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 language | English |
|---|---|
| Pages (from-to) | 557-565 |
| Number of pages | 9 |
| Journal | Journal of Neuroscience Research |
| Volume | 62 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Nov 15 2000 |
Fingerprint
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 journal › Article
}
TY - JOUR
T1 - Antioxidants J811 and 17β-estradiol granule cells from methylmercury-induced apoptotic cell death
AU - Daré, E.
AU - Götz, M. E.
AU - Zhivotovsky, B.
AU - Manzo, L.
AU - Ceccatelli, S.
PY - 2000/11/15
Y1 - 2000/11/15
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Calpain
KW - CGC
KW - Methylmercury
KW - Radical scavengers
UR - http://www.scopus.com/inward/record.url?scp=0034668745&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034668745&partnerID=8YFLogxK
U2 - 10.1002/1097-4547(20001115)62:4<557::AID-JNR10>3.0.CO;2-9
DO - 10.1002/1097-4547(20001115)62:4<557::AID-JNR10>3.0.CO;2-9
M3 - Article
C2 - 11070499
AN - SCOPUS:0034668745
VL - 62
SP - 557
EP - 565
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
SN - 0360-4012
IS - 4
ER -