Snyder Gretchen L, Vanover Kimberly E
Molecular Neuropharmacology, Intra-Cellular Therapies Inc (ITI), 430 East 29th Street, Suite 900, New York, NY, 10016, USA.
Clinical Development, Intra-Cellular Therapies Inc (ITI), 430 East 29th Street, Suite 900, New York, NY, 10016, USA.
Adv Neurobiol. 2017;17:385-409. doi: 10.1007/978-3-319-58811-7_14.
Schizophrenia is a pervasive neuropsychiatric disorder affecting over 1% of the world's population. Dopamine system dysfunction is strongly implicated in the etiology of schizophrenia. Data support the long-standing concept of schizophrenia as a disease characterized by hyperactivity within midbrain (striatal D2) dopamine systems. In addition, there is now considerable evidence that glutamate neurotransmission, mediated through NMDA-type receptors, is deficient in patients with schizophrenia and that hypoactivity in cortical dopamine and glutamate pathways is a key feature of this serious mental disorder. While current antipsychotic medications-with a common mechanism involving dopamine D2 receptor antagonism or pre-synaptic partial agonism-adequately address positive symptoms of the disease, such as the acute hallucinations and delusions, they fail to substantially improve negative features, such as social isolation, and can further compromise poor cognitive function associated with schizophrenia. In fact, cognitive impairment is a core feature of schizophrenia. The treatment of cognitive impairment and other residual symptoms associated with schizophrenia, therefore, remains a significant unmet medical need. With current cell-surface receptor-based pharmacology falling short of addressing these core cognitive symptoms, more recent approaches to treatment development have focused on processes within the cell. In this review, we discuss the importance of cyclic nucleotide (cNT) phosphodiestereases (PDEs)-intracellular enzymes that control the activity of key second messenger signaling pathways in the brain-which have been proposed as targets for new schizophrenia therapies. We also discuss the challenge facing those developing drugs to target specific PDE enzymes involved in psychopathology without involving other systems that produce concomitant side effects.
精神分裂症是一种广泛存在的神经精神障碍，影响着全球超过1%的人口。多巴胺系统功能障碍在精神分裂症的病因学中具有重要影响。数据支持了长期以来关于精神分裂症的概念，即该疾病的特征是中脑（纹状体D2）多巴胺系统功能亢进。此外，现在有大量证据表明，通过NMDA型受体介导的谷氨酸神经传递在精神分裂症患者中存在缺陷，并且皮质多巴胺和谷氨酸通路的功能减退是这种严重精神障碍的一个关键特征。虽然目前的抗精神病药物——其共同机制涉及多巴胺D2受体拮抗或突触前部分激动——能够充分缓解该疾病的阳性症状，如急性幻觉和妄想，但它们未能显著改善阴性特征，如社交隔离，并且可能进一步损害与精神分裂症相关的较差认知功能。事实上，认知障碍是精神分裂症的一个核心特征。因此，治疗与精神分裂症相关的认知障碍和其他残留症状仍然是一项重大的未满足医疗需求。由于目前基于细胞表面受体的药理学方法无法解决这些核心认知症状，最近的治疗开发方法已将重点放在细胞内过程上。在这篇综述中，我们讨论了环核苷酸（cNT）磷酸二酯酶（PDEs）的重要性——这些细胞内酶控制着大脑中关键第二信使信号通路的活性——它们已被提议作为新型精神分裂症治疗的靶点。我们还讨论了那些开发针对参与精神病理学的特定PDE酶的药物所面临的挑战，同时避免涉及会产生伴随副作用的其他系统。
