Methimazole-induced cell death in rat olfactory receptor neurons occurs via apoptosis triggered through mitochondrial cytochrome c-mediated caspase-3 activation pathway.
The administration of methimazole is known to induce cell death in rat olfactory receptor neurons (ORNs). We investigated whether this injury occurs via apoptosis or through necrosis and whether it involves the extrinsic or intrinsic pathway. Rats were intraperitoneally injected with vehicle (control) or 300 mg/kg methimazole. The experimental animals were also administered vehicle or a caspase-3 or caspase-9 inhibitor 30 min earlier. The administration of methimazole induced cell death predominantly in the mature ORNs and partially reduced olfactory sensitivity in the rats; the injured cells were TUNEL-positive and showed a nuclear staining pattern. This insult induced cytochrome c release from the mitochondria and a significant increase in the immunoreactivity of activated caspase-3 and caspase-9 as well as that of cleaved poly-ADP-ribose-polymerase; in addition, it caused a significant increase in the fluorogenic activity of caspase-3 and caspase-9. However, it did not affect the immunoreactivity of activated caspase-8 or the fluorogenic activity of caspase-8. Pretreatment with a caspase-3 or caspase-9 inhibitor nearly completely prevented the morphologic, biochemical, and functional changes induced by methimazole. These findings suggest strongly that methimazole-induced cell death in rat ORNs is predominantly apoptosis; moreover, the majority of this apoptotic cell death is triggered through mitochondrial cytochrome c-mediated caspase-3 activation pathway, and both caspase-3 and caspase-9 inhibitors can prevent methimazole-induced cell death in the ORNs.
Sakamoto
Takashi
T
Department of Otolaryngology, Mutual Aid Association for Tokyo Metropolitan Teachers and Officials, Sanraku Hospital, Tokyo, Japan.
Kondo
Kenji
K
Kashio
Akinori
A
Suzukawa
Keigo
K
Yamasoba
Tatsuya
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism*; D004789:Enzyme Activation; D007150:Immunohistochemistry; D008297:Male; D008713:Methimazole / Q000494:pharmacology*; D018034:Olfactory Receptor Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D008713:Methimazole; D045304:Cytochromes c; D053148:Caspase 3