Inherent desensitisation-preventing properties of a novel, subtype-selective AMPA receptor agonist, (S)-CPW 399, as a possible explanation for its excitotoxic action in cultured cerebellar granule cells
| Autor: | Colin Sinclair, Angus Grieve, Elena Morelli, Ettore Novellino, Arne Schousboe, Giuseppe Campiani, Roger Griffiths, Helen Reavy |
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| Přispěvatelé: | Sinclair, C, Reavy, H, Grieve, A, Schousboe, A, Morelli, Elena, Novellino, E, Campiani, G, Griffiths, R. |
| Rok vydání: | 2003 |
| Předmět: |
Agonist
medicine.drug_class Excitotoxicity Kainate receptor Pyrimidinones AMPA receptor Pharmacology Biology Cytoplasmic Granules medicine.disease_cause Mice Cellular and Molecular Neuroscience chemistry.chemical_compound Cerebellum Excitatory Amino Acid Agonists medicine Animals Receptors AMPA Cells Cultured Alanine L-Lactate Dehydrogenase Cell Biology nervous system chemistry CNQX NMDA receptor Calcium NBQX Cyclothiazide Neuroscience medicine.drug |
| Zdroj: | Neurochemistry International. 42:499-510 |
| ISSN: | 0197-0186 |
| DOI: | 10.1016/s0197-0186(02)00141-9 |
| Popis: | The synthesis and pharmacological characterisation of (S)-CPW 399 as a novel, potent and subtype-selective agonist of the AMPA receptor was recently reported. Studies have been extended to investigate its excitotoxic action in primary cultures of mouse cerebellar granule cells. (S)-CPW 399 induced neuronal cell death in a time- and concentration-dependent manner (EC(50) approximately 70 microM) at 24-h exposure. (S)-CPW-induced neuronal death could be prevented by co-administration with either of the AMPA/kainate selective receptor antagonists 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione (NBQX) or by the 2,3-benzodiazepine, GYKI 53655 (a selective AMPA receptor antagonist); while no protection was afforded by either the NMDA receptor antagonist D,L(+/-)-2-amino-5-phosphonopentanoate (APV) or by nifedipine (an L-type calcium channel antagonist) when used alone or in combination. Cyclothiazide, which blocks AMPA receptor desensitisation, caused minimal potentiation of (S)-CPW 399-induced neuronal death, supporting accumulating evidence that (S)-CPW 399 is a full AMPA receptor agonist that markedly prevents a receptor desensitised conformation. (S)-AMPA, (S)-willardiine (a naturally-occurring heterocyclic excitatory amino acid) and its halogenated derivative, (S)-5-fluorowillardiine, had no deleterious effect on neuronal viability when used alone but each, in the presence of cyclothiazide, induced a concentration-dependent excitotoxic cell death with a rank order of potency (fluorowillardiineAMPA=willardiine). (S)-CPW 399 stimulated an increase in intracellular free-calcium levels ([Ca(2+)](i)) in a concentration-dependent fashion (EC(50) approximately 5 microM) attaining a value of six-fold that of 'resting' cells at maximum stimulation; achieved at approximately 100 microM (S)-CPW 399. The (S)-CPW 399-stimulated increase in [Ca(2+)](i) was virtually abolished by GYKI 53655, NBQX, CNQX and by cobalt ions; markedly inhibited by nifedipine and marginally affected by D-APV. These results suggest that (S)-CPW 399 may be used as a pharmacological tool to aid in the investigation of the role of AMPA receptors in excitotoxicity and their molecular mechanisms of desensitisation. |
| Databáze: | OpenAIRE |
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