Premium
Minocycline suppresses experimental autoimmune encephalomyelitis by increasing tissue inhibitors of metalloproteinases
Author(s) -
Niimi Naoko,
Kohyama Kuniko,
Matsumoto Yoh
Publication year - 2013
Publication title -
neuropathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.701
H-Index - 61
eISSN - 1440-1789
pISSN - 0919-6544
DOI - 10.1111/neup.12039
Subject(s) - experimental autoimmune encephalomyelitis , matrix metalloproteinase , gelatinase , minocycline , spinal cord , multiple sclerosis , encephalomyelitis , downregulation and upregulation , medicine , gelatinase a , metalloproteinase , immunology , pathology , chemistry , biochemistry , psychiatry , gene , antibiotics
Matrix metalloproteinases ( MMP s) 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 MMP s 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 RNA s ( siRNA s) for MMP ‐2, MMP ‐9, and minocycline, all of which have MMP ‐inhibiting functions. Minocycline, but not siRNA s, 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 mRNA s 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 E nz C hek G elatinase/ C ollagenase assay using tissue containing native MMP s and TIMP s 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 MMP s at mRNA and protein levels but that it suppresses gelatinase activities by upregulating TIMP s. Thus, MMP ‐targeted therapies should be designed after the mechanisms of candidate drugs have been considered.