Department of Psychiatry, University of Illinois at Chicago, College of Medicine, Psychiatric Institute, 1601 Taylor, Chicago, IL 60612, USA.
Neuropharmacology. 2011 Jun;60(7-8):1007-16. doi: 10.1016/j.neuropharm.2010.10.021. Epub 2010 Nov 11.
It is becoming increasingly clear that a dysfunction of the GABAergic/glutamatergic network in telencephalic brain structures may be the pathogenetic mechanism underlying psychotic symptoms in schizophrenia (SZ) and bipolar (BP) disorder patients. Data obtained in Costa's laboratory (1996-2009) suggest that this dysfunction may be mediated primarily by a downregulation in the expression of GABAergic genes (e.g., glutamic acid decarboxylase₆₇[GAD₆₇] and reelin) associated with DNA methyltransferase (DNMT)-dependent hypermethylation of their promoters. A pharmacological strategy to reduce the hypermethylation of GABAergic promoters is to administer drugs, such as the histone deacetylase (HDAC) inhibitor valproate (VPA), that induce DNA-demethylation when administered at doses that facilitate chromatin remodeling. The benefits elicited by combining VPA with antipsychotics in the treatment of BP disorder suggest that an investigation of the epigenetic interaction of these drugs is warranted. Our studies in mice suggest that when associated with VPA, clinically relevant doses of clozapine elicit a synergistic potentiation of VPA-induced GABAergic promoter demethylation. Olanzapine and quetiapine (two clozapine congeners) also facilitate chromatin remodeling but at doses higher than used clinically, whereas haloperidol and risperidone are inactive. Hence, the synergistic potentiation of VPA's action on chromatin remodeling by clozapine appears to be a unique property of the dibenzepines and is independent of their action on catecholamine or serotonin receptors. By activating DNA-demethylation, the association of clozapine or its derivatives with VPA or other more potent and selective HDAC inhibitors may be considered a promising treatment strategy for normalizing GABAergic promoter hypermethylation and the GABAergic gene expression downregulation detected in the postmortem brain of SZ and BP disorder patients. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
越来越明显的是，大脑前额叶结构中 GABA 能/谷氨酸能网络的功能障碍可能是精神分裂症（SZ）和双相情感障碍（BP）患者精神病症状的发病机制。Costa 实验室（1996-2009 年）获得的数据表明，这种功能障碍可能主要是由 GABA 能基因（如谷氨酸脱羧酶 67[GAD67]和 reelin）的表达下调介导的，这与它们启动子的 DNA 甲基转移酶（DNMT）依赖性超甲基化有关。一种减少 GABA 能启动子超甲基化的药理学策略是使用药物，如组蛋白去乙酰化酶（HDAC）抑制剂丙戊酸（VPA），当以促进染色质重塑的剂量给药时，该药物会诱导 DNA 去甲基化。在 BP 障碍的治疗中，将 VPA 与抗精神病药联合使用所带来的益处表明，有必要研究这些药物的表观遗传相互作用。我们在小鼠中的研究表明，当与 VPA 联合使用时，临床相关剂量的氯氮平会协同增强 VPA 诱导的 GABA 能启动子去甲基化。奥氮平和喹硫平（氯氮平的两种同系物）也促进染色质重塑，但剂量高于临床使用，而氟哌啶醇和利培酮则没有作用。因此，氯氮平对 VPA 对染色质重塑作用的协同增强似乎是二苯并氮杂䓬类药物的独特特性，并且与它们对儿茶酚胺或 5-羟色胺受体的作用无关。通过激活 DNA 去甲基化，氯氮平或其衍生物与 VPA 或其他更有效和选择性的 HDAC 抑制剂的联合使用，可能被认为是一种有前途的治疗策略，可用于使 SZ 和 BP 障碍患者死后大脑中检测到的 GABA 能启动子超甲基化和 GABA 能基因表达下调正常化。本文是特刊“神经药理学趋势：纪念 Erminio Costa”的一部分。
