The effects of dose and route of administration of PSI on behavioural and biochemical indices of neuronal degeneration in the rat brain.

Repeated subcutaneous administration of proteasome inhibitor 1 [PSI, Z-Ile-Glu(OtBu)-Ala-Leu-CHO] to rats causes progressive motor deficits and nigral dopaminergic cell loss in our laboratories, but this is controversial since others have not reproduced these findings. For this reason, we have investigated the role that the dose of PSI and its route of administration have on motor activity and neuronal loss in rat brain. PSI (8, 12 or 16 mg/kg, s.c.) was administered to female Wistar rats on 6 occasions on alternative days over 2 weeks. Subsequently PSI (8 mg/kg) was administered by oral, s.c. and i.p. routes on alternate days to separate groups of animals. Rats were assessed for motor function on a weekly basis up to 5 months after the end of PSI treatment. Locomotor activity was decreased following s.c. administration of 8 and 12 mg/kg PSI but not following 16 mg/kg. In subsequent experiments PSI (8 mg/kg) decreased motor activity after p.o. but not i.p. administration. PSI 8 mg/kg s.c. or p.o., but not i.p., caused neuronal loss in the substantia nigra, raphe nuclei, locus coeruleus, nucleus basalis of Meynert and dorsal motor nucleus of vagus. These data confirm that systemic administration of PSI reduces locomotor activity in rats and induces widespread neuronal degeneration in brain. However, the effects of PSI and its time course of action are dose and route dependent.