Antioxidants J811 and 17β-estradiol granule cells from methylmercury-induced apoptotic cell death

E. Daré, M. E. Götz, B. Zhivotovsky, L. Manzo, S. Ceccatelli

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Cerebellar granule cells (CGC) have provided a reliable model for studying the toxicity of methylmercury (MeHg), a well-known neurotoxicant contaminating the environment. In the present study we report that doses of MeHg ranging from 0.1 μM to 1.5 μM activated apoptosis, as shown by cell shrinkage, nuclear condensation, and formation of high-molecular-weight DNA fragments. Nevertheless, caspase-3-like activity was not significantly induced, and the broad caspase inhibitor Z-VAD-FMK was not capable of protecting the cells. This argues for a minor role of caspases in the intracellular pathways leading to MeHg-induced cell death in CGC. Instead, proteolyric fragments obtained by specific calpain cleavage of procaspase-3 and α-fodrin were increased consistently in samples exposed to MeHg, pointing to a substantial activation of calpain. Notably, two antioxidants, 17β-estradiol (10 μM) and the Δ 8,9-dehydro derivative of 17α-estradiol J811 (10 μM), protected from MeHg damage, preventing morphological alterations, chromatin fragmentation, and activation of calpain. These findings underscore the key role of oxidative stress in MeHg toxicity, placing it upstream of calpain activation. The shielding effect of the 17β-estradiol and the radical scavenger J811 is potentially relevant for the development of therapeutic strategies for MeHg intoxication. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)557-565
Number of pages9
JournalJournal of Neuroscience Research
Volume62
Issue number4
DOIs
Publication statusPublished - Nov 15 2000

Fingerprint

Calpain
Estradiol
Cell Death
Antioxidants
Caspase 3
Caspase Inhibitors
Caspases
Chromatin
Oxidative Stress
Molecular Weight
Apoptosis
DNA
Therapeutics

Keywords

  • Apoptosis
  • Calpain
  • CGC
  • Methylmercury
  • Radical scavengers

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Antioxidants J811 and 17β-estradiol granule cells from methylmercury-induced apoptotic cell death. / Daré, E.; Götz, M. E.; Zhivotovsky, B.; Manzo, L.; Ceccatelli, S.

In: Journal of Neuroscience Research, Vol. 62, No. 4, 15.11.2000, p. 557-565.

Research output: Contribution to journalArticle

Daré, E. ; Götz, M. E. ; Zhivotovsky, B. ; Manzo, L. ; Ceccatelli, S. / Antioxidants J811 and 17β-estradiol granule cells from methylmercury-induced apoptotic cell death. In: Journal of Neuroscience Research. 2000 ; Vol. 62, No. 4. pp. 557-565.
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