Decreased glutathione levels and altered antioxidant defense in an animal model of schizophrenia: long-term effects of perinatal phencyclidine administration.
Perinatal phencyclidine (PCP) administration to rodents represents one of the more compelling animal models of schizophrenia. There is evidence that decreased glutathione (GSH) levels and oxidative stress mediated through free radicals in the central nervous system are involved in the pathophysiology of this disease. Limited data are available on the role of free radicals in neurotoxicity induced by NMDA-receptor antagonists. The aim of this study was to elucidate the long-term effects of perinatal phencyclidine administration on superoxide dismutase (SOD), catalase (CAT), gamma-glutamyl cisteine ligase (gamma-GCL), glutathione peroxidase (GPx), glutathione reductase (GR) and levels of lipid peroxides as well as GSH content. The Wistar rats were treated on the 2nd, 6th, 9th and 12th postnatal (PN) days with either phencyclidine (10mg/kg) or saline and sacrificed on PN70. The activities of antioxidant enzymes and level of lipid peroxides and GSH were determined in dorsolateral frontal cortex (dlFC), hippocampus, thalamus and caudate nucleus. Expression of SOD1 and SOD2 was determined by immunoblot. Region-specific changes of the measured parameters were observed. Decreased content of reduced GSH and altered activities of GR, GPx and SOD were determined in dlFC. In hippocampus, reduced GSH content and decreased activities of GPx and GR were accompanied with increased activity of gamma-GCL and increased level of lipid peroxides. gamma-GCL and GSH content were also decreased in caudate nucleus, while in thalamus major findings are increased levels of lipid peroxides and GR activity and decreased gamma-GCL activity. It can be concluded that perinatal PCP administration produces long-term alteration of antioxidant defense. Further studies are necessary in order to clarify role of redox dysregulation in the pathogenetic mechanism of schizophrenia.
Radonjić
Nevena V
NV
Institute of Clinical and Medical Biochemistry, School of Medicine, University of Belgrade, Pasterova 2, Belgrade 11000, Serbia.
Knezević
Iva D
ID
Vilimanovich
Urosh
U
Kravić-Stevović
Tamara
T
Marina
Ljiljana V
LV
Nikolić
Tatjana
T
Todorović
Veljko
V
Bumbasirević
Vladimir
V
Petronijević
Natasa D
ND
D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism; D010622:Phencyclidine / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism*; D013997:Time Factors
D000975:Antioxidants; D005609:Free Radicals; D005978:Glutathione; D010622:Phencyclidine