Kumari Shilpa, Bagri Kajal, Deshmukh Rahul
Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, 151001, Punjab, India.
Department of Pharmacology, Central University of Punjab, Bathinda, 151001, Punjab, India.
Inflammopharmacology. 2025 Feb;33(2):593-603. doi: 10.1007/s10787-024-01638-1. Epub 2025 Jan 14.
Alzheimer's Disease (AD), a progressive and age-associated neurodegenerative disorder, is primarily characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Despite advances in targeting Aβ-mediated neuronal damage with anti-Aβ antibodies, these treatments provide only symptomatic relief and fail to address the multifactorial pathology of the disease. This necessitates the exploration of novel therapeutic approaches and a deeper understanding of molecular signaling mechanisms underlying AD. Phosphodiesterases (PDEs), particularly Phosphodiesterase 4 (PDE4), play a pivotal role in regulating cyclic adenosine monophosphate (cAMP), a key molecule involved in memory consolidation and cognitive function. PDE4 inhibitors have demonstrated potential in enhancing memory and cognition in preclinical models of AD by modulating cAMP signaling. However, their clinical translation has been limited due to challenges such as adverse effects, narrow therapeutic windows, and low specificity in mechanism of action. This review bridges the gap between preclinical discoveries and clinical applications of PDE4 inhibitors in AD. It highlights preclinical evidence supporting the neuroprotective and anti-inflammatory effects of PDE4 inhibitors while addressing challenges in their clinical development, including issues of safety, efficacy, and disease-specific targeting. By integrating findings from both preclinical and clinical studies, we provide a comprehensive understanding of the therapeutic potential of PDE4 inhibitors in AD. Furthermore, this review outlines future research directions aimed at optimizing PDE4 inhibition strategies for AD treatment, offering a roadmap to translate foundational insights into clinical realities.
阿尔茨海默病（AD）是一种与年龄相关的进行性神经退行性疾病，主要特征为β淀粉样蛋白（Aβ）斑块和神经原纤维缠结。尽管使用抗Aβ抗体靶向Aβ介导的神经元损伤方面取得了进展，但这些治疗仅提供症状缓解，未能解决该疾病的多因素病理学问题。这就需要探索新的治疗方法，并更深入地了解AD潜在的分子信号传导机制。磷酸二酯酶（PDEs），特别是磷酸二酯酶4（PDE4），在调节环磷酸腺苷（cAMP）中起关键作用，cAMP是参与记忆巩固和认知功能的关键分子。PDE4抑制剂已在AD临床前模型中通过调节cAMP信号显示出增强记忆和认知的潜力。然而，由于不良反应、治疗窗窄和作用机制特异性低等挑战，它们的临床转化受到限制。本综述弥合了PDE4抑制剂在AD临床前发现与临床应用之间的差距。它强调了支持PDE4抑制剂神经保护和抗炎作用的临床前证据，同时解决了其临床开发中的挑战，包括安全性、有效性和疾病特异性靶向等问题。通过整合临床前和临床研究的结果，我们全面了解了PDE4抑制剂在AD中的治疗潜力。此外，本综述概述了旨在优化AD治疗中PDE4抑制策略的未来研究方向，为将基础见解转化为临床现实提供了路线图。
