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CNS effects of a novel Phosphodiesterase 4B selective inhibitor A‐33
Author(s) -
Zhang Chong,
Xu Ying,
O'Donnell James
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.931.4
Subject(s) - rolipram , creb , tail suspension test , antidepressant , pharmacology , behavioural despair test , open field , hippocampus , medicine , phosphodiesterase inhibitor , hippocampal formation , phosphodiesterase , endocrinology , chemistry , biochemistry , transcription factor , gene , enzyme
Phosphodiesterase 4 (PDE4) inhibitors such as Rolipram, have been studied extensively for their roles in alleviating mood and cognitive abnormalities, such as depression, anxiety and learning and memory deficits in rodents. However, one major hurdle in this field is the dose‐limiting side effects, i.e. nausea and vomiting. Targeting specific subtypes of PDE4 might produce similar therapeutic effects while reducing the unwanted side effects. This study aims to characterize the CNS effects of the first PDE4B selective inhibitor A‐33. In vitro studies using the mouse hippocampal cell line HT‐22 indicate that A‐33 dose‐dependently increased cAMP levels and phosphorylation of CREB (cAMP response element binding protein), which peaked at 12 h after treatment. In mice, A‐33 significantly reduced the immobility time of in the forced swim and tail suspension tests, 2 classical rodent tests for depressive behaviors. A‐33 also significantly increased expression of phosphorylated CREB in the mouse hippocampus 2h after i.p. administration of the compound, to a level that is comparable to those induced by rolipram. However, A‐33 did not exhibit any anxiolytic‐like or memory enhancing effects in the study. Moreover, A‐33 was also tested for its potential to induce emesis in a rodent surrogate test, ketamine/xylazine induced anesthesia duration. It did not cause a significant reduction of duration of anesthesia, which is consistent with a previous report stating its non‐emetogenic property in ferrets. In summary, the current study shows that A‐33 exhibits antidepressant‐like effects that is comparable to rolipram without causing any significant adverse effects.