VRX-03011, a novel 5-HT4 agonist, enhances memory and hippocampal acetylcholine efflux
| Autor: | Paul E. Gold, Frank Lezoualc'h, Yael Marantz, Sharon Shacham, Silvia Noiman, Sylvain J. Robert, Joseph Rutkowski, Aline Dumuis, Joël Bockaert, Michael E. Ragozzino, Eric G. Mohler, Monique Gastineau |
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| Rok vydání: | 2007 |
| Předmět: |
Agonist
medicine.medical_specialty Pyridones medicine.drug_class Thiophenes Hippocampal formation Ligands Transfection Hippocampus Neuroprotection Cellular and Molecular Neuroscience Cognition Memory Internal medicine medicine Animals Receptor 5-HT receptor Pharmacology Chemistry Spontaneous alternation Acetylcholine Rats Serotonin Receptor Agonists Endocrinology Acetylcholinesterase inhibitor Models Animal Receptors Serotonin 5-HT4 medicine.drug |
| Zdroj: | Neuropharmacology. 53:563-573 |
| ISSN: | 0028-3908 |
| DOI: | 10.1016/j.neuropharm.2007.06.016 |
| Popis: | Recent evidence suggests that 5-hydroxytryptamine (5-HT)(4) receptor activity enhances cognition and provides neuroprotection. Here we report the effects of VRX-03011, a novel partial 5-HT(4) agonist, that is both potent (K(i) approximately 30 nM) and highly selective (K(i)5 microM for all other 5-HT receptors tested). In separate experiments, rats received VRX-03011 (0.1-10 mg/kg i.p.) 30 min prior to spontaneous alternation testing in a no-delay or a 30-s delay condition. VRX-03011 (1, 5 and 10 mg/kg, but not 0.1 mg/kg) significantly enhanced delayed spontaneous alternation performance while none of the doses enhanced performance in the no-delay test. VRX-03011 (1 and 5 mg/kg) concomitantly enhanced hippocampal acetylcholine output and delayed spontaneous alternation scores compared to that of vehicle controls, but had no effect on hippocampal acetylcholine release under a resting condition. Moreover, suboptimal doses of VRX-03011 and the acetylcholinesterase inhibitor galanthamine combined to enhance memory. VRX-03011 also regulated amyloid precursor protein (APP) metabolism by inducing a concentration-dependent increase in the non-amyloidogenic soluble form of APP (sAPPalpha) with an EC(50) approximately 1--10 nM. VRX-03011 had no effect on contractile properties in guinea pig ileum or colon preparations with an EC(50)10 microM and did not alter rat intestinal transit at doses up to 10 mg/kg. These findings suggest that VRX-03011 may represent a novel treatment for Alzheimer's disease that reduces cognitive impairments and provides neuroprotection without gastrointestinal side effects. |
| Databáze: | OpenAIRE |
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