Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
Department of Biology, San Diego State University, San Diego, CA, USA.
Mol Neurobiol. 2020 Jan;57(1):372-392. doi: 10.1007/s12035-019-01719-1. Epub 2019 Jul 30.
Autotaxin (ATX) is a soluble extracellular enzyme that is abundant in mammalian plasma and cerebrospinal fluid (CSF). It has two known enzymatic activities, acting as both a phosphodiesterase and a phospholipase. The majority of its biological effects have been associated with its ability to liberate lysophosphatidic acid (LPA) from its substrate, lysophosphatidylcholine (LPC). LPA has diverse pleiotropic effects in the central nervous system (CNS) and other tissues via the activation of a family of six cognate G protein-coupled receptors. These LPA receptors (LPARs) are expressed in some combination in all known cell types in the CNS where they mediate such fundamental cellular processes as proliferation, differentiation, migration, chronic inflammation, and cytoskeletal organization. As a result, dysregulation of LPA content may contribute to many CNS and PNS disorders such as chronic inflammatory or neuropathic pain, glioblastoma multiforme (GBM), hemorrhagic hydrocephalus, schizophrenia, multiple sclerosis, Alzheimer's disease, metabolic syndrome-induced brain damage, traumatic brain injury, hepatic encephalopathy-induced cerebral edema, macular edema, major depressive disorder, stress-induced psychiatric disorder, alcohol-induced brain damage, HIV-induced brain injury, pruritus, and peripheral nerve injury. ATX activity is now known to be the primary biological source of this bioactive signaling lipid, and as such, represents a potentially high-value drug target. There is currently one ATX inhibitor entering phase III clinical trials, with several additional preclinical compounds under investigation. This review discusses the physiological and pathological significance of the ATX-LPA-LPA receptor signaling axis and summarizes the evidence for targeting this pathway for the treatment of CNS diseases.
自分泌酶（ATX）是一种可溶性细胞外酶，在哺乳动物血浆和脑脊液（CSF）中含量丰富。它具有两种已知的酶活性，既是磷酸二酯酶又是磷脂酶。其大多数生物学作用与其从底物溶血磷脂酰胆碱（LPC）中释放溶血磷脂酸（LPA）的能力有关。LPA 通过激活其同源 G 蛋白偶联受体家族，在中枢神经系统（CNS）和其他组织中具有多种多效性作用。这些 LPA 受体（LPAR）在 CNS 中所有已知细胞类型中以某种组合表达，在那里它们介导增殖、分化、迁移、慢性炎症和细胞骨架组织等基本细胞过程。因此，LPA 含量的失调可能导致许多 CNS 和 PNS 疾病，如慢性炎症或神经性疼痛、多形性胶质母细胞瘤（GBM）、出血性脑积水、精神分裂症、多发性硬化症、阿尔茨海默病、代谢综合征引起的脑损伤、创伤性脑损伤、肝性脑病引起的脑水肿、黄斑水肿、重度抑郁症、应激引起的精神障碍、酒精引起的脑损伤、HIV 引起的脑损伤、瘙痒和周围神经损伤。现在已知 ATX 活性是这种生物活性信号脂质的主要生物学来源，因此代表了一个潜在的高价值药物靶点。目前有一种 ATX 抑制剂正在进入 III 期临床试验，还有几种额外的临床前化合物正在研究中。本文综述了 ATX-LPA-LPA 受体信号轴的生理和病理意义，并总结了靶向该途径治疗 CNS 疾病的证据。
