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

• Published in: Brain research Vol. 1354; pp. 236 - 242
• Main Authors: Bukhatwa, Salma, Zeng, Bai-Yun, Rose, Sarah, Jenner, Peter
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.10.2010; Elsevier
• Subjects: Administration, Oral; Adult and adolescent clinical studies; Analysis of Variance; Animals; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Brain - pathology; Cell Count; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dose; Dose-Response Relationship, Drug; Female; Immunohistochemistry; Injections, Intraperitoneal; Injections, Subcutaneous; Medical sciences; Motor Activity - drug effects; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurology; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Oligopeptides - administration & dosage; Oligopeptides - pharmacology; Organic mental disorders. Neuropsychology; Parkinson's disease; Proteasome; PSI; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rats, Wistar; Route; Tyrosine 3-Monooxygenase - metabolism; Parkinson's disease; Dose; Route; PSI; Proteasome; Multicatalytic endopeptidase complex; Rat; Central nervous system; Parkinson disease; Route of administration; Encephalon; Dose activity relation; Degenerative disease; Degeneration; Behavior; Nervous system diseases; Enzyme; Rodentia; Enzyme inhibitor; Cerebral disorder; Peptidases; Vertebrata; Mammalia; Animal; Central nervous system disease; Hydrolases; Extrapyramidal syndrome
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2010.07.060

Abstract Repeated subcutaneous administration of proteasome inhibitor 1 [PSI, Z-Ile-Glu(O t Bu)-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.