磷酸二酯酶抑制剂在抑郁症治疗中的研究进展

doi:10.19803/j.1672-8629.20250626

摘要/Abstract

摘要： 目的综述磷酸二酯酶抑制剂（Phosphodiesterase Inhibitors, PDEIs）在抑郁症治疗中的作用机制、研究进展及临床应用前景。方法通过检索PubMed、Web of Science、中国知网等数据库,筛选相关文献,系统梳理PDEIs的分类、神经调控机制、临床前及临床研究结果。结果 PDEIs通过调节环磷酸腺苷（Cyclic Adenosine Monophosphate, cAMP）/环磷酸鸟苷（Cyclic Guanosine Monophosphate, cGMP）信号通路,影响神经元可塑性、神经递质释放及神经炎症反应,在多种抑郁模型中表现出抗抑郁效果。其中,磷酸二酯酶4（Phosphodiesterase 4, PDE4）、磷酸二酯酶5（Phosphodiesterase 5, PDE5）等亚型抑制剂在临床前和部分临床研究中显示出快速起效、改善认知等优势,但也存在胃肠道副作用、血脑屏障穿透效率等问题。结论 PDEIs作为抑郁症治疗的新兴靶点具有重要潜力,未来需通过优化亚型选择性、改进递药系统及开展联合治疗研究,进一步提升其临床应用价值。

关键词: 磷酸二酯酶抑制剂, 抑郁症, 神经炎症, 抗抑郁药物, 作用机制, 治疗进展

Abstract: Objective To review the mechanisms of action, advances in research, and clinical potential of phosphodiesterase inhibitors (PDEIs) for the treatment of depression. Methods Such databases as PubMed, Web of Science, and the China National Knowledge Infrastructure (CNKI) were searched for related literature. The retrieved studies were screened and analyzed to summarize the classification of PDEs, their neuroregulatory mechanisms, and preclinical and clinical findings related to depression. Results PDEIs were found to produce antidepressant effects in various animal models primarily by modulating cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP) signaling pathways. These effects involved enhancement in neuronal plasticity, regulation of neurotransmitter release, and attenuation of neuroinflammatory responses. Inhibitors targeting specific subtypes, such as phosphodiesterase-4 (PDE4) and phosphodiesterase-5 (PDE5), showed such potential advantages as rapid onset of action and cognitive improvement in preclinical and some clinical studies. However, challenges persisted, including gastrointestinal side effects and variable blood-brain barrier penetration efficiency. Conclusion PDEIs are promising as an emerging class of therapeutic agents for depression. Subsequent research should focus on optimizing subtype selectivity, developing advanced drug delivery systems, and exploring rational combination therapies to maximize their clinical utility.

Key words: Phosphodiesterase Inhibitors, Depression, Neuroinflammation, Antidepressant Drugs, Mechanism of Action, Therapeutic Advances

中图分类号:

R971

刘猛, 方可, 张远, 张震, 魏良兵. 磷酸二酯酶抑制剂在抑郁症治疗中的研究进展[J]. 中国药物警戒, 2025, 22(10): 1188-1193.

LIU Meng, FANG Ke, ZHANG Yuan, ZHANG Zhen, WEI Liangbing. Research Advances in Phosphodiesterase Inhibitors for the Treatment of Depression[J]. Chinese Journal of Pharmacovigilance, 2025, 22(10): 1188-1193.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://zgywjj.magtechjournal.com/CN/10.19803/j.1672-8629.20250626

https://zgywjj.magtechjournal.com/CN/Y2025/V22/I10/1188

参考文献

[1] NGUYEN T, LE L, VU T, et al.Resuscitation from Respiratory Arrest Due to Life-Threatening Ventricular Arrhythmias in a Patient with Amitriptyline Intoxication: an Old Problem in a New Era[J]. International Medical Case Reports Journal, 2024, 17: 949-957.
[2] HASSAN G, KAMAR SA, RADY HY, et al.A Study of Roflumilast Treatment on Functional and Structural Changes in Hippocampus in Depressed Adult Male Wistar Rats[J]. PLoS One, 2024, 19(2): e0296187.
[3] CHEN SC, CHEN YH, SONG Y, et al. Upregulation of Phosph-odiesterase 7A Contributes to Concurrent Pain and Depression via Inhibition of cAMP-PKA-CREB-BDNF Signaling and Neuroinfl-ammation in the Hippocampus of Mice[J]. Int J Neuropsychopharmacol, 2024, 27(10): pyae040.
[4] YANG HW, KHO AR, LEE SH, et al.A Phosphodiesterase 4 (PDE4) Inhibitor, Amlexanox, Reduces Neuroinflammation and Neuronal Death after Pilocarpine-Induced Seizure[J]. Neurotherapeutics, 2024, 21(4): e00357.
[5] CHANTAKUL R, GIRARD C, SENEJOUX F, et al.Discovery of Natural Phosphodiesterase 5 Inhibitors from Dalbergia Cochinchinensis Pierre Leaves Using LC-QTOF-MS(2)[J]. Plants (Basel), 2025, 14(11): 1652.
[6] TADINADA SM, WALAH EN, MUKHERJEE U, et al.Differential Effects of Phosphodiesterase 4A5 on cAMP-Dependent Forms of Long-Term Potentiation[J]. J Physiol, 2024, 18: 39693518 .
[7] HEGDE S, CAPELL WR, IBRAHIM BA, et al.Phosphodiesterase 11A (PDE11A), Enriched in Ventral Hippocampus Neurons, Is Required for Consolidation of Social but Not Nonsocial Memories in Mice[J]. Neuropsychopharmacology, 2016, 41(12): 2920-2931.
[8] HAINSWORTH AH, ARANCIO O, ELAHI FM, et al.PDE5 Inhibitor Drugs for Use in Dementia[J]. Alzheimers Dement (NY), 2023, 9(3): e12412.
[9] WU J, QIN D, LIANG Z, et al.Dysregulation of Astrocyte-Derived Matrix Gla Protein Impairs Dendritic Spine Development in Pyridoxine-Dependent Epilepsy[J]. Mol Ther, 2025, 33(4): 1785-1802.
[10] METKAR SK, YAN Y, LU Y, et al.Phosphodiesterase 2 and Its Isoform A as Therapeutic Targets in the Central Nervous System Disorders[J]. CNS Neurol Disord Drug Targets, 2024, 23(8): 941-955.
[11] SA DEGHI MA, HEMMATI S, YOUSEFI-MANESH H, et al.Cilostazol Pretreatment Prevents PTSD-related Anxiety Behavior through Reduction of Hippocampal Neuroinflammation[J]. Naunyn Schmiedebergs Arch Pharmacol, 2024, 397(1): 133-144.
[12] ISHIHARA Y, ANDO M, GOTO Y, et al.A Novel Selective Phosphodiesterase 9 Inhibitor, Irsenontrine (E2027), Enhances GluA1 Phosphorylation in Neurons and Improves Learning and Memory via Cyclic GMP Elevation[J]. Neuropharmacology, 2025, 273: 110428.
[13] QIU NZ, HOU HM, GUO TY, et al.Phosphodiesterase 8 (PDE8): Distribution and Cellular Expression and Association with Alzheimer's Disease[J]. Neurochem Res, 2024, 49(8): 1993-2004.
[14] MARSHALL RD, MENNITI FS, TEPPER MA.A Novel PDE10A Inhibitor for Tourette Syndrome and Other Movement Disorders[J]. Cells, 2024, 13(14): 1230.
[15] ZAKI ES, SAYED RH, SAAD MA, et al.Roflumilast Ameliorates Ovariectomy-Induced Depressive-Like Behavior in Rats via Activation of AMPK/mTOR/ULK1-Dependent Autophagy Pathway[J]. Life Sci, 2023, 327: 121806.
[16] ZHANG B, JIANG MY, LUO WH, et al.Phosphodiesterase 2 (PDE2) Inhibitors: an Updated Patent Review (2017-Present)[J]. Expert Opin Ther Patm, 2024, 34(11): 1105-1119.
[17] PRICKAERTS J, KERCKHOFFS J, POSSEMIS N, et al.Roflumilast and Cognition Enhancement: a Translational Perspective[J]. Biomedicine & Pharmacotherapy, 2024, 181: 117707.
[18] CONG YF, LIU FW, XU L, et al.Rolipram Ameliorates Memory Deficits and Depression-Like Behavior in APP/PS1/tau Triple Transgenic Mice: Involvement of Neuroinflammation and Apoptosis via cAMP Signaling[J]. Int J Neuropsychopharmacol, 2023, 26(9): 585-598.
[19] XIE J, BI B, QIN Y, et al.Inhibition of Phosphodiesterase-4 Suppresses HMGB1/RAGE Signaling Pathway and NLRP3 Inflammasome Activation in Mice Exposed to Chronic Unpredictable Mild Stress[J]. Brain Behav Immun, 2021, 92: 67-77.
[20] BERNARDUS SAAYMAN JL, HARVEY BH, WEGENER G, et al.Sildenafil, Alone and in Combination with Imipramine or Escitalopram, Display Antidepressant-Like Effects in an Adrenocorticotropic Hormone-Induced (ACTH) Rodent Model of Treatment-Resistant Depression[J]. European Journal of Pharmacology, 2024, 969: 176434.
[21] LIM I, MASUTANI T, HASHITANI H, et al.Inhibition of PDE-4 Isoenzyme Attenuates Frequency and Overall Contractility of Agonist-Evoked Ureteral Phasic Contractions[J]. Pharmacol Res Perspect, 2024, 12(1): e1175.
[22] BILAL A, ABBASI NUH.Randomized Placebo Controlled Trial of Sildenafil Citrate, Cognitive Behavior Sex Therapy and Integrated Treatment in Men Diagnosed with Non Organic Erectile Dysfunction[J]. Sex Med, 2022, 10(1): 100464.
[23] PAN X, CHEN L, SHAN C, et al.Inhibition of Phosphodiesterase 2 Ameliorates Post-Traumatic Stress-Induced Alcohol Intake Disorder by Regulating cAMP/cGMP Signaling[J]. Int J Neuropsychoph-armacol, 2022, 25(11): 936-945.
[24] SUGIMOTO K, NOMURA S, SHIRAO S, et al.Cilostazol Decreases Duration of Spreading Depolarization and Spreading Ischemia after Aneurysmal Subarachnoid Hemorrhage[J]. Ann Neurol, 2018, 84(6): 873-885.
[25] HEBB AL, ROBERTSON HA, DENOVAN-WRIGHT EM.Phosphodiesterase 10A Inhibition Is Associated with Locomotor and Cognitive Deficits and Increased Anxiety in Mice[J]. Eur Neuropsychopharmacol, 2008, 18(5): 339-363.
[26] SINGH NK, SINGH P, VARSHNEY P, et al.Multimodal Action of Phosphodiesterase 5 Inhibitors Against Neurodegenerative Disorders: an Update Review[J]. J Biochem Mol Toxicol, 2024, 38(11): e70021.
[27] ZHANG C, XUE ZH, LUO WH, et al.The Therapeutic Potential of Phosphodiesterase 9 (PDE9) Inhibitors: a Patent Review (2018-present)[J]. Expert Opin Ther Pat, 2024, 34(9): 759-772.
[28] LI Y, WANG Z, MA S, et al.Chemical Space Exploration and Machine Learning-Based Screening of PDE7A Inhibitors[J]. Pharmaceuticals (Basel), 2025, 18(4): 444.
[29] SHERPA RT, KOZIOL-WHITE CJ, PANETTIERI RA JR.Advancing Obstructive Airway Disease Treatment: Dual PDE3/4 Inhibition as a Therapeutic Strategy[J]. Cells, 2025, 14(9): 659.
[30] RIBAUDO G, ONGARO A, ZAGOTTO G, et al.Therapeutic Potential of Phosphodiesterase Inhibitors against Neurodegeneration: the Perspective of the Medicinal Chemist[J]. ACS Chem Neurosci, 2020, 11(12): 1726-1739.
[31] SAINIMNUAN S, CHIMPRASIT A, HANNONGBUA S, et al.Role of Interaction Mode of Phenanthrene Derivatives as Selective PDE5 Inhibitors Using Molecular Dynamics Simulations and Quantum Chemical Calculations[J]. Molecular Diversity, 2024, 29(2): 1683-1696.
[32] GOBEJISHVILI L, RODRIGUEZ WE, BAUER P, et al.Novel Liposomal Rolipram Formulation for Clinical Application to Reduce Emesis[J]. Drug Design, Development and Therapy, 2022, 16: 1301-1309.
[33] PETERS DE.Antidepressants for Inflammatory Bowel Disease? Multimodal Effects of Amitriptyline in Murine Colitis[J]. J Pharmacol Exp Ther, 2025, 392(3): 103382.