Crosstalk between phosphodiesterase 7 and glycogen synthase kinase-3: two relevant therapeutic targets for neurological disorders.
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.
Instituto de Investigaciones Biomédicas (CSIC-UAM), Arturo Duperier, 4, 28029-Madrid, Spain.
Jose A
JA
Morales-Garcia
Valle
V
Palomo
Miriam
M
Redondo
Sandra
S
Alonso-Gil
Carmen
C
Gil
Ana
A
Martinez
Ana
A
Perez-Castillo
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000633:toxicity; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009573:Nitrites; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7