In cortical cultures of trisomy 16 mouse brain the upregulated metallothionein-I/II fails to respond to H sub(2)O sub(2) exposure or glutamate receptor stimulation

• Published in: Brain research 1998-03, Vol.787 (2), p.292-298
• Main Authors: Scortegagna, M, Galdzicki, Z, Rapoport, SI, Hanbauer, I
• Format: Article
• Language: English
• ISSN: 0006-8993

To assess whether a defective oxidative defense may contribute to Down's syndrome, we studied the regulation of the metallothionein(MT)-I/II isoforms in primary cultures of cerebral cortex from fetal trisomy 16 mice and their euploid littermates. Western blot analysis showed that MT-I/II was upregulated and the protein carbonyl content was higher in trisomy 16 compared with euploid cultures. Addition of N -acetyl-l-cysteine to the culture medium reduced the increment of MT-I/II in trisomy 16 cortical cells. In euploid, but not trisomic cortical cultures, kainic acid, trans-( plus or minus )-ACPD, or H sub(2)O sub(2) exposure elicited a dose-dependent increase of the MT-I/II immunoblots. In trisomic cells, the MT-I/II immunoblot densities were not increased beyond their elevated basal levels. In contrast, 25 mu M Pb induced MT-I/II, to a similar extent, in cortical cultures from euploid and trisomy 16 mice. This suggests that the antioxidant--but not the metal--response element of the MT-I/II promoter was altered by increased oxidative stress. Our data suggest that, in the trisomy 16 mouse, the effects of increased production of reactive oxygen species, due to the increased SOD-1, GluR5, or amyloid precursor protein gene dosage, is exacerbated by an insufficient or missing antioxidant response.