磷酸二酯酶4抑制剂在中枢神经系统疾病中的作用研究进展

Research progress on phosphodiesterase 4 inhibitors in central nervous system diseases

磷酸二酯酶(PDE)通过催化细胞内的环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP)的水解参与调节神经元可塑性、突触发生、突触传递、记忆形成和认知功能等细胞生理过程及功能发挥。大量基础和临床研究证明PDE4抑制剂主要通过抑制cAMP水解、提高cAMP含量,增强其下游效应,从而改善中枢神经系统疾病的发生和发展。PDE4抑制剂可提高长时程增强效应、海马神经元cAMP反应元件结合蛋白(CREB)的磷酸化和记忆相关Arc基因的表达,从而改善认知和记忆障碍以及阿尔茨海默病样症状;通过减轻α-突触核蛋白诱导的细胞毒性,增加miR-124-3p对细胞活性的作用而抵抗帕金森病的发生发展;可激活cAMP/PKA/CREB通路,从而减弱神经炎症和氧化应激,增强神经可塑性,改善精神分裂症;通过抑制海马的晚期糖基化终末产物受体(RAGE)、Toll样受体4和NOD样受体热蛋白结构域相关蛋白3通路降低小胶质细胞激活和IL-1β产生,下调HMGB1/RAGE信号通路和抑制炎症因子,在抑郁症中发挥作用;通过减少小脑神经胶质细胞损伤,增加伤害性感受阈值,改善相互学习和记忆缺陷,从而在孤独症谱系障碍的治疗中发挥作用;通过调节cAMP含量影响脆性X智力低下蛋白表达,有望应用于脆性X染色体综合征治疗;促进少突胶质祖细胞分化并增强髓鞘形成而影响多发性硬化症治疗。PDE4与双向情感障碍也有关,可能作为治疗靶点之一。目前还有不少PDE4抑制剂处于中枢神经系统疾病的临床试验阶段。本文综述了PDE4抑制剂治疗中枢神经系统疾病的基础研究和临床试验进展,以期为中枢神经系统疾病的预防和治疗提供新的思路,为中枢神经系统药物的研发提供新策略。

Phosphodiesterases(PDE)are involved in the regulation of cellular physiological processes and neurological functions,including neuronal plasticity,synaptogenesis,synaptic transmission,memory formation and cognitive functions by catalyzing the hydrolysis of intracellular cyclic adenosine monophosphate(cAMP)and cyclic guanosine monophosphate(cGMP).Many basic and clinical studies have shown that PDE4 inhibitors block or ameliorate the occurrence and development of central nervous system(CNS)diseases by inhibiting cAMP hydrolysis,increasing cAMP content and enhancing its downstream effects.PDE4 inhibitors have long-term potentiation effect,which can enhance phosphorylation of cAMP response element binding protein(CREB)and upregulate expression of memory related Arc genes in hippocampal neurons,thereby improving cognitive impairment and Alzheimer’s disease-like symptoms.They can also delay the occurrence and development of Parkinson’s disease by reducing the cytotoxicity induced byα-syn and increasing the effect of miR-124-3p on cell functions.Alteration of PDE4 activity is the molecular basis for psychosis and some cognitive disorders,therefore it is considered as a therapeutic target for schizophrenia.PDE4 inhibitors play a role in depression by inhibiting the advanced glycation end product receptor(RAGE),TLR4 and NLRP3 pathways in the hippocampus,reducing the activation of microglia and the production of IL-1β,down-regulating HMGB1/RAGE signaling pathway and inhibiting inflammatory factors.PDE4 inhibitor plays a role in the treatment of autism spectrum disorder by reducing the damage of cerebellar glial cells,increasing nociceptive threshold,and improving mutual learning and memory deficits.PDE4 inhibitors might be used in the treatment of fragile X syndrome by regulating the level of cAMP and affecting the expression of fragile X mental retardation protein(FMRP).PDE4 inhibitors can also promote the differentiation of oligodendrocyte progenitor cells and enhance myelination,which has potential in the treatment of multiple sclerosis.PDE4 is also related to bipolar disorder,which may be one of the therapeutic targets.At present,several PDE4 inhibitors are in clinical trials for the treatment of CNS diseases.This article reviews and discusses the progress on basic research and clinical trials of PDE4 inhibitors in CNS diseases,providing a reference for the prevention and treatment of CNS diseases and the development of new drugs.