Cyclosporine A-induced hyperactivity in rats: is it mediated by immunosuppression, neurotrophism, or both?
Cyclosporine A (CsA) immunosuppressive treatment has become an adjunctive therapy in neural transplantation of dopamine-secreting cells for treatment of Parkinson's disease (PD). Recently, CsA and its analogues have been shown to promote trophic effects against neurodegenerative disorders, and therefore CsA may have direct beneficial effects on dopaminergic neurons and dopamine-mediated behaviors. The present study examined the interaction between the reported CsA-induced hyperactivity and the possible alterations in nigral tyrosine hydroxylase (TH)-immunoreactive neurons in rats with damaged blood-brain barrier. CsA was administered at a therapeutic dose (10 mg/kg/day, IP, for 9 days) used in neural transplantation protocol for PD animal models. CsA-treated animals displayed significantly higher general spontaneous locomotor activity than control animals at drug injection days 7 and 9. Histological assays at day 9 revealed that there was a significant increase in TH-immunoreactive neurons in the nigra of CsA-treated rats compared to that of the vehicle-treated rats. The nigral TH elevation was accompanied by suppressed calcium-phosphotase calcineurin activity, indicating an inhibition of host immune response. This is the first report of CsA exerting simultaneous immunosuppressive and neurotrophic effects, as well as increasing general spontaneous locomotor behavior. These results support the utility of CsA as a therapeutic agent for PD and other movement disorders.
Borlongan
C V
CV
National Institutes of Health, National Institute on Drug Abuse, Intramural Research Program, Cellular Neurobiology, Baltimore, MD 21224, USA. cborlong@intra.nida.nih.gov
Stahl
C E
CE
Fujisaki
T
T
Sanberg
P R
PR
Watanabe
S
S
D000818:Animals; D001812:Blood-Brain Barrier; D019703:Calcineurin / Q000302:isolation & purification; D016572:Cyclosporine / Q000009:adverse effects*; D004298:Dopamine / Q000378:metabolism; D005260:Female; D006948:Hyperkinesis / Q000139:chemically induced* / Q000209:etiology*; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D008959:Models, Neurological; D009043:Motor Activity; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000201:enzymology / Q000254:growth & development; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D014446:Tyrosine 3-Monooxygenase; D019703:Calcineurin; D004298:Dopamine