RNA interference-mediated phosphodiesterase-4D splice variants knockdown in the prefrontal cortex produces antidepressant-like and cognition-enhancing effects.
Summary of "RNA interference-mediated phosphodiesterase-4D splice variants knockdown in the prefrontal cortex produces antidepressant-like and cognition-enhancing effects."
Phosphodiesterase 4 (PDE4) inhibitors produce potent antidepressant-like and cognition-enhancing effects. However, their clinical utility is limited by the major side effect of emesis, which appears to be PDE4 isoform-specific. Although PDE4D subtype plays the pivotal role in these therapeutic profiles, it is also the primary subtype responsible for emesis. Therefore, the aim of present research was to investigate whether long-form PDE4D variants mediate antidepressant-like and cognition-enhancing effects, but are irrespective with emesis. EXPERIMENTAL
In mice microinfused with lentiviral vectors that contained shRNA-mir hairpin structure targeting long-form PDE4Ds into bilateral prefrontal cortices, the tail-suspension and forced-swim tests were used to measure antidepressant-like effects; novel object recognition and Morris water-maze tasks were used to determine cognition-enhancing effects. The emetic potential was assessed by alpha2 adrenergic receptor-mediated anesthesia, a surrogate measure of emesis. Intracellular cAMP signaling was analyzed by time-resolved fluorescence resonance energy transfer immunoassay and Western-blot. Dendritic complexity was assessed by Golgi staining. KEY
Microinfusions of lentiviral PDE4D-shRNA down-regulated PDE4D4 and PDE4D5, and imitated the antidepressant-like and cognition-enhancing effects of the prototypical PDE4 inhibitor rolipram. The behavioral effects were related to dendritic complexity and mediated by the increased cAMP signaling. In addition, these effects were not enhanced in the presence of rolipram. Finally, while rolipram shortened the duration of combined anesthesia, RNA interference-mediated PDE4D knockdown in the prefrontal cortex did not. CONCLUSIONS AND
These data suggest that long-form PDE4Ds, at least PDE4D4 and PDE4D5, may be the promising targets for the development of PDE4 variant-selective inhibitors as the new pharmacotherapies for depressive disorders and neurodegenerative diseases involving memory deficits.
Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
This article was published in the following journal.
Name: British journal of pharmacology
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/23003922
- DOI: http://dx.doi.org/10.1111/j.1476-5381.2012.02225.x
Medical and Biotech [MESH] Definitions
The rostral part of the frontal lobe, bounded by the inferior precentral fissure in humans, which receives projection fibers from the mediodorsal nucleus of the thalamus. The prefrontal cortex receives afferent fibers from numerous structures of the diencephalon, mesencephalon, and limbic system as well as cortical afferents of visual, auditory, and somatic origin.
Cyclic Nucleotide Phosphodiesterases, Type 4
A cyclic nucleotide phosphodiesterase subfamily that is found predominantly in inflammatory cells and may play role in regulation of CELL-MEDIATED IMMUNITY. The enzyme family includes over twenty different variants that occur due to multiple alternative splicing of the mRNA of at least four different genes.
Gene Knockdown Techniques
The artificial induction of GENE SILENCING by the use of RNA INTERFERENCE to reduce the expression of a specific gene. It includes the use of DOUBLE-STRANDED RNA, such as SMALL INTERFERING RNA and RNA containing HAIRPIN LOOP SEQUENCE, and ANTI-SENSE OLIGONUCLEOTIDES.
Phosphodiesterase 4 Inhibitors
Compounds that specifically inhibit PHOSPHODIESTERASE 4.
Phosphodiesterase 3 Inhibitors
Compounds that specifically inhibit PHOSPHODIESTERASE 3.
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