Metallothionein-1+2 protect the CNS after a focal brain injury.
We have evaluated the physiological relevance of metallothionein-1+2 (MT-1+2) in the CNS following damage caused by a focal cryolesion onto the cortex. In comparison to normal mice, transgenic mice overexpressing the MT-1 isoform (TgMTI* mice) showed a significant decrease of the number of activated microglia/macrophage and of CD3+ T lymphocytes in the area surrounding the lesion, while astrocytosis was increased. The TgMTI* mice showed a diminished peripheral macrophage but not CD3 T cell response to the cryolesion. This altered inflammatory response produced a decreased expression of the proinflammatory cytokines IL-1beta, IL-6, and TNF-alpha and an increased expression of the growth factors bFGF, TGFbeta1, and VEGF in the TgMTI* mice relative to control mice, which might be related to the increased angiogenesis and regeneration of the parenchyma of the former mice. The overexpression of MT-1 dramatically reduced the cryolesion-induced oxidative stress and neuronal apoptosis. Remarkably, these effects were also obtained by the intraperitoneal administration of MT-2 to both normal and MT-1+2 knock-out mice. These results fully support the notion that MT-1+2 are essential in the CNS for coping with focal brain injury and suggest a potential therapeutic use of these proteins.
Giralt
Mercedes
M
Departamento de Biología Celular, de Fisiología y de Inmunología, Unidad de Fisiología Animal, Facultad de Ciencias, Universidad Autónoma de Barcelona, Bellaterra, Barcelona, Spain 08193.
Penkowa
Milena
M
Lago
Natalia
N
Molinero
Amalia
A
Hidalgo
Juan
J
D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection; D018450:Disease Progression; D004660:Encephalitis / Q000209:etiology / Q000473:pathology; D005615:Freezing; D005786:Gene Expression Regulation / Q000187:drug effects; D006133:Growth Substances / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007274:Injections, Intraperitoneal; D008264:Macrophages / Q000473:pathology; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D020033:Protein Isoforms / Q000494:pharmacology; D013601:T-Lymphocytes / Q000473:pathology
D016207:Cytokines; D006133:Growth Substances; D020033:Protein Isoforms; D008668:Metallothionein