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PDE4 as a target for cognition enhancement
Wito Richter1, Frank S Menniti, Han-Ting Zhang
1University of California San Francisco, Department of Obstetrics, Gynecology and Reproductive Sciences, San Francisco, CA 94143-0556, USA. richterw@obgyn.ucsf.edu
Expert Opinion on Therapeutic Targets
|July 26, 2013
Summary
Inhibiting phosphodiesterase 4 (PDE4) enzymes enhances memory and cognition. Targeting specific PDE4 subtypes offers a promising strategy for developing effective cognition-enhancing drugs while minimizing side effects like nausea.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are critical second messengers in brain function, influencing memory and learning.
- Cyclic nucleotide phosphodiesterases (PDEs) inactivate these messengers, making them key targets for cognitive enhancement therapies.
Purpose of the Study:
- To review the properties and functions of the phosphodiesterase 4 (PDE4) enzyme family.
- To highlight the procognitive and memory-enhancing effects observed upon PDE4 inhibition.
Main Methods:
- Review of existing literature on PDE4 properties and functions.
- Analysis of preclinical data from rodent models with selective PDE4 subtype ablation.
Main Results:
- PAN-selective PDE4 inhibitors demonstrate memory- and cognition-enhancing effects in preclinical models.
- These inhibitors also exhibit neuroprotective and neuroregenerative properties.
- Selective ablation studies reveal unique, non-redundant functions for individual PDE4 subtypes in the brain.
Conclusions:
- Targeting specific PDE4 subtypes, variants, or conformational states is crucial for maximizing therapeutic benefits.
- This approach aims to mitigate side effects such as emesis and nausea associated with broad PDE4 inhibition.
- Developing isoform-specific PDE4 inhibitors holds significant therapeutic potential for cognitive disorders.
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