Reversible inhibition of intracellular calcium influx through NMDA receptors by imidazoline I(2) receptor antagonists.
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.
Jiang
Susan X
SX
Experimental NeuroTherapeutics Laboratory, Institute for Biological Sciences, National Research Council Canada, 1200 Montreal Road, Bldg M54, Ottawa, Ontario, Canada K1A 0R6.
Zheng
Rong-Yuan
RY
Zeng
Jin-Qi
JQ
Li
Xiao-Li
XL
Han
Zhao
Z
Hou
Sheng T
ST
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology; D018698:Glutamic Acid / Q000633:toxicity; D019329:Idazoxan / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D054755:Imidazoline Receptors / Q000037:antagonists & inhibitors*; D042541:Intracellular Space / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D057054:Molecular Imaging; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; C487767:imidazoline receptor 2; D018698:Glutamic Acid; C103723:2-(2-benzofuranyl)-2-imidazoline; D002118:Calcium; D019329:Idazoxan