Therapeutic efficacy of atypical antipsychotic drugs by targeting multiple stress-related metabolic pathways.
Therapeutic efficacy of atypical antipsychotic drugs by targeting multiple stress-related metabolic pathways.
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非典型抗精神病药物针对多种应激相关代谢途径的治疗效果
DOI：
10.1038/tp.2017.94
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发表时间：
2017-05-16
影响因子：
6.8
通讯作者：
Yao JK
中科院分区：
文献类型：
--
作者：
Cai HL;Jiang P;Tan QY;Dang RL;Tang MM;Xue Y;Deng Y;Zhang BK;Fang PF;Xu P;Xiang DX;Li HD;Yao JK
精神分裂症（SZ）被认为是一种多因素的大脑疾病，涉及许多生化途径的缺陷。SZ患者对目前SZ的药物治疗表现出不同的反应，因为这种疾病的异质性。应激在SZ的病理生理学途径和治疗反应中具有重要作用。非典型抗精神病药物（AAPD）通过调节下丘脑-垂体-肾上腺（HPA）轴的应激反应，靶向作用于前额叶皮质（PFC）和海马，发挥抗应激作用。评价AAPD的效果（如氯氮平、利培酮和阿立哌唑）对应激的影响，我们比较了慢性不可预测的轻度应激（CHNS）大鼠HPA轴激活模型和长期地塞米松暴露（LTDE）大鼠HPA轴抑制模型之间PFC和海马神经化学谱的变化，使用基于超高效液相色谱-质谱（UPLC-MS/MS）的代谢组学方法和多标准评估。我们鉴定了许多应激诱导的生物标志物，包括肌酸、胆碱、肌苷、次黄嘌呤、尿酸、尿囊酸、溶血磷脂酰胆碱（LysoPC）、磷脂酰乙醇胺（PE）、皮质酮和孕酮。具体而言，途径富集和相关性分析表明，应激通过干扰肌酸磷酸肌酸回路和嘌呤途径诱导氧化损伤，导致过度的膜破裂。此外，我们的数据表明，AAPD测试部分恢复压力引起的赤字增加肌酸，孕酮和PE的水平。因此，本研究结果为以下假设提供了理论基础：使用三磷酸腺苷燃料、抗氧化剂和ω-3脂肪酸作为补充剂的联合治疗可能对AAPD治疗后的治疗结果具有协同作用。
Schizophrenia (SZ) is considered to be a multifactorial brain disorder with defects involving many biochemical pathways. Patients with SZ show variable responses to current pharmacological treatments of SZ because of the heterogeneity of this disorder. Stress has a significant role in the pathophysiological pathways and therapeutic responses of SZ. Atypical antipsychotic drugs (AAPDs) can modulate the stress response of the hypothalamic–pituitary–adrenal (HPA) axis and exert therapeutic effects on stress by targeting the prefrontal cortex (PFC) and hippocampus. To evaluate the effects of AAPDs (such as clozapine, risperidone and aripiprazole) on stress, we compared neurochemical profile variations in the PFC and hippocampus between rat models of chronic unpredictable mild stress (CUMS) for HPA axis activation and of long-term dexamethasone exposure (LTDE) for HPA axis inhibition, using an ultraperformance liquid chromatography–mass spectrometry (UPLC–MS/MS)-based metabolomic approach and a multicriteria assessment. We identified a number of stress-induced biomarkers comprising creatine, choline, inosine, hypoxanthine, uric acid, allantoic acid, lysophosphatidylcholines (LysoPCs), phosphatidylethanolamines (PEs), corticosterone and progesterone. Specifically, pathway enrichment and correlation analyses suggested that stress induces oxidative damage by disturbing the creatine–phosphocreatine circuit and purine pathway, leading to excessive membrane breakdown. Moreover, our data suggested that the AAPDs tested partially restore stress-induced deficits by increasing the levels of creatine, progesterone and PEs. Thus, the present findings provide a theoretical basis for the hypothesis that a combined therapy using adenosine triphosphate fuel, antioxidants and omega-3 fatty acids as supplements may have synergistic effects on the therapeutic outcome following AAPD treatment.