Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6229ER, the Netherlands; Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt 3500, Belgium.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6229ER, the Netherlands; Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt 3500, Belgium; Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht 6629ER, the Netherlands.
Biomed Pharmacother. 2024 Aug;177:117009. doi: 10.1016/j.biopha.2024.117009. Epub 2024 Jun 21.
Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates signal transduction pathways pivotal for numerous biological functions. Intracellular cAMP levels are spatiotemporally regulated by their hydrolyzing enzymes called phosphodiesterases (PDEs). It has been shown that increased cAMP levels in the central nervous system (CNS) promote neuroplasticity, neurotransmission, neuronal survival, and myelination while suppressing neuroinflammation. Thus, elevating cAMP levels through PDE inhibition provides a therapeutic approach for multiple CNS disorders, including multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, and Alzheimer's disease. In particular, inhibition of the cAMP-specific PDE4 subfamily is widely studied because of its high expression in the CNS. So far, the clinical translation of full PDE4 inhibitors has been hampered because of dose-limiting side effects. Hence, focusing on signaling cascades downstream activated upon PDE4 inhibition presents a promising strategy, offering novel and pharmacologically safe targets for treating CNS disorders. Yet, the underlying downstream signaling pathways activated upon PDE(4) inhibition remain partially elusive. This review provides a comprehensive overview of the existing knowledge regarding downstream mediators of cAMP signaling induced by PDE4 inhibition or cAMP stimulators. Furthermore, we highlight existing gaps and future perspectives that may incentivize additional downstream research concerning PDE(4) inhibition, thereby providing novel therapeutic approaches for CNS disorders.
环磷酸腺苷（cAMP）是一种关键的第二信使，调节着许多生物功能的信号转导途径。细胞内的 cAMP 水平通过其水解酶，即磷酸二酯酶（PDEs），在时空上得到调节。已经表明，中枢神经系统（CNS）中 cAMP 水平的升高促进了神经可塑性、神经传递、神经元存活和髓鞘形成，同时抑制了神经炎症。因此，通过抑制 PDE 来提高 cAMP 水平为多种 CNS 疾病提供了一种治疗方法，包括多发性硬化症、中风、脊髓损伤、肌萎缩侧索硬化症、创伤性脑损伤和阿尔茨海默病。特别是，由于 cAMP 特异性 PDE4 亚家族在 CNS 中的高表达，对其的抑制受到了广泛的研究。迄今为止，由于存在剂量限制的副作用，全 PDE4 抑制剂的临床转化一直受到阻碍。因此，关注 PDE4 抑制后激活的信号级联反应是一种很有前途的策略，为治疗 CNS 疾病提供了新的、药理学上安全的靶点。然而，PDE（4）抑制后激活的下游信号通路仍部分难以捉摸。本综述全面概述了关于 PDE4 抑制或 cAMP 刺激诱导的 cAMP 信号下游介质的现有知识。此外，我们强调了现有的差距和未来的展望，这可能会激励对 PDE（4）抑制的更多下游研究，从而为 CNS 疾病提供新的治疗方法。
