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 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.
Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA. eknott@emory.edu.
Eric P
EP
Knott
The Miami Project to Cure Paralysis, The Miller School of Medicine at the University of Miami, Miami, FL 33136, USA. m_assi2010@live.com.
Mazen
M
Assi
The Miami Project to Cure Paralysis, The Miller School of Medicine at the University of Miami, Miami, FL 33136, USA. sudhee26@med.miami.edu.
Sudheendra N R
SN
Rao
The Miami Project to Cure Paralysis, The Miller School of Medicine at the University of Miami, Miami, FL 33136, USA. mghosh@med.miami.edu.|The Department of Neurological Surgery, The Miller School of Medicine at the University of Miami, Miami, FL 33136, USA. mghosh@med.miami.edu.
Mousumi
M
Ghosh
The Miami Project to Cure Paralysis, The Miller School of Medicine at the University of Miami, Miami, FL 33136, USA. DPearse@med.miami.edu.|The Department of Neurological Surgery, The Miller School of Medicine at the University of Miami, Miami, FL 33136, USA. DPearse@med.miami.edu.|The Neuroscience Program, The Miller School of Medicine at the University of Miami, Miami, FL 33136, USA. DPearse@med.miami.edu.|The Interdisciplinary Stem Cell Institute, The Miller School of Medicine at the University of Miami, Miami, FL 33136, USA. DPearse@med.miami.edu.|Bruce Wayne Carter Department of Veterans Affairs Medical Center, Miami, FL 33136, USA. DPearse@med.miami.edu.
Damien D
DD
Pearse
D000818:Animals; D002490:Central Nervous System / Q000502:physiology; D002493:Central Nervous System Diseases / Q000517:prevention & control; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D015290:Second Messenger Systems; D015398:Signal Transduction / Q000187:drug effects*
D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP
CNS; PDE; cell death; clinical trials; cyclic AMP; cyclic GMP; cyclic nucleotides; phosphodiesterase; phosphodiesterase inhibitor; regeneration; repair