RESUMO
Schizophrenia is a neuropsychiatric disorder that features neural oxidative stress and glutathione (GSH) deficits. Oxidative stress is augmented in brain tissue of GFAP.HMOX1 transgenic mice which exhibit schizophrenia-relevant characteristics. The whey protein isolate, Immunocal® serves as a GSH precursor upon oral administration. In this study, we treated GFAP.HMOX1 transgenic mice daily with either Immunocal (33mg/ml drinking water) or equivalent concentrations of casein (control) between the ages of 5 and 6.5 months. Immunocal attenuated many of the behavioral, neurochemical and redox abnormalities observed in GFAP.HMOX1 mice. In addition to restoring GSH homeostasis in the CNS of the transgenic mice, the whey protein isolate augmented GSH reserves in the brains of wild-type animals. These results demonstrate that consumption of whey protein isolate augments GSH stores and antioxidant defenses in the healthy and diseased mammalian brain. Whey protein isolate supplementation (Immunocal) may constitute a safe and effective modality for the management of schizophrenia, an unmet clinical imperative.
Assuntos
Cisteína/administração & dosagem , Suplementos Nutricionais , Glutationa/agonistas , Esquizofrenia/dietoterapia , Esquizofrenia/genética , Proteínas do Soro do Leite/administração & dosagem , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Glutationa/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacos , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologiaRESUMO
Delineation of key molecules that act epigenetically to transduce diverse stressors into established patterns of disease would facilitate the advent of preventive and disease-modifying therapeutics for a host of neurological disorders. Herein, we demonstrate that selective overexpression of the stress protein heme oxygenase-1 (HO-1) in astrocytes of novel GFAP.HMOX1 transgenic mice results in subcortical oxidative stress and mitochondrial damage/autophagy; diminished neuronal reelin content (males); induction of Nurr1 and Pitx3 with attendant suppression of their targeting miRNAs, 145 and 133b; increased tyrosine hydroxylase and α-synuclein expression with downregulation of the targeting miR-7b of the latter; augmented dopamine and serotonin levels in basal ganglia; reduced D1 receptor binding in nucleus accumbens; axodendritic pathology and altered hippocampal cytoarchitectonics; impaired neurovascular coupling; attenuated prepulse inhibition (males); and hyperkinetic behavior. The GFAP.HMOX1 neurophenotype bears resemblances to human schizophrenia and other neurodevelopmental conditions and implicates glial HO-1 as a prime transducer of inimical (endogenous and environmental) influences on the development of monoaminergic circuitry. Containment of the glial HO-1 response to noxious stimuli at strategic points of the life cycle may afford novel opportunities for the effective management of human neurodevelopmental and neurodegenerative conditions.
Assuntos
Astrócitos/metabolismo , Encéfalo/patologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Heme Oxigenase-1/metabolismo , Esquizofrenia/genética , Esquizofrenia/patologia , Estimulação Acústica , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Astrócitos/ultraestrutura , Benzamidas/farmacocinética , Benzazepinas/farmacocinética , Monoaminas Biogênicas/metabolismo , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Dopaminérgicos/farmacocinética , Embrião de Mamíferos , Ensaio de Imunoadsorção Enzimática , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/genética , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Heme Oxigenase-1/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Inibição Psicológica , Fluxometria por Laser-Doppler , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , RNA Mensageiro/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Proteína Reelina , Esquizofrenia/fisiopatologia , Filtro Sensorial/genética , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Trítio/farmacocinética , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
Heme oxygenase-1 (HO-1) mRNA and protein levels are diminished in Alzheimer disease (AD) blood, cerebrospinal fluid (CSF) and choroid plexus. Herein, the presence of a heme oxygenase-1 suppressor (HOS) factor was ascertained by astroglial bioassay, biochemical techniques and immunofluorescence confocal microscopy. We report significantly augmented plasma HOS activity in AD patients relative to healthy elderly and neurological controls. The HOS factor was determined to be a 50-100 kDa heat-labile, heparin-binding glycoprotein that is unrelated to antioxidant ingestion, plasma total antioxidant capacity, circulating cortisol levels or apolipoprotein E epsilon4 carrier status. HOS bioactivity was recapitulated by exogenous alpha(1)-antitrypsin. alpha(1)-antitrypsin levels were significantly increased in AD plasma and correlated with HOS activity and MMSE scores. alpha(1)-antitrypsin immunodepletion attenuated HOS activity of AD plasma. In AD brain, alpha(1)-antitrypsin immunoreactivity was augmented and co-distributed with HO-1. HOS activity of alpha(1)-antitrypsin may curtail HO-1-dependent derangement of cerebral iron homeostasis and account for diminished HO-1 expression in AD peripheral tissues.