Copper/zinc chelation by clioquinol reduces spinal cord white matter damage and behavioral deficits in a murine MOG-induced multiple sclerosis model.
The present study aimed to evaluate the therapeutic potential of clioquinol (CQ), a metal chelator, on multiple sclerosis pathogenesis. Experimental autoimmune encephalomyelitis was induced by immunization with myelin oligodendrocyte glycoprotein (MOG(35-55)) in female mice. Three weeks after the initial immunization, demyelination and immune cell infiltration in the spinal cord were analyzed. CQ (30mg/kg) was given by gavage once per day for the entire experimental course. CQ profoundly reduced the daily clinical score and incidence rate of EAE mice. The CQ-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination and reduced infiltration by encephalitogenic immune cells including CD4, CD8, CD20 and F4/80 positive cells. CQ also remarkably inhibited EAE-associated BBB disruption and MMP-9 activation. Autophagy contributes to clearance of aggregated proteins in astrocytes and neurons. The present study found that EAE increased the induction of autophagy and CQ further increased this expression. Furthermore, the present study found that post-treatment with CQ also reduced the clinical score of EAE and spinal cord demyelination. These results demonstrate that CQ inhibits the clinical features and neuropathological changes associated with EAE. The present study suggests that transition metals may be involved in several steps of multiple sclerosis pathogenesis.
Department of Physiology, Hallym University, College of Medicine, Chuncheon, Republic of Korea.
Bo Young
BY
Choi
Bong Geom
BG
Jang
Jin Hee
JH
Kim
Jae-Nam
JN
Seo
Guang
G
Wu
Min
M
Sohn
Tae Nyoung
TN
Chung
Sang Won
SW
Suh
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D002614:Chelating Agents / Q000494:pharmacology*; D007464:Clioquinol / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000473:pathology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology; D015032:Zinc / Q000378:metabolism
D002614:Chelating Agents; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D003300:Copper; D007464:Clioquinol; D015032:Zinc