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RESEARCH ARTICLE
Year : 2018  |  Volume : 13  |  Issue : 8  |  Page : 1447-1454

Local inhibition of matrix metalloproteinases reduced M2 macrophage activity and impeded recovery in spinal cord transected rats after treatment with fibroblast growth factor-1 and nerve grafts


1 Department and Institute of Pharmacology, National Yang-Ming University; Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, China
2 Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, China
3 Department of Applied Chemistry, Chaoyang University of Technology, Taichung, Taiwan, China
4 Department and Institute of Pharmacology, National Yang-Ming University; Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital; Center for Neural Regeneration, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, China

Correspondence Address:
Henrich Cheng
Department and Institute of Pharmacology, National Yang-Ming University; Neural Regeneration Laboratory, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital; Center for Neural Regeneration, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
China
Meng-Jen Lee
Department of Applied Chemistry, Chaoyang University of Technology, Taichung, Taiwan
China
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Source of Support: This work was supported by the National Science Council (102-2320-B-324-001), China. This study was also supported by grants from Taipei Veterans General Hospital (V103E6-001 & V104E6-001) and by grants (MOST 104-2314-B-010-012-MY3, MOST 105-2314-B-010-013-MY2 and MOST 106-2632-B-324-001) from the Ministry of Science and Technology in Taiwan, China, Conflict of Interest: None


DOI: 10.4103/1673-5374.235302

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Alternatively activated macrophages (M2 macrophages) promote central nervous system regeneration. Our previous study demonstrated that treatment with peripheral nerve grafts and fibroblast growth factor-1 recruited more M2 macrophages and improved partial functional recovery in spinal cord transected rats. The migration of macrophages is matrix metalloproteinase (MMP) dependent. We used a general inhibitor of MMPs to influence macrophage migration, and we examined the migration of macrophage populations and changes in spinal function. Rat spinal cords were completely transected at T8, and 5 mm of spinal cord was removed (group T). In group R, spinal cord-transected rats received treatment with fibroblast growth factor-1 and peripheral nerve grafts. In group RG, rats received the same treatment as group R with the addition of 200 μM GM6001 (an MMP inhibitor) to the fibrin mix. We found that MMP-9, but not MMP-2, was upregulated in the graft area of rats in group R. Local application of the MMP inhibitor resulted in a reduction in the ratio of arginase-1 (M2 macrophage subset)/inducible nitric oxide synthase-postive cells. When the MMP inhibitor was applied at 8 weeks postoperation, the partial functional recovery observed in group R was lost. This effect was accompanied by a decrease in brain-derived neurotrophic factor levels in the nerve graft. These results suggested that the arginase-1 positive population in spinal cord transected rats is a migratory cell population rather than the phenotypic conversion of early iNOS+ cells and that the migration of the arginase-1+ population could be regulated locally. Simultaneous application of MMP inhibitors or promotion of MMP activity for spinal cord injury needs to be considered if the coadministered treatment involves M2 recruitment.


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