASJC Scopus Subject Areas
- Neurology
- Developmental Neuroscience
Keywords
- ICH
- Neuroinflammation
- PDGF-D
- PDGFR-β
- Fibrinolysin/administration & dosage
- Male
- Brain Edema/drug therapy
- Platelet-Derived Growth Factor/metabolism
- Aminocaproic Acid/administration & dosage
- Nerve Tissue Proteins/metabolism
- Receptor, Platelet-Derived Growth Factor beta/metabolism
- Fibrinolytic Agents/administration & dosage
- Gene Expression Regulation/drug effects
- Disease Models, Animal
- Microglia/drug effects
- RNA, Small Interfering/administration & dosage
- Basal Ganglia/drug effects
- Exploratory Behavior/drug effects
- Cerebral Hemorrhage/complications
- Protein Kinase Inhibitors/administration & dosage
- Macrophages/drug effects
- Animals
- Encephalitis/drug therapy
- Mice
- Imatinib Mesylate/administration & dosage