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Vitamin E deficiency increases susceptibility of the BALB/c mouse to MDMA-induced dopaminergic neurotoxicity.
Johnson EA; Shvedova AA; Kisin E; O'Callaghan JP; Kommineni C; Miller DB
Toxicologist 2000 Mar; 54(1):21
The mechanism of 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity has been hypothesized to involve the formation of toxic free radical species. Since Vitamin E is a potent radical scavenger, we tested whether Vitamin E deficiency affects susceptibility to MDMA-induced dopaminergic neurotoxicity. Male BALB/c mice (3-4 weeks old) were kept on control (Vit. E, 50 IU/kg) and Vitamin E deficient (<10 IU/kg) diets for twenty weeks. Vitamin E levels in brain of deficient mice were reduced 75% compared to controls. Vitamin E deficient and control mice were randomly assigned to the following groups: saline 200 ul, (every 2 hrs X 4, s.c), or MDMA 5 mg/kg, (every 2 hrs X 4, s.c.) or 10 mg/kg (every 2 hrs X 4, s.c.). Rectal temperatures were assessed every 2 hours during the dose period. Vitamin E deficient animals exhibited MDMA-induced temperature modulation that was similar to control animals. Seventy-two hours following the first dose, animals were sacrificed and brains were dissected for determination of Vitamin E, glutathione, total antioxidant reserve, protein thiols, dopamine, DOPAC, HVA, and Glial Fibrillary Acidic Protein (GFAP), and livers were analyzed by histopathology. Animals given the Vitamin E deficient diet exhibited neurotoxic responses at the lowest dose of MDMA, while mice on the control diet were undamaged. Striatal dopamine was reduced by 47%, DOPAC by 44%, and HVA by 29%, while GFAP was elevated 3 fold. Neurotoxic responses were also observed at 72 hrs at the higher dose of MDMA, in both diet groups. In the Vitamin E deficient mice MDMA caused greater hepatic necrosis compared with controls. These data indicate that Vitamin E deficiency increases susceptibility to MDMA-induced neurotoxicity and hepatic necrosis and provide support for a free-radical mediated mechanism of toxicity.
Laboratory animals; Animals; Animal studies; Neurotoxicity; Histopathology; Neurotoxic effects; Neurotoxins; Neurotoxicology; Free radicals; Toxic effects; Toxins
Issue of Publication
The Toxicologist. Society of Toxicology 39th Annual Meeting, March 19-23, 2000, Philadelphia, Pennsylvania
Page last reviewed: April 9, 2021
Content source: National Institute for Occupational Safety and Health Education and Information Division