Metallothionein I+II expression and their role in experimental autoimmune encephalomyelitis.
We examined the expression and roles of neuroprotective metallothionein-I+II (MT-I+II) in the rat CNS in experimental autoimmune encephalomyelitis (EAE), an animal model for the human autoimmune disease, multiple sclerosis (MS). EAE caused significant macrophage activation, T-lymphocyte infiltration, and astrogliosis in spinal cord, brain stem, and cerebellum, which peaked 14-18 days after immunization. The remission of symptoms and histopathological changes began at days 19-21 and were completed by days 30-40. MT-I+II expression was increased significantly in EAE infiltrates. In order to study the effects of increased MT levels, we administered Zn-MT-II intraperitoneally (i.p.) to rats during EAE. Clinically, Zn-MT-II treatment reduced the severity of EAE symptoms and mortality in a time- and dose-dependent manner. Histopathologically, Zn-MT-II increased reactive astrogliosis and decreased macrophages and T lymphocytes significantly in the CNS. In spleen sections, the number of macrophages both in control and EAE-sensitized rats was reduced by Zn-MT-II, while the number of lymphocytes remained unaltered by Zn-MT-II. Therefore, we suggest that MT-II has peripheral mechanisms of action on macrophages, while T lymphocytes are affected locally in the CNS. During EAE, oxidative stress was decreased by Zn-MT-II, which could contribute to the diminished clinical scores observed. None of the effects caused by Zn-MT-II could be attributable to the zinc content. These results suggest MT-I+II as potentially useful factors for the treatment of EAE/MS.
Penkowa
M
M
Department of Medical Anatomy, Panum Institute, University of Copenhagen, Copenhagen, Denmark. m.penkowa@mai.ku.dk
Hidalgo
J
J
D000818:Animals; D001253:Astrocytes / Q000276:immunology; D001812:Blood-Brain Barrier / Q000502:physiology; D001933:Brain Stem / Q000276:immunology / Q000473:pathology; D002531:Cerebellum / Q000276:immunology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D005911:Gliosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007167:Immunotherapy; D008264:Macrophages / Q000276:immunology; D008668:Metallothionein / Q000032:analysis / Q000096:biosynthesis* / Q000493:pharmacokinetics; D017628:Microglia / Q000276:immunology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D015032:Zinc / Q000493:pharmacokinetics
D005609:Free Radicals; D008668:Metallothionein; D015032:Zinc