Metallothionein reduces central nervous system inflammation, neurodegeneration, and cell death following kainic acid-induced epileptic seizures.
We examined metallothionein (MT)-induced neuroprotection during kainic acid (KA)-induced excitotoxicity by studying transgenic mice with MT-I overexpression (TgMT mice). KA induces epileptic seizures and hippocampal excitotoxicity, followed by inflammation and delayed brain damage. We show for the first time that even though TgMT mice were more susceptible to KA, the cerebral MT-I overexpression decreases the hippocampal inflammation and delayed neuronal degeneration and cell death as measured 3 days after KA administration. Hence, the proinflammatory responses of microglia/macrophages and lymphocytes and their expression of interleukin (IL)-1, IL-6, IL-12, tumor necrosis factor-alpha and matrix metalloproteinases (MMP-3, MMP-9) were significantly reduced in hippocampi of TgMT mice relative to wild-type mice. Also by 3 days after KA, the TgMT mice showed significantly less delayed damage, such as oxidative stress (formation of nitrotyrosine, malondialdehyde, and 8-oxoguanine), neurodegeneration (neuronal accumulation of abnormal proteins), and apoptotic cell death (judged by TUNEL and activated caspase-3). This reduced bystander damage in TgMT mice could be due to antiinflammatory and antioxidant actions of MT-I but also to direct MT-I effects on the neurons, in that significant extracellular MT presence was detected. Furthermore, MT-I overexpression stimulated astroglia and increased immunostaining of antiinflammatory IL-10, growth factors, and neurotrophins (basic fibroblastic growth factor, transforming growth factor-beta, nerve growth factor, brain-derived neurotrophic factor, glial-derived neurotrophic factor) in hippocampus. Accordingly, MT-I has different functions that likely contribute to the increased neuron survival and improved CNS condition of TgMT mice. The data presented here add new insight into MT-induced neuroprotection and indicate that MT-I therapy could be used against neurological disorders.
Penkowa
Milena
M
Department of Medical Anatomy, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Florit
Sergi
S
Giralt
Mercedes
M
Quintana
Albert
A
Molinero
Amalia
A
Carrasco
Javier
J
Hidalgo
Juan
J
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002493:Central Nervous System Diseases / Q000517:prevention & control*; D004827:Epilepsy / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007378:Interleukins / Q000378:metabolism; D007608:Kainic Acid; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000517:prevention & control*; D016874:Neurofibrillary Tangles / Q000378:metabolism; D013194:Staining and Labeling / Q000379:methods; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D005904:Glial Fibrillary Acidic Protein; D006133:Growth Substances; D007378:Interleukins; C002744:3-nitrotyrosine; D014443:Tyrosine; C024829:8-hydroxyguanine; D006147:Guanine; D008668:Metallothionein; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D007608:Kainic Acid