N-[4-(3-ethoxy-2-hydropropoxy)phenyl] acrylamide selectively induces apoptosis of cerebellar granule cells in vivo and in vitro in rats.
Oral administration of N-[4-(3-ethoxy-2-hydropropoxy)phenyl] acrylamide (EHA) induced selective granule cell destruction in the granular layer of the cerebellar cortex together with neurological signs, such as delayed righting reflex, gait or truncal ataxia, and convulsion. Neuropathologically, it caused multifocal granule cell destruction with nuclear pyknosis and spongiosis of the neuropile in the granular layer. Other neurons, including Purkinje cells, were spared. Ultrastructurally, damaged granule cells showed aggregation of nuclear chromatin and cytoplasmic edema, but cytoplasmic organelles were preserved. The brain uptake index of 14C-labeled EHA was similar to that of H2O. When EHA was added to rat cerebellar tissue cultures, only the granule cells showed nuclear pyknosis, aggregation of nuclear chromatin, and karyorrhexis with cytoplasmic swelling. These granule cells were positive for DNA fragmentation by the TUNEL method. These results suggest that EHA permeates the blood vessel wall and directly affects the cerebellar granule cells, resulting in selective granule cell apoptosis.
Tanaka
G
G
Drug Safety Research Laboratory, Taiho Pharmaceutical Co., Tokushima, Japan.
Okeda
R
R
D000178:Acrylamides / Q000633:toxicity*; D000818:Animals; D018926:Anti-Allergic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D001190:Arylsulfonates / Q000633:toxicity; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015847:Interleukin-4 / Q000037:antagonists & inhibitors; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013452:Sulfonium Compounds / Q000633:toxicity
D000178:Acrylamides; D018926:Anti-Allergic Agents; D001190:Arylsulfonates; D013452:Sulfonium Compounds; D015847:Interleukin-4; C073028:suplatast tosilate