Research progress on phosphodiesterase 4 inhibitors in central nervous system diseases

Phosphodiesterases (PDE) are involved in the regulation of cellular physiological processes and neurological functions, including neuronal plasticity, synapto-genesis, synaptic transmission, memory formation and cognitive functions by catalyzing the hydrolysis of intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Many basic and clinical studies have shown that PDE4 inhibitors block or ameliorate the occurrence and development of central nervous system (CNS) diseases by inhibiting cAMP hydrolysis, increasing cAMP content and enhancing its downstream effects. PDE4 inhibitors have long-term potentiation effect, which can enhance phosphorylation of cAMP response element binding protein (CREB) and upregulate expression of memory related Arc genes in hippocampal neurons, thereby improving cognitive impairment and Alzheimer's disease-like symptoms. They can also delay the occurrence and development of Parkinson's disease by reducing the cytotoxicity induced by α-syn and increasing the effect of miR-124-3p on cell functions. Alteration of PDE4 activity is the molecular basis for psychosis and some cognitive disorders, therefore it is considered as a therapeutic target for schizophrenia. PDE4 inhibitors play a role in depression by inhibiting the advanced glycation end product receptor (RAGE), TLR4 and NLRP3 pathways in the hippocampus, reducing the activation of microglia and the production of IL-1β, down-regulating HMGB1/RAGE signaling pathway and inhibiting inflammatory factors. PDE4 inhibitor plays a role in the treatment of autism spectrum disorder by reducing the damage of cerebellar glial cells, increasing nociceptive threshold, and improving mutual learning and memory deficits. PDE4 inhibitors might be used in the treatment of fragile X syndrome by regulating the level of cAMP and affecting the expression of fragile X mental retardation protein (FMRP). PDE4 inhibitors can also promote the differentiation of oligodendrocyte progenitor cells and enhance myelination, which has potential in the treatment of multiple sclerosis. PDE4 is also related to bipolar disorder, which may be one of the therapeutic targets. At present, several PDE4 inhibitors are in clinical trials for the treatment of CNS diseases. This article reviews and discusses the progress on basic research and clinical trials of PDE4 inhibitors in CNS diseases, providing a reference for the prevention and treatment of CNS diseases and the development of new drugs.