TY - JOUR
T1 - Beyond PDE4 inhibition
T2 - A comprehensive review on downstream cAMP signaling in the central nervous system
AU - Donders, Zoë
AU - Skorupska, Iga Joanna
AU - Willems, Emily
AU - Mussen, Femke
AU - Broeckhoven, Jana Van
AU - Carlier, Aurélie
AU - Schepers, Melissa
AU - Vanmierlo, Tim
N1 - Funding Information:
Figures were created using \u201CServer Medical Art,\u201D licensed under a Creative Commons Attribution 3.0 License. Authors are funded by Fonds Wetenschappelijk Onderzoek (FWO-Vlaanderen) (1SH2E24N, G042121N, 1209123N, and 1272324N) and Bijzonder Onderzoeksfonds (BOF) (BOF22DOC15).
Funding Information:
Figures were created using \u201CServer Medical Art,\u201D licensed under a Creative Commons Attribution 3.0 License. Authors are funded by FWO (1SH2E24N, G042121N, 1209123 N, and 1272324 N) and BOF (BOF22DOC15).
Publisher Copyright:
© 2024 The Authors
PY - 2024/8/1
Y1 - 2024/8/1
N2 - Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates signal transduction pathways pivotal for numerous biological functions. Intracellular cAMP levels are spatiotemporally regulated by their hydrolyzing enzymes called phosphodiesterases (PDEs). It has been shown that increased cAMP levels in the central nervous system (CNS) promote neuroplasticity, neurotransmission, neuronal survival, and myelination while suppressing neuroinflammation. Thus, elevating cAMP levels through PDE inhibition provides a therapeutic approach for multiple CNS disorders, including multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, and Alzheimer's disease. In particular, inhibition of the cAMP-specific PDE4 subfamily is widely studied because of its high expression in the CNS. So far, the clinical translation of full PDE4 inhibitors has been hampered because of dose-limiting side effects. Hence, focusing on signaling cascades downstream activated upon PDE4 inhibition presents a promising strategy, offering novel and pharmacologically safe targets for treating CNS disorders. Yet, the underlying downstream signaling pathways activated upon PDE(4) inhibition remain partially elusive. This review provides a comprehensive overview of the existing knowledge regarding downstream mediators of cAMP signaling induced by PDE4 inhibition or cAMP stimulators. Furthermore, we highlight existing gaps and future perspectives that may incentivize additional downstream research concerning PDE(4) inhibition, thereby providing novel therapeutic approaches for CNS disorders.
AB - Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates signal transduction pathways pivotal for numerous biological functions. Intracellular cAMP levels are spatiotemporally regulated by their hydrolyzing enzymes called phosphodiesterases (PDEs). It has been shown that increased cAMP levels in the central nervous system (CNS) promote neuroplasticity, neurotransmission, neuronal survival, and myelination while suppressing neuroinflammation. Thus, elevating cAMP levels through PDE inhibition provides a therapeutic approach for multiple CNS disorders, including multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, and Alzheimer's disease. In particular, inhibition of the cAMP-specific PDE4 subfamily is widely studied because of its high expression in the CNS. So far, the clinical translation of full PDE4 inhibitors has been hampered because of dose-limiting side effects. Hence, focusing on signaling cascades downstream activated upon PDE4 inhibition presents a promising strategy, offering novel and pharmacologically safe targets for treating CNS disorders. Yet, the underlying downstream signaling pathways activated upon PDE(4) inhibition remain partially elusive. This review provides a comprehensive overview of the existing knowledge regarding downstream mediators of cAMP signaling induced by PDE4 inhibition or cAMP stimulators. Furthermore, we highlight existing gaps and future perspectives that may incentivize additional downstream research concerning PDE(4) inhibition, thereby providing novel therapeutic approaches for CNS disorders.
KW - CAMP signaling
KW - Central nervous system
KW - Neurodegenerative diseases
KW - PDE4 inhibition
KW - Phosphodiesterases
U2 - 10.1016/j.biopha.2024.117009
DO - 10.1016/j.biopha.2024.117009
M3 - (Systematic) Review article
SN - 0753-3322
VL - 177
JO - Biomedicine & Pharmacotherapy
JF - Biomedicine & Pharmacotherapy
M1 - 117009
ER -