Minocycline suppresses experimental autoimmune encephalomyelitis by increasing tissue inhibitors of metalloproteinases.

Abstract

Matrix metalloproteinases (MMPs) that are secreted by activated T cells play a significant role in degradation of the extracellular matrix around the blood vessels and facilitate autoimmune neuroinflammation; however, it remains unclear how MMPs act in lesion formation and whether MMP-targeted therapies are effective in disease suppression. In the present study, we attempted to treat experimental autoimmune encephalomyelitis (EAE) by administration of small interfering RNAs (siRNAs) for MMP-2, MMP-9, and minocycline, all of which have MMP-inhibiting functions. Minocycline, but not siRNAs, significantly suppressed disease development. In situ zymography revealed that gelatinase activities were almost completely suppressed in the spinal cords of minocycline-treated animals, while significant gelatinase activities were measured in the EAE lesions of control animals. However, MMP-2 and MMP-9 mRNAs and proteins in the spinal cords of treated rats were unexpectedly upregulated. At the same time, mRNA for tissue inhibitors of MMPs (TIMP)-1 and -2 were also upregulated. The EnzChek Gelatinase/Collagenase assay using tissue containing native MMPs and TIMPs demonstrated that gelatinase activity levels in the spinal cords of treated rats were suppressed to the same level as those in normal spinal cord tissues. Finally, double immunofluorescent staining demonstrated that MMP-9 immunoreactivities of treated rats were almost the same as those of control rats and that MMP-9 and TIMP-1 immunoreactivities were colocalized in the spinal cord. These findings suggest that minocycline administration does not suppress MMPs at mRNA and protein levels but that it suppresses gelatinase activities by upregulating TIMPs. Thus, MMP-targeted therapies should be designed after the mechanisms of candidate drugs have been considered.

• Authors: Naoko Niimi, Kuniko Kohyama, Yoh Matsumoto
• Journal: Neuropathology : official journal of the Japanese Society of Neuropathology (Neuropathology) Vol. 33 Issue 6 Pg. 612-20 (Dec 2013) ISSN: 1440-1789 [Electronic] Australia
• PMID: 23581743 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Japanese Society of Neuropathology.

Chemical References

• Enzyme Inhibitors
• RNA, Small Interfering
• Tissue Inhibitor of Metalloproteinases
• Gelatinases
• Matrix Metalloproteinases
• Minocycline

Topics

• Animals
• Encephalomyelitis, Autoimmune, Experimental (enzymology)
• Enzyme Inhibitors (pharmacology)
• Gelatinases (biosynthesis)
• Matrix Metalloproteinases (biosynthesis)
• Minocycline (pharmacology)
• RNA, Small Interfering
• Rats
• Rats, Inbred Lew
• Real-Time Polymerase Chain Reaction
• Spinal Cord (drug effects, enzymology)
• Tissue Inhibitor of Metalloproteinases (biosynthesis)
• Up-Regulation