Involvement of caspase 3-like protease in methylmercury-induced apoptosis of primary cultured rat cerebral microglia.
Methylmercury (MeHg) has been implicated to induce massive neurodegeneration by disruption of neuron-glia interactions besides a direct potent neurotoxicity. In the present study, we examined potential cytotoxic effects of MeHg on primary cultured rat microglia. Following treatment with a relatively low concentration (0.5 microM) of MeHg, microglia had induced cell death accompanied by DNA fragmentation and an activation of caspase-3-like protease. MeHg-induced microglial death was significantly suppressed by the caspase-3-like protease inhibitor benzyloxycarbonyl-Try-Val-Ala-Asp-fluoromethyl-ketone indicating the occurrence of caspase-3-like protease-executed apoptosis. The aspartic protease inhibitor pepstatin A had a partial but significant inhibitory effect on MeHg-induced microglial apoptosis. These results indicate that a relatively low concentration of MeHg predominantly induces caspase-3-like protease-executed apoptosis of microglia, while the endosomal/lysosomal system is also partially involved in the cell death pathway.
Nishioku
T
T
Department of Pharmacology, Faculty of Dentistry, Kyushu University, 812-8582, Fukuoka, Japan.
Takai
N
N
Miyamoto
K
K
Murao
K
K
Hara
C
C
Yamamoto
K
K
Nakanishi
H
H
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D003374:Coumarins / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D008767:Methylmercury Compounds / Q000494:pharmacology*; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D003374:Coumarins; D015853:Cysteine Proteinase Inhibitors; D008767:Methylmercury Compounds; D009842:Oligopeptides; C096022:acetyl-tyrosyl-valyl-alanyl-aspartyl-7-amino-4-methylcoumarinamide; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases