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Crosstalk between phosphodiesterase 7 and glycogen synthase kinase-3: two relevant therapeutic targets for
Jose A Morales-Garcia1, Valle Palomo, Miriam Redondo
1Instituto de Investigaciones Biomédicas (CSIC-UAM), Arturo Duperier, 4, 28029-Madrid, Spain.
Abstract:
Chronic neuroinflammation has been increasingly recognized as a primary mechanism underlying acute brain injury and neurodegenerative diseases. Enhanced expression of diverse pro-inflammatory agents in glial cells has been shown to contribute to the cell death that takes place in these disorders. Previous data from our group have shown that different inhibitors of the cyclic adenosine monophosphate (cAMP) specific phosphodiesterase 7 (PDE7) and glycogen synthase kinase-3 (GSK-3) enzymes are potent anti-inflammatory agents in different models of brain injury. In this study, we investigated cross-talk between PDE7 and GSK-3, two relevant therapeutic targets for neurological disorders, using a chemical approach. To this end, we compared specific inhibitors of GSK-3 and PDE7 with dual inhibitors of both enzymes with regard to anti-inflammatory effects in primary cultures of glial cells treated with lipopolysaccharide. Our results show that the GSK-3 inhibitors act exclusively by inhibition of this enzyme. By contrast, PDE7 inhibitors exert their effects via inhibition of PDE7 to increase intracellular cAMP levels but also through indirect inhibition of GSK-3. Activation of protein kinase A by cAMP results in phosphorylation of Ser9 of GSK-3 and subsequent inhibition. Our results indicate that the indirect inhibition of GSK-3 by PDE7 inhibitors is an important mechanism that should be considered in the future development of pharmacological treatments.
Insights
Cyclic adenosine monophosphate (cAMP) phosphodiesterase 7 (PDE7) inhibitors reduce neuroinflammation by increasing cAMP levels and indirectly inhibiting glycogen synthase kinase-3 (GSK-3). This cross-talk offers new therapeutic strategies for brain injury and neurodegenerative diseases.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Chronic neuroinflammation is a key factor in acute brain injury and neurodegenerative diseases.
- Glial cell-expressed pro-inflammatory agents contribute to cell death in these conditions.
- Inhibitors of cyclic adenosine monophosphate (cAMP) phosphodiesterase 7 (PDE7) and glycogen synthase kinase-3 (GSK-3) show anti-inflammatory potential.
Purpose of the Study:
- To investigate the cross-talk between PDE7 and GSK-3, crucial therapeutic targets for neurological disorders.
- To compare the anti-inflammatory effects of specific PDE7 and GSK-3 inhibitors versus dual inhibitors.
Main Methods:
- Utilized a chemical approach comparing specific and dual inhibitors.
- Assessed anti-inflammatory effects in primary glial cell cultures stimulated with lipopolysaccharide.
- Analyzed the mechanisms of action for GSK-3 and PDE7 inhibitors.
Main Results:
- GSK-3 inhibitors acted solely through GSK-3 inhibition.
- PDE7 inhibitors reduced inflammation by inhibiting PDE7, increasing cAMP, and indirectly inhibiting GSK-3.
- cAMP-mediated activation of protein kinase A led to GSK-3 phosphorylation and inhibition.
Conclusions:
- PDE7 inhibitors exert anti-inflammatory effects through a dual mechanism involving direct PDE7 inhibition and indirect GSK-3 inhibition.
- The indirect inhibition of GSK-3 by PDE7 inhibitors is a significant mechanism for pharmacological development.
- This cross-talk understanding is vital for developing novel treatments for neurological disorders.
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