Immunosuppression and oxidative stress induced by acute and chronic exposure to cocaine in rat.
The objective of the present study was to verify if immunosuppression caused by cocaine (CO) can be mediated, at least in part, by increased formation of oxidative metabolites and reactive oxygen species (ROS) in rat. Pharmacokinetics of cocaine and its metabolites, cell-mediated immune function and cytokines production, biomarkers of cell redox state maintenance and lipidic peroxidation, and variations of activity in the enzymatic systems involved in cell antioxidant defence were measured in spleen of Wistar rats acutely and chronically treated with cocaine.C(max), AUC, and t(1/2) of norcocaine (NC) significantly increased after chronic exposure to cocaine while kinetic parameters of benzoylecgonine (BE) significantly decreased. A decrease in cultured T-lymphocytes proliferation and natural killer (NK) cell activity, a high increase of immunosuppressive cytokines and a switch from Th1-type cytokines to Th2-type cytokines together with an unbalance toward anti-inflammatory cytokines recovered within 4 h after acute treatment while subsisted for 14 days after chronic treatment. A significant increase in ascorbic acid (AA), reduced glutathione and glutathione reductase (GR) with a simultaneous decrease in oxidized glutathione were observed in the first hours after acute administration. Conversely, the increase in oxidized glutathione and malondialdehyde (MDA) production and the simultaneous depletion of reduced glutathione and ascorbic acid persisted at least 24 h after chronic cocaine treatment as well as the increase in the activities of glutathione reductase, glutathione peroxidase (GPx) and superoxide dismutase (SOD). The results suggest that chronic cocaine administration affects cellular enzyme and non-enzyme-mediated antioxidant defence systems and promotes immunotoxicity in rat. Cocaine N-oxidative metabolism may be an indirect contributor, via oxidative stress.
Pacifici
Roberta
R
Clinical Biochemistry Department, Istituto Superiore di Sanità, V le Regina Elena 299, 00161 Rome, Italy. pacifici@iss.it
Fiaschi
Anna Ida
AI
Micheli
Lucia
L
Centini
Fabio
F
Giorgi
Giorgio
G
Zuccaro
Piergiorgio
P
Pichini
Simona
S
Di Carlo
Simonetta
S
Bacosi
Antonella
A
Cerretani
Daniela
D
D000818:Animals; D001205:Ascorbic Acid / Q000276:immunology; D003042:Cocaine / Q000008:administration & dosage / Q000633:toxicity*; D016207:Cytokines / Q000276:immunology; D005979:Glutathione Peroxidase / Q000276:immunology; D005980:Glutathione Reductase / Q000276:immunology; D007111:Immunity, Cellular / Q000187:drug effects* / Q000276:immunology; D007274:Injections, Intraperitoneal; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects* / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D013482:Superoxide Dismutase / Q000276:immunology
D016207:Cytokines; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D003042:Cocaine; D001205:Ascorbic Acid