Phosphodiesterase 4 as a therapeutic target in Parkinson's disease recent advances

Parkinson's disease (PD), as a common neurodegenerative disorder, is experiencing a continuously increasing incidence worldwide. Patients not only suffer from core motor dysfunction such as tremors, bradykinesia, and muscle rigidity, but also often present with a series of non-motor symptoms including olfactory decline. Phosphodiesterase 4 (PDE4) plays a crucial role in the complex pathological process of PD. As the main hydrolase regulating the intracellular level of cyclic adenosine monophosphate (cAMP), PDE4 is responsible for dynamically regulating this important second messenger molecule with extensive physiological functions. It is worth noting that the dysregulation of the cAMP signaling pathway has been proven to be closely associated with the occurrence and development of neurodegenerative diseases. We will first outline the molecular structural characteristics of PDE4 and its regional and cell-specific distribution in the central nervous system. The focus will be on the multiple and complex roles of PDE4 and the cAMP signal it regulates in the pathogenesis of PD, covering its regulation of networks such as oxidative stress damage, ferroptosis, and endoplasmic reticulum stress (ERS). This paper explores the theoretical basis and latest experimental evidence for the application of PDE4 inhibitors as potential neuroprotective agents or disease-modifying therapies in the treatment of PD. At the same time, it systematically reviews the improvement strategies such as subtype-selective inhibitors, novel drug delivery systems, and structural optimization in response to the key challenges currently faced in the development of PDE4 inhibitors, such as drug selectivity, central permeability, and side effects. Through a systematic analysis of existing research, it deepens the understanding of the regulatory network of PDE4 in PD and provides theoretical basis and forward-looking perspectives for the future development of efficient and safe targeted PDE4 therapeutic drugs and the exploration of new strategies for early prevention and disease process intervention in PD.