Evidences for a progressive microglial activation and increase in iNOS expression in rats submitted to a neurodevelopmental model of schizophrenia: Reversal by clozapine

• Published in: Schizophrenia research Vol. 151; no. 1; pp. 12 - 19
• Main Authors: Ribeiro, Bruna Mara Machado, do Carmo, Marta Regina Santos, Freire, Rosemayre Souza, Rocha, Nayrton Flávio Moura, Borella, Vládia Célia Moreira, de Menezes, Antonio Teles, Monte, Aline Santos, Gomes, Patrícia Xavier Lima, de Sousa, Francisca Cléa Florenço, Vale, Mariana Lima, de Lucena, David Freitas, Gama, Clarissa Severino, Macêdo, Danielle
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.12.2013; Elsevier
• Subjects: Adult and adolescent clinical studies; Age Factors; Animals; Animals, Newborn; Antipsychotic Agents - therapeutic use; Biological and medical sciences; Brain - drug effects; Brain - pathology; Clozapine; Clozapine - therapeutic use; Developmental Disabilities - drug therapy; Developmental Disabilities - etiology; Disease Models, Animal; Lipid Peroxidation - drug effects; Male; Malondialdehyde - metabolism; Maze Learning - drug effects; Medical sciences; Microglia - metabolism; Microglia - pathology; Neonate; Neuroinflammation; Neuropharmacology; Neuroprogression; Nitric Oxide Synthase Type II - metabolism; Oxidative Stress - drug effects; Pharmacology. Drug treatments; Poly I-C - pharmacology; PolyI:C; Psychiatry; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Psychoses; Rats; Rats, Wistar; Reflex, Startle - drug effects; Schizophrenia; Schizophrenia - chemically induced; Schizophrenia - complications; PolyI:C; Schizophrenia; Neuroprogression; Neuroinflammation; Neonate; Clozapine; Human; Dibenzodiazepine derivatives; Atypical antipsychotic; Rat; Neuroleptic; Psychotropic; Neuroglia; Rodentia; Activation; Microglia; Polyl:C; Psychosis; Vertebrata; Mammalia; D2 Dopamine receptor; Newborn; Animal; Models; Antagonist
• ISSN: 0920-9964; 1573-2509
• DOI: 10.1016/j.schres.2013.10.040

Abstract Schizophrenia was proposed as a progressive neurodevelopmental disorder. In this regard herein we attempted to determine progressive inflammatory and oxidative alterations induced by a neonatal immune challenge and its possible reversal by clozapine administration. For this end, Wistar rats at postnatal day (PN) 5–7 were administered the viral mimetic polyriboinosinic–polyribocytidilic acid (polyI:C) or saline. A distinct group of animals additionally received the antipsychotic drug clozapine (25 mg/kg) from PN60 to 74. At PN35 (periadolescence), 60 (adult) and 74 (adulthood) the animals were submitted to behavioral determinations of prepulse inhibition of the startle (PPI) and Y maze task for working memory evaluation. At PN35 and 74 the animals were sacrificed and the hippocampus (HC), prefrontal cortex (PFC) and striatum (ST) immunostained for Iba-1, a microglial marker, and inducible nitric oxide synthase (iNOS). At PN74 oxidative stress parameters, such as, reduced glutathione levels (GSH) and lipid peroxidation were determined. The results showed a progressive increase of microglial activation and iNOS immunostaining from PN35 to PN74 mainly in the CA2 and CA3 regions of the HC and in the ST. At PN74 neonatal challenge also induced an oxidative imbalance. These inflammatory alterations were accompanied by deficits in PPI and working memory only in adult life that were reversed by clozapine. Clozapine administration reversed microglial activation and iNOS increase, but not the alterations of oxidative stress parameters. Taken together these results give further evidences for a neuroprogressive etiology and course of schizophrenia and that clozapine may partly alleviate this process.