Abstract
The pleiotropic function of 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent pathways in health and disease led to the development of pharmacological phosphodiesterase inhibitors (PDE-I) to attenuate cAMP degradation. While there are many isotypes of PDE, a predominant role of PDE4 is to regulate fundamental functions, including endothelial and epithelial barrier stability, modulation of inflammatory responses and cognitive and/or mood functions. This makes the use of PDE4-I an interesting tool for various therapeutic approaches. However, due to the presence of PDE4 in many tissues, there is a significant danger for serious side effects. Based on this, the aim of this review is to provide a comprehensive overview of the approaches and effects of PDE4-I for different therapeutic applications. In summary, despite many obstacles to use of PDE4-I for different therapeutic approaches, the current data warrant future research to utilize the therapeutic potential of phosphodiesterase 4 inhibition.
Highlights
A milestone in the discoveries of cellular signaling was the identification of the second messenger, 30,50 -cyclic adenosine monophosphate, by Earl Sutherland et al, 1957
In an ECLS-rat model with cardiac arrest, we showed that continuous IV application of PDE4-I after ROSC effectively reduced the kidney histopathology injury score and improved kidney function [85]
cigarette smoke (CS) may reduce the anti-inflammatory effect of cyclic adenosine monophosphate (cAMP), because Epac1, but not Epac2, expression is downregulated by CS in pulmonary artery smooth muscle (PASM) and lung tissue from COPD patients [101]
Summary
A milestone in the discoveries of cellular signaling was the identification of the second messenger, 30 ,50 -cyclic adenosine monophosphate (cAMP), by Earl Sutherland et al, 1957. UCR1 has a phosphorylation site of cAMP-dependent protein kinase A (PKA) and UCR2 may have an inhibitory effect on the PDE4 catalytic unit and interact with. The phosphorylation of the ERK-units inhibits hydrolytic activity of the long PDE4 form, has weak or no effect on the super-short form and can increase hydrolytic activity of the short. D have the extracellular signal-reguprotein directly activated by cAMP 1 and 2); CREB (cAMP response element binding protein); lated kinase (ERK)-phosphorylation subunits, which are inserted in the catalytic. HARBS are exclusively located in the brain tissue, mainly in the hippocampus, frontal cortex and olfactory bulb, whereas LARBS are present in both the brain and peripheral tissues These cerebral “HARBS” regions are targets for other antidepressant medication. This melody is not yet fully explored, and the understanding of the function, regulation and distribution of the specific PDE4 subtypes may offer the development of specific inhibitors to create a mechanism-based therapeutic approach
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