Metallothionein I+II expression and their role in experimental autoimmune encephalomyelitis

Abstract

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. GLIA 32:247–263, 2000. © 2000 Wiley‐Liss, Inc.

Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis

“…Zinc metallothioneins have been suggested to have a role in preventing demyelination and neurodegeneration as well as decreasing inflammation during EAE and MS. Increased expression of metallothioneins I and II has been detected in microglia, macrophages and astrocytes in both MS and EAE (Espejo et al, 2001;Lock et al, 2002;Penkowa and Hidalgo, 2000). Treatment of rats with zinc metallothionein II prior to or during EAE significantly decreased the amount of demyelination and axonal loss compared to controls (Penkowa and Hidalgo, 2003).…”

Metallothioneins and brain injury: What transgenic mice tell us

“…Thus, significant upregulation of these proteins has been observed in a number of human neurological diseases, including Alzheimer's disease (55,(79)(80)(81)(82)), Pick's disease (79), short-course Creutzfeld-Jakob disease (72), amyotrophic lateral sclerosis (83)(84)(85), and multiple sclerosis (86,87). Experiments carried out in animal models fully demonstrated the response of MT-1&2 to brain damage elicited by inflammatory factors such as lipopolysaccharides (11, 15, 24, 88), stress (62,(89)(90)(91), glutamate analogues (37,51,59,(92)(93)(94)(95), cryogenic injury (28,32,66,71), stroke/ischemia (17, [95][96][97][98], familial amyotrophic lateral sclerosis models (38,67,99,100), multiple sclerosis models (101)(102)(103), and gliotoxins (104)(105)(106).…”

“…Exciting perspectives are opened by the fact that exogenously applied MT-2 mimicked MT-1 transgenic overexpression, causing a significant clinical improvement in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (101,130), and protecting against traumatic brain injury (126, 131), calling for the therapeutic use of these proteins. It is still unknown whether the MT protein acts extracellularly or is incorporated somehow into the cell, but considering the potential importance of this result, further work in this regard is welcome.…”

Increased demyelination and axonal damage in metallothionein I+II-deficient mice during experimental autoimmune encephalomyelitis

“…The immunoreaction was visualized using 0.015 % H 2 O 2 in 3,3-diaminobenzidinetetrahydrochloride (DAB)/TBS for 10 min at room temperature. Standard control stainings without primary antibody were performed as previously described [3]. A further control for some cytokines and growth factors was to preabsorb the primary antibodies with their corresponding antigenic proteins.…”

“…Vol. 60,2003 Research Article 187 Standard control stainings were performed as previously described [3,14].…”