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Metallothionein 1+2 protect the CNS during neuroglial degeneration induced by 6‐aminonicotinamide
Author(s) -
Penkowa Milena,
Giralt Mercedes,
Camats Jordi,
Hidalgo Juan
Publication year - 2002
Publication title -
journal of comparative neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.855
H-Index - 209
eISSN - 1096-9861
pISSN - 0021-9967
DOI - 10.1002/cne.10149
Subject(s) - astrogliosis , biology , tunel assay , terminal deoxynucleotidyl transferase , oxidative stress , astrocyte , nitric oxide synthase , nitrotyrosine , microglia , apoptosis , neurotoxicity , neuroprotection , endocrinology , medicine , microbiology and biotechnology , nitric oxide , inflammation , central nervous system , immunology , biochemistry , pharmacology , toxicity
6‐Aminonicotinamide (6‐AN) is a niacin antagonist, which leads to degeneration of gray matter astrocytes. Metallothionein 1+2 (MT‐1+2) are neuroprotective factors in the central nervous system (CNS), and to determine the roles for MT after 6‐AN, we have examined transgenic mice overexpressing MT‐1 (TgMTI* mice) after an i.p. injection with 6‐AN. In control mice injected with 6‐AN, astrocytes in specific gray matter areas of the brainstem showed degeneration. Reactive astrocytes surrounded the degenerated areas, which were heavily infiltrated by macrophages and T lymphocytes. MT‐1+2 expression was significantly decreased in the damaged brainstem areas, but it increased in reactive astrocytes surrounding these areas and also in infiltrating macrophages. The levels of oxidative stress, as determined by immunoreactivity for inducible nitric‐oxide synthase (iNOS), malondialdehyde (MDA), and nitrotyrosine (NITT), and the number of terminal deoxynucleotidyl transferase [TdT]‐mediated deoxyuridine triphosphate [dUTP]‐digoxigenin nick end labeling–positive (TUNEL+), caspase‐3+ apoptotic cells were significantly increased in the brainstem of normal mice after 6‐AN. In the TgMTI* mice, the 6‐AN–induced tissue damage was decreased in comparison to control mice, and they showed significantly reduced numbers of recruited macrophages and T lymphocytes, and a drastic reduction of oxidative stress and apoptotic cell death. In addition, the accompanying reactive astrogliosis was increased in the transgenic mice. To further study the potential protective role of MT, we administered intraperitoneally Zn‐MT‐2 to 6‐AN–injected normal mice and found essentially the same results as those obtained in TgMTI* mice. Thus, we hereby report that endogenous MT‐1 overexpression and exogenous MT‐2 treatment have significant neuroprotective roles during CNS pathological conditions. J. Comp. Neurol. 444:174–189, 2002. © 2002 Wiley‐Liss, Inc.