Exposure to an Environmental Neurotoxicant Hastens the Onset of Amyotrophic Lateral Sclerosis-Like Phenotype in Human Cu2+/Zn2+ Superoxide Dismutase 1 G93A Mice: Glutamate-Mediated Excitotoxicity
| Autor: | Frank O. Johnson, William D. Atchison, Dawn M. Parsell, Yukun Yuan, Ravindra K. Hajela, Alisha Chitrakar |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty Transgene Excitotoxicity Glutamic Acid Mice Transgenic AMPA receptor Gene mutation Toxicology medicine.disease_cause Calcium in biology Superoxide dismutase Mice Internal medicine Excitatory Amino Acid Agonists medicine Animals Humans Genetic Predisposition to Disease Pharmacology biology Superoxide Dismutase Chemistry Amyotrophic Lateral Sclerosis Glutamate receptor Glutamic acid Methylmercury Compounds Phenotype Endocrinology Biochemistry biology.protein Molecular Medicine |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 338:518-527 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.110.174466 |
| Popis: | Mice expressing the human Cu(2+)/Zn(2+) superoxide dismutase 1 (hSOD1) gene mutation (hSOD1(G93A); G93A) were exposed to methylmercury (MeHg) at concentrations that did not cause overt motor dysfunction. We hypothesized that low concentrations of MeHg could hasten development of the amyotrophic lateral sclerosis (ALS)-like phenotype in G93A mice. MeHg (1 or 3 ppm/day in drinking water) concentration-dependently accelerated the onset of rotarod failure in G93A, but not wild-type, mice. At the time of rotarod failure, MeHg increased Fluo-4 fluorescence (free intracellular calcium concentration [Ca(2+)](i)) in soma of brainstem-hypoglossal nucleus. These motor neurons control intrinsic and some extrinsic tongue function and exhibit vulnerability in bulbar-onset ALS. The α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione reduced [Ca(2+)](i) in all G93A mice, irrespective of MeHg treatment. N-acetyl spermine, which antagonizes Ca(2+)-permeable AMPA receptors, further reduced [Ca(2+)](i) more effectively in MeHg-treated than untreated G93A mice, suggesting that MeHg-treated mice have a greater Ca(2+)-permeable AMPA receptor contribution. The non-Ca(2+) divalent cation chelator N,N,N',N'-tetrakis(pyridylmethyl)ethylenediamine reduced Fluo-4 fluorescence in all G93A mice; FluoZin-(Zn(2+) indicator) fluorescence was increased in all MeHg-treated mice. Thus in G93A mice Zn(2+) apparently contributed measurably to the MeHg-induced effect. This is the initial demonstration of accelerated onset of ALS-like phenotype in a genetically susceptible organism by exposure to low concentrations of an environmental neurotoxicant. Increased [Ca(2+)](i) induced by the G93A-MeHg interaction apparently was associated with Ca(2+)-permeable AMPA receptors and may contribute to the hastened development of ALS-like phenotypes by subjecting motor neurons to excessive elevation of [Ca(2+)](i), leading to excitotoxic cell death. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|