ONO-1603, a potential antidementia drug, shows neuroprotective effects and increases m(3)-muscarinic receptor mRNA levels in differentiating rat cerebellar granule neurons

We have reported that the antidementia drug tetrahydroaminoacridine (THA; 30 mu M) is neuroprotective and neurotrophic and selectively increases m(3)-muscarinic acetylcholine receptor (mAChR) mRNA levels in differentiating cerebellar granule cells. Here, we examined whether novel prolyl endopeptidase inhibitor ONO-1603, a potential antidementia drug, induces similar effects in these cerebellar neurons. Supplement of ONO-1603 (0.03 mu M) to cultures grown in 15 mM KCl-containing media was found to markedly promote neuronal survival and neurite outgrowth and enhance [H-3]N-methylscopolamine binding to mAChRs. Moreover, ONO-1603 increased the level of m(3)-mAChR mRNA and stimulated mAChR-mediated phosphoinositide turnover. The common actions of ONO-1603 and THA suggest that these properties could be related to their putative antidementia activities and that this model system may be used to screen for drugs effective in the treatment for Alzheimer's disease.