Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: Marked differences between various antipsychotic drugs

There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes, with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations. Glial-like cells (GaMg glioma and CCF-STTG1 astrocytoma cell lines) displayed more pronounced drug-induced SREBP activation compared to the response in HCN2 human cortical neurons and SH-SY5Y neuroblastoma cells, indicating that antipsychotic-induced activation of lipogenesis is most prominent in glial cells.Our present data show a marked variation in the ability of different antipsychotics to induce SREBP-controlled transcriptional activation of lipogenesis in cultured human CNS-relevant cells. We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs.Schizophrenia is a chronic and serious psychiatric disorder affecting about 1 % of the population worldwide. Several lines of evidence point towards schizophrenia as a neurodevelopmental disorder, and the involvement of myelin- and oligodendrocyte abnormalities in the pathophysiology of the disease has been suggested [1-5]. Myelin is formed by oligodendroglial cells and consists mainly of cholesterol, produced de novo in the CNS [6]. Together, cholesterol and apolipoprotein E (ApoE) can serve as a glial growth factor in synaptogenesis [7].Antipsychotic drugs, such as haloperidol and clozapine, are used to treat and ameliorate the symptoms of schizophrenia and act, at least in part, by blockage of dopamine D2-like receptors in the brain. Antipsychotics are usually classified into two main groups, namely typical (e.g. haloperidol and chlorpromazine) and atypical drugs (e.g. clozapine, olanzapine, risperidone and ziprasidone). The typical antipsychotic drugs are all dopamine D2-receptor antagonists, whereas the atypical drugs generally have a more diverse receptor binding profile, suggesting that other neurotransmitters than dopamine mig