Park Min Kyu, Yang Hyun Wook, Woo Seo Young, Kim Dong Yeon, Son Dae-Soon, Choi Bo Young, Suh Sang Won
Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea.
Division of Data Science, Data Science Convergence Research Center, Hallym University, Chuncheon 24252, Republic of Korea.
Cells. 2025 Jan 9;14(2):86. doi: 10.3390/cells14020086.
Phosphodiesterase (PDE) enzymes regulate intracellular signaling pathways crucial for brain development and the pathophysiology of neurological disorders. Among the 11 PDE subtypes, PDE4 and PDE5 are particularly significant due to their regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling, respectively, which are vital for learning, memory, and neuroprotection. This review synthesizes current evidence on the roles of PDE4 and PDE5 in neurological health and disease, focusing on their regulation of second messenger pathways and their implications for brain function. Elevated PDE4 activity impairs synaptic plasticity by reducing cAMP levels and protein kinase A (PKA) activity, contributing to cognitive decline, acute brain injuries, and neuropsychiatric conditions such as bipolar disorder and schizophrenia. Similarly, PDE5 dysregulation disrupts nitric oxide (NO) signaling and protein kinase G (PKG) pathways, which are involved in cerebrovascular homeostasis, recovery after ischemic events, and neurodegenerative processes in Alzheimer's, Parkinson's, and Huntington's diseases. PDE4 and PDE5 are promising therapeutic targets for neurological disorders. Pharmacological modulation of these enzymes offers potential to enhance cognitive function and mitigate pathological mechanisms underlying brain injuries, neurodegenerative diseases, and psychiatric disorders. Further research into the regulation of PDE4 and PDE5 will advance therapeutic strategies for these conditions.
磷酸二酯酶（PDE）可调节对大脑发育和神经疾病病理生理学至关重要的细胞内信号通路。在11种PDE亚型中，PDE4和PDE5尤为重要，因为它们分别调节环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP）信号，而这两种信号对学习、记忆和神经保护至关重要。本综述综合了目前关于PDE4和PDE5在神经健康和疾病中作用的证据，重点关注它们对第二信使通路的调节及其对脑功能的影响。PDE4活性升高会通过降低cAMP水平和蛋白激酶A（PKA）活性来损害突触可塑性，导致认知能力下降、急性脑损伤以及双相情感障碍和精神分裂症等神经精神疾病。同样，PDE5失调会破坏一氧化氮（NO）信号和蛋白激酶G（PKG）通路，这些通路参与脑血管稳态、缺血事件后的恢复以及阿尔茨海默病、帕金森病和亨廷顿病中的神经退行性过程。PDE4和PDE5是神经疾病很有前景的治疗靶点。对这些酶进行药理学调节有可能增强认知功能，并减轻脑损伤、神经退行性疾病和精神疾病背后的病理机制。对PDE4和PDE5调节的进一步研究将推动针对这些疾病的治疗策略发展。
