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-hydro-propoxy)phenyl] acrylamide (E HA) induced selective granule cell destruction in the granular layer of the cerebellar cortex together with neurological signs, such as delayed righti ng reflex, gait or truncal ataxia, and convulsion. Neuropathologically, it caused multifocal granule cell destruction with nuclear pyknosis and spongi osis of the neuropile in the granular layer. Other neurons, including Purki nje cells, were spared. Ultrastructurally, damaged granule cells showed agg regation of nuclear chromatin and cytoplasmic edema, but cytoplasmic organe lles were preserved. The brain uptake index of C-14-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 chromati n, and karyorrhexis with cytoplasmic swelling. These granule cells were pos itive for DNA fragmentation by the TUNEL method. These results suggest that EHA permeates the blood vessel wall and directly affects the cerebellar gr anule cells, resulting in selective granule cell apoptosis.