Reversible inhibition of intracellular calcium influx through NMDA receptors by imidazoline I2 receptor antagonists
| Autor: | Jin-Qi Zeng, Susan X. Jiang, Xiao-Li Li, Rongyuan Zheng, Zhao Han, Sheng T. Hou |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_specialty
Neurotoxins Intracellular Space Excitotoxicity Glutamic Acid Imidazoline receptor Pharmacology medicine.disease_cause Receptors N-Methyl-D-Aspartate Neuroprotection Mice chemistry.chemical_compound Uncompetitive antagonist Idazoxan Internal medicine medicine Animals Benzofurans Cerebral Cortex Neurons Imidazoles Memantine Molecular Imaging Neuroprotective Agents Endocrinology nervous system chemistry NMDA receptor Calcium Imidazoline Receptors Agmatine medicine.drug |
| Zdroj: | European Journal of Pharmacology. 629:12-19 |
| ISSN: | 0014-2999 |
| DOI: | 10.1016/j.ejphar.2009.11.063 |
| Popis: | Intracellular calcium ([Ca(2+)]i) influx through N-methyl-d-aspartic acid (NMDA) receptors in cortical neurons is central to NMDA receptor-mediated excitotoxicity. Drugs that uncompetitively modulate NMDA receptor-mediated [Ca(2+)]i influx are potential leads for development to treat NMDA receptor-mediated neuronal damage since these drugs spare NMDA receptor normal functions. Ligands to alpha(2)-adrenoceptors and imidazoline I(2) receptors confer neuroprotection possibility through modulating NMDA receptor-mediated [Ca(2+)]i influx. Here, we investigated the characteristics of several ligands to alpha(2)-adrenoceptors and imidazoline I(2) receptor, in inhibiting NMDA receptor-mediated [Ca(2+)]i influx in cultured cortical neurons using a ratiometric calcium imaging technique. In contrast to MK801, which non-reversibly blocks NMDA receptor-mediated [Ca(2+)]i influx, imidazoline I(2) receptor antagonists, Idazoxan, and 2-(2-benzofuranyl)-2-imidazoline (2-BFI)-mediated inhibition of [Ca(2+)]i influx can be rapidly reversed when removed, in a manner similar to that of memantine, an uncompetitive antagonist to NMDA receptors. Interestingly, ligands to alpha(2)-adrenoceptors, including agmatine sulfate and yohimbine, and a ligand to the nicotinic receptor, levamisol, neither inhibited NMDA receptor-mediated [Ca(2+)]i influx, nor provided neuroprotection against glutamate toxicity, suggesting selective inhibition of NMDA receptor activities. The inhibition of NMDA receptor by Idazoxan and 2-BFI also led to the suppression of NMDA receptor-mediated calpain activity as a result of blocking NMDA receptor activity, rather than through direct inhibition of calpain activity. Collectively, these studies demonstrated that imidazoline I(2) receptor antagonists transiently and reversibly block NMDA receptor-mediated [Ca(2+)]i influx. These compounds are leads for further development as uncompetitive antagonists to NMDA receptor-mediated excitotoxicity. |
| Databáze: | OpenAIRE |
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