Crosstalk between Phosphodiesterase 7 and Glycogen
Synthase Kinase-3: Two Relevant Therapeutic Targets for Neurological
Disorders
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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