Roy Dhritiman, Balasubramanian Shivaramakrishnan, Krishnamurthy Praveen Thaggikuppe, Sola Piyong, Rymbai Emdormi
Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, The Nilgiris, Ooty, 643001, Tamil Nadu, India.
Cell Mol Neurobiol. 2023 Aug;43(6):2713-2741. doi: 10.1007/s10571-023-01349-1. Epub 2023 Apr 19.
Clinicians and researchers are exploring safer and novel treatment strategies for treating the ever-prevalent Parkinson's disease (PD) across the globe. Several therapeutic strategies are used clinically for PD, including dopamine replacement therapy, DA agonists, MAO-B blockers, COMT blockers, and anticholinergics. Surgical interventions such as pallidotomy, particularly deep brain stimulation (DBS), are also employed. However, they only provide temporal and symptomatic relief. Cyclic adenosine monophosphate (cAMP) is one of the secondary messengers involved in dopaminergic neurotransmission. Phosphodiesterase (PDE) regulates cAMP and cGMP intracellular levels. PDE enzymes are subdivided into families and subtypes which are expressed throughout the human body. PDE4 isoenzyme- PDE4B subtype is overexpressed in the substantia nigra of the brain. Various studies have implicated multiple cAMP-mediated signaling cascades in PD, and PDE4 is a common link that can emerge as a neuroprotective and/or disease-modifying target. Furthermore, a mechanistic understanding of the PDE4 subtypes has provided perceptivity into the molecular mechanisms underlying the adverse effects of phosphodiesterase-4 inhibitors (PDE4Is). The repositioning and development of efficacious PDE4Is for PD have gained much attention. This review critically assesses the existing literature on PDE4 and its expression. Specifically, this review provides insights into the interrelated neurological cAMP-mediated signaling cascades involving PDE4s and the potential role of PDE4Is in PD. In addition, we discuss existing challenges and possible strategies for overcoming them.
临床医生和研究人员正在探索更安全、新颖的治疗策略，以治疗全球范围内日益普遍的帕金森病（PD）。临床上用于治疗PD的几种治疗策略包括多巴胺替代疗法、多巴胺激动剂、单胺氧化酶B（MAO-B）阻滞剂、儿茶酚-O-甲基转移酶（COMT）阻滞剂和抗胆碱能药物。也采用手术干预措施，如苍白球切开术，特别是深部脑刺激（DBS）。然而，它们只能提供暂时的症状缓解。环磷酸腺苷（cAMP）是参与多巴胺能神经传递的二级信使之一。磷酸二酯酶（PDE）调节细胞内cAMP和环磷酸鸟苷（cGMP）的水平。PDE酶可细分为多个家族和亚型，在人体各处均有表达。PDE4同工酶-PDE4B亚型在大脑黑质中过度表达。各种研究表明，多种cAMP介导的信号级联反应与PD有关，而PDE4是一个共同环节，可能成为神经保护和/或疾病修饰靶点。此外，对PDE4亚型的机制理解为磷酸二酯酶4抑制剂（PDE4Is）不良反应的分子机制提供了洞察力。用于PD的有效PDE4Is的重新定位和开发备受关注。本综述批判性地评估了关于PDE4及其表达的现有文献。具体而言，本综述深入探讨了涉及PDE4的相关神经学cAMP介导的信号级联反应以及PDE4Is在PD中的潜在作用。此外，我们还讨论了现有挑战及克服这些挑战的可能策略。
