title: Metallothionein prevents neurodegeneration and central nervous system cell death after treatment with gliotoxin 6-aminonicotinamide.
abstract: Transgenic expression of interleukin-6 (IL-6) in the CNS under the control of the glial fibrillary acidic protein (GFAP) gene promoter (GFAP-IL6 mice) induces significant inflammation and neurodegeneration but also affords neuroprotection against acute traumatic brain injury. This neuroprotection is likely mediated by the IL-6-induced protective factors metallothioneins-I and -II (MT-I+II). Here we evaluate the neuroprotective roles of IL-6 vs. MT-I+II during 6-aminonicotinamide (6-AN)-induced neurotoxicity, by using GFAP-IL6 mice and transgenic mice overexpressing MT-I (TgMT) as well as GFAP-IL6 mice crossed with TgMT mice (GFAP-IL6 x TgMT). 6-AN caused acute damage of brainstem gray matter areas identified by necrosis of astrocytes, followed by inflammatory responses. After 6-AN-induced toxicity, secondary damage was observed, consisting of oxidative stress, neurodegeneration, and apoptotic cell death. We hereby show that the primary injury caused by 6-AN was comparable in wild-type and GFAP-IL6 mice, but MT-I overexpression could significantly protect the brain tissue. As expected, GFAP-IL6 mice showed increased CNS inflammation with more gliosis, macrophages, and lymphocytes, including increased cytokine expression, relative to the other mice. However, GFAP-IL6 mice showed reduced oxidative stress (judged from nitrotyrosine, malondialdehyde, and 8-oxoguanine stainings), neurodegeneration (accumulation of neurofibrillary tangles), and apoptosis (determined from TUNEL and caspase-3). MT-I+II expression was significantly higher in GFAP-IL6 mice than in wild types, which may contribute to the IL-6-induced neuroprotection. In support of this, overexpression of MT-I in GFAP-IL6 x TgMT as well as TgMT mice protected the brainstem tissue significantly from 6-AN-induced toxicity and secondary brain tissue damage. Overall, the results demonstrate that brain MT-I+II proteins are fundamental neuroprotective factors, which in the future may become therapeutic agents.
authors.affiliation: Department of Medical Anatomy, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Milena
authors.initials: M
authors.lastname: Penkowa
authors.forename: Albert
authors.initials: A
authors.lastname: Quintana
authors.forename: Javier
authors.initials: J
authors.lastname: Carrasco
authors.forename: Mercedes
authors.initials: M
authors.lastname: Giralt
authors.forename: Amalia
authors.initials: A
authors.lastname: Molinero
authors.forename: Juan
authors.initials: J
authors.lastname: Hidalgo
mesh_terms: D015120:6-Aminonicotinamide; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005609:Free Radicals / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism; D009498:Neurotoxins; D018384:Oxidative Stress / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D005609:Free Radicals; D005904:Glial Fibrillary Acidic Protein; D015850:Interleukin-6; D018696:Neuroprotective Agents; D009498:Neurotoxins; D015120:6-Aminonicotinamide; D008668:Metallothionein; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases