Effects of an Inhibitor of Monocyte Recruitment on Recovery from Traumatic Brain Injury in Mice Treated with Granulocyte Colony-Stimulating Factor.

Shijie Song,Cesar Borlongan,Sandra Acosta,Xiaoyuan Kong,Juan Sanchez-Ramos,Vasyl Sava

doi:10.3390/ijms18071418

Abstract

Administration of the hematopoietic growth factor granulocyte-colony stimulating Factor (G-CSF) has been reported to enhance recovery from controlled cortical impact (CCI) in rodent models. G-CSF exerts actions in both the periphery (stimulation of hematopoiesis) and in the brain, where it serves as a neurotrophic factor, promoting neuronal survival and stimulating neural stem/progenitor cell proliferation in the hippocampus. In order to distinguish the direct CNS actions of G-CSF from its peripheral actions, experiments were designed to block the recruitment of peripheral monocytes to the site of the lesion produced by CCI. The selective C-C motif receptor 2 (CCR2) antagonist (RS504303) was co-administered with G-CSF for three days after CCI in a chimeric mouse previously transplanted with GFP-expressing (GFP+) blood stem-progenitor cells. Results: The drug significantly impaired infiltration of GFP+ bone marrow-derived cells to the frontal cortex and striatum without impeding recovery performance and hippocampal neurogenesis in the behavioral test, the Radial Arm Water Maze (RAWM). Administration of the CCR2 antagonist alone, without G-CSF, was effective in promoting recovery in RAWM. These results support the hypothesis that the direct action of G-CSF on neural cells, independent of its hematopoietic effects, is primarily responsible for enhanced recovery from CCI. In addition, this study confirms the importance of CCR2 and its ligand, monocyte chemotactic protein-1 (MCP-1), in mediating the inflammatory response following CCI.

Highlights

Granulocyte colony-stimulating factor (G-CSF) is one of several hematopoietic cytokines that regulates the production of circulating blood cells by the bone marrow
Two weeks after cortical impact (CCI), the cohort of mice treated with G-CSF exhibited an increased infiltration of GFP+ cells into the right frontal cortex and striatum (Figures 1 and 2)
One-way analysis of variance (ANOVA) followed by Sidak’s multiple comparison tests show that co-administration of the C motif receptor 2 (CCR2) antagonist with G-CSF resulted in significant decreases in the GFP+ signal compared to G-CSF treatment (p < 0.05) (Figure 3)

Summary

Introduction

Granulocyte colony-stimulating factor (G-CSF) is one of several hematopoietic cytokines that regulates the production of circulating blood cells by the bone marrow. G-CSF is commonly used to treat leukopenia, but it has been investigated in animal models of stroke. G-CSF administration was reported to reduce brain damage and improve functional outcomes [1,2,3,4]. G-CSF treatment has been shown to promote recovery from traumatic brain injury traumatic brain injury (TBI) in rodent models. Administration of intraperitoneal G-CSF (via osmotic minipump) in a rat model of TBI was shown to improve recovery of motor function compared to the control group [5]. Intravenous (i.v.) administration of G-CSF (300 μg/kg) seven days after controlled cortical impact (CCI) to rats promoted transient motor benefits. G-CSF modestly increased hippocampal and subventricular zone (SVZ) neurogenesis and diminished microgliosis eight weeks after the TBI [6]

Methods

Results

Conclusion