Cargando…

Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair

A wide diversity of perturbations of the central nervous system (CNS) result in structural damage to the neuroarchitecture and cellular defects, which in turn are accompanied by neurological dysfunction and abortive endogenous neurorepair. Altering intracellular signaling pathways involved in inflam...

Descripción completa

Detalles Bibliográficos
Autores principales: Knott, Eric P., Assi, Mazen, Rao, Sudheendra N. R., Ghosh, Mousumi, Pearse, Damien D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412282/
https://www.ncbi.nlm.nih.gov/pubmed/28338622
http://dx.doi.org/10.3390/ijms18040696
_version_ 1783232963096346624
author Knott, Eric P.
Assi, Mazen
Rao, Sudheendra N. R.
Ghosh, Mousumi
Pearse, Damien D.
author_facet Knott, Eric P.
Assi, Mazen
Rao, Sudheendra N. R.
Ghosh, Mousumi
Pearse, Damien D.
author_sort Knott, Eric P.
collection PubMed
description A wide diversity of perturbations of the central nervous system (CNS) result in structural damage to the neuroarchitecture and cellular defects, which in turn are accompanied by neurological dysfunction and abortive endogenous neurorepair. Altering intracellular signaling pathways involved in inflammation and immune regulation, neural cell death, axon plasticity and remyelination has shown therapeutic benefit in experimental models of neurological disease and trauma. The second messengers, cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), are two such intracellular signaling targets, the elevation of which has produced beneficial cellular effects within a range of CNS pathologies. The only known negative regulators of cyclic nucleotides are a family of enzymes called phosphodiesterases (PDEs) that hydrolyze cyclic nucleotides into adenosine monophosphate (AMP) or guanylate monophosphate (GMP). Herein, we discuss the structure and physiological function as well as the roles PDEs play in pathological processes of the diseased or injured CNS. Further we review the approaches that have been employed therapeutically in experimental paradigms to block PDE expression or activity and in turn elevate cyclic nucleotide levels to mediate neuroprotection or neurorepair as well as discuss both the translational pathway and current limitations in moving new PDE-targeted therapies to the clinic.
format Online
Article
Text
id pubmed-5412282
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-54122822017-05-05 Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair Knott, Eric P. Assi, Mazen Rao, Sudheendra N. R. Ghosh, Mousumi Pearse, Damien D. Int J Mol Sci Review A wide diversity of perturbations of the central nervous system (CNS) result in structural damage to the neuroarchitecture and cellular defects, which in turn are accompanied by neurological dysfunction and abortive endogenous neurorepair. Altering intracellular signaling pathways involved in inflammation and immune regulation, neural cell death, axon plasticity and remyelination has shown therapeutic benefit in experimental models of neurological disease and trauma. The second messengers, cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), are two such intracellular signaling targets, the elevation of which has produced beneficial cellular effects within a range of CNS pathologies. The only known negative regulators of cyclic nucleotides are a family of enzymes called phosphodiesterases (PDEs) that hydrolyze cyclic nucleotides into adenosine monophosphate (AMP) or guanylate monophosphate (GMP). Herein, we discuss the structure and physiological function as well as the roles PDEs play in pathological processes of the diseased or injured CNS. Further we review the approaches that have been employed therapeutically in experimental paradigms to block PDE expression or activity and in turn elevate cyclic nucleotide levels to mediate neuroprotection or neurorepair as well as discuss both the translational pathway and current limitations in moving new PDE-targeted therapies to the clinic. MDPI 2017-03-24 /pmc/articles/PMC5412282/ /pubmed/28338622 http://dx.doi.org/10.3390/ijms18040696 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Knott, Eric P.
Assi, Mazen
Rao, Sudheendra N. R.
Ghosh, Mousumi
Pearse, Damien D.
Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair
title Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair
title_full Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair
title_fullStr Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair
title_full_unstemmed Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair
title_short Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair
title_sort phosphodiesterase inhibitors as a therapeutic approach to neuroprotection and repair
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412282/
https://www.ncbi.nlm.nih.gov/pubmed/28338622
http://dx.doi.org/10.3390/ijms18040696
work_keys_str_mv AT knottericp phosphodiesteraseinhibitorsasatherapeuticapproachtoneuroprotectionandrepair
AT assimazen phosphodiesteraseinhibitorsasatherapeuticapproachtoneuroprotectionandrepair
AT raosudheendranr phosphodiesteraseinhibitorsasatherapeuticapproachtoneuroprotectionandrepair
AT ghoshmousumi phosphodiesteraseinhibitorsasatherapeuticapproachtoneuroprotectionandrepair
AT pearsedamiend phosphodiesteraseinhibitorsasatherapeuticapproachtoneuroprotectionandrepair