| 1 | BMC Neurosci 2006 -1 7: 69 |
|---|---|
| PMID | 17052361 |
| Title | Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: marked differences between various antipsychotic drugs. |
| Abstract | The etiology of精神分裂症is unknown, but neurodevelopmental disturbances, myelin- and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder. Cholesterol is an essential component of myelin and has proved important for synapse formation. Recently, we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element-binding protein (SREBP) transcription factors. We here compare the action of chlorpromazine, haloperidol, clozapine, olanzapine, risperidone and ziprasidone on SREBP activation and SREBP-controlled gene expression (ACAT2, HMGCR, HMGCS1, FDPS, SC5DL,DHCR7, LDLR, FASN and SCD1) in four CNS-relevant human cell lines. 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. |
| SCZ Keywords | 精神分裂症 |
| 2 | Mol. Pharmacol. 2010 Sep 78: 486-96 |
| PMID | 20558592 |
| Title | Antipsychotic drugs regulate hedgehog signaling by modulation of 7-dehydrocholesterol reductase levels. |
| Abstract | Recently we identified GANT61, a small-molecule antagonist of Gli transcription factors, which are the final effectors of the mammalian Hedgehog (HH) signaling pathway. Here we describe a diamine substructure of GANT61 that carries the biological activity and show that this part of the molecule is structurally related to trans-1,4-bis(2-chlorobenzaminomethyl)cyclohexane dihydrochloride (AY9944), an inhibitor of the enzymatic activity and transcriptional inducer of 7-dehydrocholesterol-reductase (DHCR7, EC 1.3.1.21). Treatment of cells with the GANT61 diamine, AY9944, or overexpression ofDHCR7results in the attenuation of Smoothened-dependent and -independent HH signaling. Whereas GANT61 function is independent ofDHCR7, AY9944 does require up-regulation of endogenousDHCR7。在line with these findings,DHCR7-modulating antipsychotic (clozapine, chlorpromazine, haloperidol) and antidepressant (imipramine) drugs regulate HH signaling in vitro and in vivo. Modulation of HH signaling may represent a hitherto undiscovered biological (side) effect of therapeutics used to treat精神分裂症and depression. |
| SCZ Keywords | 精神分裂症 |