Changes in brain hydrolytic enzyme activities in rats treated with cholesterol biosynthesis inhibitor, AY9944

Intraperitoneal administration of AY9944 causes accumulation of 7-dehydrocholesterol, appearance of abnormal neuronal cytoplasmic lamellar inclusions containing acid phosphatase activities, and degeneration of oligodendroglial cells. In the present study, we attempted to correlate appearance and disappearance of abnormal inclusions, oligodendroglial degeneration, activities of lysosomal enzymes, and accumulation of 7-dehydrocholesterol. One group of 5-day-old rats received daily injection of AY9944, 30 mg/kg, for 30 days. Other groups received the same daily dosage but only in 10 consecutive days, starting from 5, 15, 25, and 35 days, respectively. Activities of 13 brain hydrolytic enzymes were determined. In the first group, activities of most enzymes increased over the controls, reaching the peak between the 15th and 25th day, corresponding to the maximum appearance of the neuronal inclusions and degenerating oligodendroglia. Despite the continued administration of AY9944 and the high tissue concentration of 7-dehydrocholesterol, activities of most enzymes declined after 25 days to relatively steady levels somewhat higher than controls. In the group which received 10-day injections, enzyme activities reached the peak at the end of the injections and then rapidly returned to normal within 10 days thereafter, corresponding to the appearance and disappearance of the abnormal inclusions. However, 7-dehydrocholesterol continued to increase for 10 days after the drug administration was discontinued. AY9944 had no direct effect on any of the enzymes in vitro. There appears to be generalized lysosomal activation concomitant with formation of abnormal neuronal inclusions in the experimental conditions.