Role of astrocytes in trimethyltin neurotoxicity.
Although the neurotoxicity of trimethyltin (TMT) is well known, mechanisms are still not clear. Glia have been proposed to mediate the toxic action of TMT on nerve cells. Accordingly, the effects of TMT were tested in primary neuronal cultures from rat cerebellum and compared to effects in astrocytes and mixed cultures. Neuronal damage observed following TMT exposure was less in the presence of astrocytes and astrocytes alone were resistant to TMT. Thus, astrocytes have a protective effect against TMT-induced neurotoxicity. TMT caused an oxidative stress in granule cell cultures involving a variety of oxidative species (O2)*-, H2O2, NO), but astrocytes were less sensitive to TMT-induced oxidative species generation. Antioxidants, glutathione and 7-nitroindazole attenuated neuronal cell death induced by TMT. It appears that oxidative stress mediates a large part of the destructive action of TMT in neuronal cultures. The presence of astrocytes appears to modulate TMT-induced oxidative stress so that TMT causes only a small increase in lipid peroxidation in mouse brain after systemic administration. Thus, TMT induces a pronounced oxidative stress in cultured neurons, but when astrocytes are present, oxidative species play a lesser role in the neurotoxic action of TMT.
Gunasekar
P G
PG
Neurotoxicology Laboratory, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Mickova
V
V
Kotyzova
D
D
Li
L
L
Borowitz
J L
JL
Eybl
V
V
Isom
G E
GE
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D051381:Rats; D014298:Trimethyltin Compounds / Q000633:toxicity*
D014298:Trimethyltin Compounds; C046488:trimethyltin; D005978:Glutathione