Quetiapine Ameliorates Schizophrenia-Like Behaviors and Protects Myelin Integrity in Cuprizone Intoxicated Mice: The Involvement of Notch Signaling Pathway

Abstract

Background:White matter disturbances and myelin impairment are key features of schizophrenia. The antipsychotic drug quetiapine can promote the maturation of oligodendrocytes, but the molecular mechanisms remain largely unknown.Methods:The schizophrenia-like behaviors, degrees of demyelination, and levels of Notch signaling molecules in forebrains of adult male C57BL/6 mice were examined after fed with cuprizone (0.2% wt/wt) in the presence or absence of 10mg/kg/d quetiapine for 6 weeks. These parameters were also observed after the transcranial injection of Notch signaling inhibitor MW167 (1mM) daily during the last week of the treatment period.Results:Quetiapine ameliorated the schizophrenia-like behaviors and decreased expression of myelin basic protein and inhibition of Notch signaling molecules, such as Notch1, Hes1, and Hes5, in the forebrain that induced by cuprizone. These beneficial effects of quetiapine were abolished by MW167.Conclusions:The antipsychotic and myelin protective effects of quetiapine are mediated by Notch signaling in a mouse model of cuprizone-induced demyelination associated with schizophrenia-like behaviors. The Notch pathway might therefore be a novel target for the development of antipsychotic drugs.

Alterations of Myelin Content in Parkinson’s Disease: A Cross-Sectional Neuroimaging Study

“…Myelin basic protein expression is increased in the striatum of rats with nigrostriatal pathway lesions who receive levodopa supplementation [ 56 ], while differentiated rat cortical oligodendrocytes express D2 and D3 dopamine mRNA and are protected from oxidative toxicity by dopamine agonists, suggesting that dopamine receptor activation affects myelination. Atypical antipsychotics, which antagonize dopamine (D 2 ) and serotonin (5-HT 2 ) receptors [ 57 ] also appear to increase or preserve myelination [ 15 , 58 ]. The regional distribution of dopaminergic radiotracers in the brain is correlated with dopamine receptor levels [ 59 ].…”

Putative neuroprotective pharmacotherapies to target the staged progression of mental illness

“…In a prospective clinical trial of quetiapine vs lithium following first episode of mania, quetiapine was inferior to lithium in preserving white matter volume (Berk et al, ). However, quetiapine was efficacious against cuprizone‐induced demyelination and schizophrenia‐like behaviour in mice (H. N. Wang et al, ; Y. Zhang et al, ). Quetiapine rescued demyelination with associated stimulation of notch signalling, a regulator of oligodendrocyte maturation and myelination.…”

Disturbance of oligodendrocyte differentiation in schizophrenia in relation to main hypothesis of the disease

“…Купризон, олигодендроцит-специфический токсин, используется для моделирования расстройств поведения у животных, характерных для шизофрении, и способен вызывать у них нарушения миелинизации в мозге и подавление дифференцировки ПОЛ [111]. Показано, что эти эффекты купризона успешно подавляются оланзапином [112], клозапином [113], а также кветиапином [114]. Наиболее изучен механизм протективного действия кветиапина.…”

“…Этот препарат обладает, по-видимому, системным действием на процессы миелинизации, поскольку способен регулировать множество генов, вовлеченных в контроль клеточного цикла [115]. Кветиапин также ингибирует сигнальные молекулы Notch-каскада, активность которых, как известно, связана с подавлением дифференцировки ПОЛ [114]. Важно отметить, что клинические исследования с использованием ДТВ подтверждают, что такие препараты, как респиредин и зипразидон, способны существенно нивелировать изменения фракционной анизотропии белого вещества мозга, вызванные обострением психоза, но только в подгруппе респондеров [116].…”