Mechanisms Of Action Of Psychoactive Drugs

精神药物的作用机制

• 批准号: 8939942
• 负责人: DE-MAW CHUANG
• 金额: $ 158.81万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8939942
• 关键词: Acute; Aftercare; Agonist; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Anticonvulsants; Antidepressive Agents; Antimanic Agents; Behavior; Behavioral; Biological Models; Bipolar Disorder; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain region; Brain-Derived Neurotrophic Factor; CXC Chemokines; Cardiovascular Diseases; Cell Density; Central Nervous System Diseases; Cerebral Ischemia; Chemosensitization; Chronic; Clinical Research; Clinical Trials; Collaborations; Cultured Cells; Diabetes Mellitus; Diet; Disease; Dose; Drug usage; Epigenetic Process; Etiology; Event; Exhibits; Experimental Animal Model; Experimental Models; Fibroblast Growth Factor; Gelatinase A; Gelatinase B; Gene Expression; Gene Targeting; General Hospitals; Genetic; Glucose; Glutamates; Glycogen Synthase Kinase 3; Goals; Growth Factor; HDAC6 gene; Heat-Shock Proteins 70; Histones; Hour; Huntington Disease; Hyperactive behavior; Hypoxia Inducible Factor; In Vitro; Infarction; Inflammation; Inherited; Injection of therapeutic agent; Ions; Ischemia; Ischemic Stroke; Ketamine; Knowledge; Life; Lithium; Liver; Locomotion; Longevity; Manic; Mediating; Mental Depression; Mental disorders; Mesenchymal Stem Cells; Messenger RNA; MicroRNAs; Middle Cerebral Artery Occlusion; Mitochondria; Modeling; Molecular; Molecular Target; Mono-S; Mood stabilizers; Moods; Mus; Nerve Degeneration; Neurobiology; Neurologic; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Obesity; Outcome; Pathology; Patients; Performance; Peripheral; Pharmaceutical Preparations; Phenotype; Preparation; Process; Property; Protein Isoforms; Proteins; Psychiatry; Psychotropic Drugs; RNA; Rattus; Recurrence; Regulation; Reporting; Research; Rodent; Role; Services; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Site; Sodium Butyrate; Staging; Stem cells; Stream; Stress; Stroke; Structure; Symptoms; Synaptic plasticity; System; Tail; Taiwan; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Thyroid Diseases; Tight Junctions; Time; Transgenic Mice; Traumatic Brain Injury; Tubulin; Valproic Acid; Vascular Endothelial Growth Factors; Veins; Work; abstracting; analog; angiogenesis; brain cell; cell motility; chemokine receptor; clinical efficacy; depressive symptoms; excitotoxicity; fatty acid metabolism; fibroblast growth factor 21; improved; in vivo; inhibitor/antagonist; insight; lymphoblastoid cell line; mTOR Signaling Pathway; mortality; mouse model; nervous system disorder; neurogenesis; neuron loss; neuroprotection; neuropsychiatry; novel; overexpression; pre-clinical; preclinical study; preconditioning; prophylactic; resilience; stem; therapeutic target

We have used various experimental model systems to test the hypothesis that glycogen synthase kinase-3 (GSK-3) and histone deacetylases (HDACs) are initial targets of lithium and valproic acid (VPA), respectively, that trigger diverse neurobiological events including neuroprotective and neurotrophic effects, anti-inflammatory effects, antidepressant effects, promotion of stem cell migration, regulation of microRNA expression, and modulation of behavioral phenotypes. Our studies identified a number of novel signaling pathways and neuroprotective and neurotrophic genes targeted by lithium and VPA, and underlying mechanisms were elucidated in both in vitro and in vivo experimental settings. Studies on the effects of mood stabilizers in the rat ischemic stoke model and animal models of Huntingtons disease (HD) were markedly expanded. The results of these studies identified previously unknown neurobiological actions induced by these mood stabilizers. In primary brain neurons, we identified a previously unknown function of fibroblast growth factor-21 (FGF-21), namely its ability to mediate the synergistic neuroprotective effects of lithium and VPA against glutamate excitotoxicity (Leng et al. Mol Psychiatry, advance online). Until now, FGF-21 has been thought to be expressed only in the peripheral systems, notably the liver, has a prominent role in regulating glucose and fatty acid metabolism, and is a putative therapeutic target for diabetes and obesity. Our results demonstrated for the first time that FGF-21 can be markedly induced in primary brain neurons and intact brain of rodents following co-treatment with lithium and VPA. More importantly, FGF-21 mediates, at least in part, the synergistic neuroprotection induced by lithium-VPA co-treatment. FGF-21s neuroprotection involves Akt-1 activation and GSK-3 inhibition; interestingly, both events also reciprocally regulate FGF-21 induction. Our recent results showed that FGF-21 RNA and protein levels were robustly decreased in the brains of ischemic rats (Wang, Z et al., in preparation) and ALS mice (Wang J et al., in preparation), suggesting that this growth factor is a novel target for therapeutic intervention of brain disorders. We expanded our studies using middle cerebral artery occlusion (MCAO) in rats as a model of focal cerebral ischemia, and made a number of original findings. Similar to the effects of lithium, we found that post-insult treatment with VPA reduced infarct volume and improved behavioral outcomes in rats that underwent MCAO. For the first time, we demonstrated that VPA robustly reduced blood-brain barrier (BBB) disruption induced by MCAO, and that this reduction was largely due to decreases in ischemia-induced matrix metalloproteinase 9 (MMP-9) overexpression and tight junction degradation (Wang et al., JCBFM, 2011). We also showed that long-term VPA treatment enhanced post-ischemic angiogenesis by upregulating hypoxia inducible factor-1alpha (HIF-1alpha ) and its downstream targets, pro-angiogenic vascular endothelial growth factor (VEGF) and MMP-2/9 (Wang et al., Stroke, 2012). In addition, tail-vein injection of mesenchymal stem cells (MSCs) into MCAO rats was found to be highly beneficial when these MSCs were primed with both lithium and VPA to induce MMP-9 and CXC chemokine receptor 4 (CXCR4), respectively, thereby promoting MSC migration to the infarct region (Tsai et al., Neuropsychopharm,, 2011; Stroke, 2012). Furthermore, we reported that HDAC inhibition by a VPA analog, sodium butyrate, enhanced post-MCAO-induced neurogenesis and oligodendrogenesis in multiple ischemic brain regions, and this effect required activation of BDNF-TrkB signaling (Kim et al., J Neurochem, 2009; AJTR, 2014). Finally, our very recent work reported microRNA (miRNA) regulation following ischemic stroke (e.g. miR-446f, miR-446h, miR-155, miR-1224, and miR-297a) and their potential for underlying the benefits of post-insult VPA treatment (e.g. miR-885-3p and miR-331) in a rat model of cerebral ischemia (Hunsberger et al., 2012), suggesting that miRNAs may underlie disease processes that contribute to numerous neurological disorders. Additionally, we found miR34a to be involved in regulating the life and death of neuronal cells in an in vitro study (Hunsberger et al., AJTR, 2013). In a pilot clinical study in collaboration with Dr. Giia-Sheun Peng of Tri-Service General Hospital in Taiwan, we found that three-month treatment with VPA commencing 3-24 hours after stroke markedly reduced neurological deficits, compared with the vehicle-treated control (Lee et al., CNS Neurosci & Thera, resubmitted). In a most recent study, we treated MCAO rats with a specific HDAC6 isoform inhibitor, tubastatin A, and found remarkable neuroprotective effects and behavioral improvements with a time window of at least 24 hours after insult (Wang Z et al., in preparation). The beneficial effects of tubastatin A were associated with tubulin hyperacetylation, and may involve neuroprotection against excitotoxicity and amelioration of defective mitochondrial transport. HD is an inherited, fatal neurodegenerative/neuropsychiatric disorder with no available treatment to halt symptom progression. We assessed the therapeutic potential of dietary treatment with lithium and/or VPA in two transgenic mouse models of HD, N171-82Q and YAC128. We detected hyperactivity of GSK-3 and HDACs in the brains of untreated HD mice, and found that daily dietary co-treatment with lithium and VPA more effectively alleviated impaired locomotion and depressive-like behaviors than mono-treatment in both mouse models of HD, and significantly prolonged the lifespan of N171-82Q mice (Chiu et al., Neuropsychophar, 2011; Sheuing et al., Int J Biol Sci, 2014). Levels of BDNF and HSP70 in the brains of both strains were also more consistently elevated by lithium-VPA co-treatment. Recently, we observed that long-term administration of a BDNF TrkB receptor agonist, LM22A, elicited behavioral benefits in N171-82Q mice (Chiu et al., SFN abstract, 2013), further supporting the roles of BDNF/TrkB signaling in HD pathology and therapy. In another ongoing study using N171-82Q mice, we found that intranasal delivery of mouse MSCs preconditioned with both lithium and VPA ameliorated behavioral deficits (Linares et al., SFN abstract, 2013), suggesting a novel avenue for HD therapeutic intervention. We have also completed projects related to the neurobiology of lithium and VPA: (1) We studied the regulation of miRNAs by mood stabilizers in order to identify novel miRNA-mediated signatures and mechanisms in patient-derived lymphoblastoid cell lines (LCLs) from BD patients who were lithium responders and non-responders. Several prominent miRNAs notably Let-7 were identified by microarray and their interactions with target mRNAs in LCLs have been studied by GRANITE (Hunsberger et al., Translational Psychiatry, resubmitted). (2) Pre- or post-treatment with lithium was shown to potentiate the rapid antidepressant effects of ketamine in chronically stressed mice by robustly reducing ketamine dose requirement and prolonging its antidepressant duration (Chiu et al., IJNN, submitted). This potentiation is associated with enhanced activation of the BDNF and mTOR signaling pathways. In summary, our recent work has markedly increased our understanding of the molecular and cellular actions of mood stabilizers, and substantially advanced our knowledge of their effects in a number of experimental models of neurodegenerative and neuropsychiatric diseases. With the completion of a number of ongoing projects, we expect to provide further mechanistic insights and set the stage for clinical investigations into the use of mood stabilizers to intervene in certain CNS disorders.

我们已经使用了各种实验模型系统来检验糖原合酶激酶3（GSK-3）和组蛋白脱乙酰基酶（HDAC）是锂和丙丙酸（VPA）的初始靶标，这些靶标分别触发了包括神经性植物生效的神经生物养殖症，分别触发了多样化的神经生物学作用，抗神经生物学作用，抗神经生物学作用，抗神经生物群生效，抗神经生物群生效综合群集，迁移，microRNA表达的调节以及行为表型的调节。我们的研究确定了许多由锂和VPA靶向的新型信号通路以及神经保护和神经营养基因，并在体外和体内实验环境中阐明了潜在的机制。对大鼠缺血性Stoke模型和亨廷顿氏病（HD）动物模型的影响的研究显着扩展。这些研究的结果确定了这些情绪稳定器引起的先前未知的神经生物学作用。 在原发性脑神经元中，我们确定了成纤维细胞生长因子21（FGF-21）的先前未知功能，即它介导锂和VPA对谷氨酸兴奋性兴奋性兴奋性的协同神经保护作用的能力（Leng等人Mol Psychiatry，在线促进）。到目前为止，人们认为FGF-21仅在外围系统中表达，尤其是肝脏，在调节葡萄糖和脂肪酸代谢中具有重要作用，并且是糖尿病和肥胖症的假定治疗靶标。我们的结果首次证明，与锂和VPA共同处理后，可以在原发性脑神经元中明显诱导FGF-21的啮齿动物的完整大脑。更重要的是，FGF-21至少部分地介导了锂-VPA共处理引起的协同神经保护。 FGF-21S神经保护涉及AKT-1激活和GSK-3抑制作用；有趣的是，这两个事件还相互调节FGF-21诱导。我们最近的结果表明，缺血性大鼠的大脑（Wang，Z等人，制备中）和ALS小鼠（Wang J等人，在制备中）的大脑中FGF-21 RNA和蛋白质水平可稳健地降低，这表明这种生长因子是对脑部疾病治疗的新靶标。 我们使用大鼠中脑动脉闭塞（MCAO）作为局灶性脑缺血模型扩展了研究，并做出了许多原始发现。与锂的作用相似，我们发现使用VPA的侵入后治疗减少了梗塞量，并改善了接受MCAO的大鼠的行为结果。我们首次证明了MCAO诱导的VPA可稳固地减少血脑屏障（BBB）破坏，并且这种减少在很大程度上是由于缺血诱导的基质金属蛋白酶9（MMP-9）过表达和紧密连接降解（Wang et al。我们还表明，长期VPA治疗通过上调缺氧诱导因子-1alpha（HIF-1Alpha）及其下游靶标，前血管生成血管生成血管内皮生长因子（VEGF）和MMP-2/9（Wang等，Stroke，Stroke，2012）。此外，当这些MSC与锂和VPA同时诱导MMP-9和CXC趋化因子受体4（CXCR4）时，发现间充质干细胞（MSC）在MCAO大鼠中的尾静脉注射非常有益，从而促进了MSC迁移到MSC的范围（TTSAI ARMING），促进了MSC的2012年，均为TTSAI Chrige（ttsai ets and）。此外，我们报道了VPA类似物，丁酸钠抑制HDAC在多个缺血性脑区域增强了MCAO后MCAO诱导的神经发生和少突可登，这种作用需要激活BDNF-trkBB信号（Kim等人（Kim等）（Kim et al。 Finally, our very recent work reported microRNA (miRNA) regulation following ischemic stroke (e.g. miR-446f, miR-446h, miR-155, miR-1224, and miR-297a) and their potential for underlying the benefits of post-insult VPA treatment (e.g. miR-885-3p and miR-331) in a rat model of cerebral ischemia (Hunsberger et al., 2012年），表明miRNA可能是导致多种神经系统疾病的疾病过程的基础。 此外，我们发现MiR34a参与了一项体外研究中的神经元细胞生命和死亡（Hunsberger等，Ajtr，2013）。在一项与台湾Tri-Service总医院的Giia-Sheun Peng博士合作的试点临床研究中，我们发现，与车辆处理的对照相比，中风后3-24小时开始使用VPA的三个月治疗明显减少了神经功能缺陷（Lee等人，CNS Neurosci＆Thera，CNS Neurosci＆Thera，Resububs）。在最近的一项研究中，我们用特定的HDAC6同工型抑制剂Tubastatin A治疗了MCAO大鼠，并发现了显着的神经保护作用和行为改善，并在侮辱后至少24小时的时间窗口（Wang Z等人）进行了时间窗口。图巴斯塔素A的有益作用与微管蛋白高乙酰化有关，可能涉及抗兴奋性毒性的神经保护作用和减轻有缺陷的线粒体转运的改善。 HD是一种遗传性致命的神经退行性/神经精神疾病，没有可用的治疗方法来阻止症状的进展。我们评估了两种HD，N171-82Q和YAC128的转基因小鼠模型中用锂和/或VPA进行饮食治疗的治疗潜力。 我们检测到未经治疗的HD小鼠大脑中GSK-3和HDAC的多动症，并发现每天与锂和VPA的每日饮食共同治疗比在HD的两只小鼠模型中更有效地缓解了相比，更有效地缓解了运动不良和抑郁样行为，并显着地延长了n11-e eTie e et e171-82 eerce eet e e et e171-82。 Neuropsychophar，2011年；两种菌株的大脑中BDNF和HSP70的水平也通过锂-VPA共同处理更加一致地升高。最近，我们观察到，长期给予BDNF TRKB受体激动剂LM22A，在N171-82Q小鼠中引起了行为益处（Chiu等，SFN摘要，2013年），进一步支持了HD病理和治疗中BDNF/TRKB信号的作用。在另一项使用N171-82Q小鼠进行的正在进行的研究中，我们发现用锂和VPA改善行为缺陷的小鼠MSC的鼻内递送（Linares等，SFN摘要，2013年），暗示了HD治疗干预的新型途径。 我们还完成了与锂和VPA神经生物学有关的项目：（1）我们研究了情绪稳定剂对miRNA的调节，以识别患者衍生的淋巴细胞细胞系（LCLS）中新型的miRNA介导的特征和机制，该病例是锂受访者的BD患者（LCLS），这些患者是锂响应者和非响应者和非 - 肾小管和非 - 偏心和非 - 偏心。几个突出的miRNA是通过微阵列鉴定的，并通过花岗岩（Hunsberger等人，转化精神病学，重新提交）研究了它们与LCL中的目标mRNA的相互作用。 （2）证明锂治疗前或治疗后可以通过稳健地减少氯胺酮剂量的需求并延长其抗抑郁药持续时间（Chiu等人，IJNN，IJNN，已提交）。这种增强与BDNF和MTOR信号通路的激活增强有关。 总而言之，我们最近的工作显着增强了我们对情绪稳定剂的分子和细胞作用的理解，并在许多神经退行性和神经精神疾病的实验模型中大大提高了我们对它们影响的了解。随着许多正在进行的项目的完成，我们预计将提供进一步的机械见解，并为使用情绪稳定器干预某些CNS疾病的临床研究奠定了基础。