Reducing Neuroinflammation in Psychiatric Disorders: Novel Target of Phosphodiesterase 4 (PDE4) and Developing of the PDE4 Inhibitors

Abstract

Multiple lines of evidence support the pathogenic role of neuroinflammation in psy‐ chiatric illness. Cyclic adenosine monophosphate (cAMP) is a critical regulator of microglia homeostasis; as the predominant negative modulator of cyclic AMP signal‐ ing within microglia, and phosphodiesterase 4 (PDE4) represents a promising target for modulating immune function. The approach for pharmacological manipulation of cAMP levels using specifc PDE4 inhibitors provokes an ant-iinflammatory response. Specifcally, PDE4 inhibitors have recently emerged as a potential therapeutic strategy for neuroinflammatory, neurodegenerative, and psychiatric diseases. Mechanistically, PDE4 inhibitors produce an anti-inflammatory and neuroprotection effect by increasing the accumulation of cAMP and activating protein kinase A (PKA), the signaling pathway of which is thought to play an important role in the development of psychiatric disorders. This chapter reviews present knowledge of the relationship between neuroinflammation and classical psychiatric disorders (major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia) and demonstrates the signaling pathways that underlie the use of PDE4 inhibitors in neuroinflammation. In addition, among the four subtypes (A-D) of PDE4, it remains unclear which one exerts suppressive effects on neuroinflammation. Understanding how PDE4 and neuroinflammation interact can reveal pathogenic clues and help target new preventive and symptomatic therapies for psychiatric illness.