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, 26 (5), 278-286

Agmatine Modulates the Phenotype of Macrophage Acute Phase After Spinal Cord Injury in Rats

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Agmatine Modulates the Phenotype of Macrophage Acute Phase After Spinal Cord Injury in Rats

Jae Hwan Kim et al. Exp Neurobiol.

Abstract

Agmatine is a decarboxylated arginine by arginine decarboxylase. Agmatine is known to be a neuroprotective agent. It has been reported that agmatine works as a NMDA receptor blocker or a competitive nitric oxide synthase inhibitor in CNS injuries. In spinal cord injury, agmatine showed reduction of neuropathic pain, improvement of locomotor function, and neuroprotection. Macrophage is a key cellular component in neuroinflammation, a major cause of impairment after spinal cord injury. Macrophage has subtypes, M1 and M2 macrophages. M1 macrophage induces a pro-inflammatory response, but M2 inspires an anti-inflammatory response. In this study, it was clarified whether the neuroprotective effect of agmatine is related with the modulation of macrophage subdivision after spinal cord injury. Spinal cord injury was induced in rats with contusion using MASCIS. Animals received agmatine (100 mg/kg, IP) daily for 6 days beginning the day after spinal cord injury. The proportion of M1 and M2 macrophages are confirmed with immunohistochemistry and FACS. CD206+ & ED1+ cells were counted as M2 macrophages. The systemic treatment of agmatine increased M2 macrophages caudal side to epicenter 1 week after spinal cord injury in immunohistochemistry. M2 macrophage related markers, Arginase-1 and CD206 mRNA, were increased in the agmatine treatment group and M2 macrophage expressing and stimulated cytokine, IL-10 mRNA, also was significantly overexpressed by agmatine injection. Among BMPs, BMP2/4/7, agmatine significantly increased only the expression of BMP2 known to reduce M1 macrophage under inflammatory status. These results suggest that agmatine reduces impairment after spinal cord injury through modulating the macrophage phenotype.

Keywords: Agmatine; M2 polarization; Macrophage; Neuroinflammation; Spinal cord injury.

Figures

Fig. 1
Fig. 1. FACS analysis of macrophages 1 week after spinal cord injury. M1 macrophages were iNOS+&ED1+ cells (A) and M2 macrophages were CD206+&ED1+ cells (B). There were no significant difference in the number of M1 and M2 macrophages between agmatine treatment group (Agm, n=3) and experimental control group (EC, n=3, C&D). Median fluorescence intensity (MFI) of iNOS was decreased with agmatine treatment (E) and MFI of CD206 was increased in agmatine treatment group (F) without significance.
Fig. 2
Fig. 2. Immunohistochemistry of macrophages 1 week after spinal cord injury. The representative coronal spinal cord sections 2 mm caudal to epicenter were shown in A. The portion of M2 macrophages (CD206+&ED1+/ED1+) was significantly increased in Agm only 2 mm caudal to epicenter compared to EC (B). Agmatine treatment significantly reduced the number of macrophages (ED1+ cells) 2 mm caudal to epicenter compared to EC (C). Agmatine treatment group (Agm, n=3); Experimental control group (EC, n=3). Scale bar is 200 um. *p<0.05.
Fig. 3
Fig. 3. The mRNA expression of immune-related molecules and cytokines 1 week after spinal cord injury. CD11b, macrophage marker, expressed similar between EC and Agm (A). Arg-1 and CD206, M2 macrophage marker, were significantly increased in Agm (B&C). Inflammatory cytokines, IL-1b and IL-6 were not changed with agmatine treatment (Agm) or without (EC, D&E) but IL-10, anti-inflammatory cytokine, was significantly increased in Agm (F). Agmatine treatment group (Agm, n=5); Experimental control group (EC, n=5). *p<0.05.
Fig. 4
Fig. 4. The mRNA expression of BMPs and GFAP 1 week after spinal cord injury. BMP2 was expressed higher in Agm than EC (A) but BMP4, BMP7 and GFAP was not changed between Agm and EC (B-D). Agmatine treatment group (Agm, n=5); Experimental control group (EC, n=5). *p<0.05.

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