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Titolo:
Mechanisms of the apoptotic and necrotic actions of trimethyltin in cerebellar granule cells
Autore:
Gunasekar, P; Li, L; Prabhakaran, K; Eybl, V; Borowitz, JL; Isom, GE;
Indirizzi:
Purdue Univ, Dept Med Chem & Mol Pharmacol, Neurotoxicol Lab, W Lafayette,IN 47907 USA Purdue Univ W Lafayette IN USA 47907 oxicol Lab, W Lafayette,IN 47907 USA Charles Univ, Dept Pharmacol & Toxicol, Fac Med, CZ-30166 Plzen, Czech Republic Charles Univ Plzen Czech Republic CZ-30166 Z-30166 Plzen, Czech Republic
Titolo Testata:
TOXICOLOGICAL SCIENCES
fascicolo: 1, volume: 64, anno: 2001,
pagine: 83 - 89
SICI:
1096-6080(200111)64:1<83:MOTAAN>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-KINASE-C; NITRIC-OXIDE; SIGNAL-TRANSDUCTION; RECEPTOR ACTIVATION; OXIDATIVE STRESS; NEUROTOXICITY; DEATH; GENERATION; INHIBITION; GLUTAMATE;
Keywords:
trimethyltin; protein kinase C; oxidative stress; excitotoxicity; cerebellar granule cell death;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
Recensione:
Indirizzi per estratti:
Indirizzo: Isom, GE Purdue Univ, Dept Med Chem & Mol Pharmacol, Neurotoxicol Lab, W Lafayette,IN 47907 USA Purdue Univ W Lafayette IN USA 47907 b, W Lafayette,IN 47907 USA
Citazione:
P. Gunasekar et al., "Mechanisms of the apoptotic and necrotic actions of trimethyltin in cerebellar granule cells", TOXICOL SCI, 64(1), 2001, pp. 83-89

Abstract

In evaluating mechanisms of trimethyltin (TMT)-initiated neuronal damage, the present study focused on involvement of reactive oxygen species, protein kinase C (PKC), and glutamate receptors. Exposure of cerebellar granule cells to TMT (0.01-0.1 muM) produced primarily apoptosis, but higher concentrations were associated with cellular lactate dehydrogenase efflux and necrosis. TMT increased generation of cellular reactive oxygen species, which was inhibited by either L-NAME (inhibitor of nitric oxide synthase, NOS) or catalase, indicating that both NO and H2O2, are formed on TMT exposure. Since chelerythrine (selective PKC inhibitor) also inhibited oxidative speciesgeneration, PKC appears to play a significant role in TMT-induced oxidative stress. The metabotropic glutamate receptor antagonist, MCPG, (but not MK-801) prevented oxidative species generation, indicating significant involvement of metabotropic receptors (but not NMDA receptors) in TMT-induced oxidative stress. NOS involvement in the action of TMT was confirmed through measurement of nitrite, which increased concentration dependently. Nitrite accumulation was blocked by L-NAME, chelerythrine, or MCPG, showing that NO is generated by TMT and that associated changes in NOS are regulated by a PKC-mediated mechanism. Oxidative damage by TMT was demonstrated by detection of elevated malondialdehyde levels. It was concluded that low concentrations of TMT (0.01-0.1 muM) cause apoptotic cell death in which oxidative signaling is an important event. Higher concentrations of TMT initiate necrotic death, which involves both an oxidative and a non-oxidative component. TMT-induced necrosis but not apoptosis in granule cells is mediated by glutamate receptors.

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Documento generato il 02/04/20 alle ore 13:07:47