| Abstract | Intracellular calcium ([Ca²⁺]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 [Ca²⁺]i influx are potential leads for development to treat NMDA receptor-mediated neuronal damage since these drugs spare NMDA receptor normal functions. Ligands to α₂-adrenoceptors and imidazoline I₂ receptors confer neuroprotection possibility through modulating NMDA receptor-mediated [Ca²⁺]i influx. Here, we investigated the characteristics of several ligands to α₂-adrenoceptors and imidazoline I₂ receptor, in inhibiting NMDA receptor-mediated [Ca²⁺]i influx in cultured cortical neurons using a ratiometric calcium imaging technique. In contrast to MK801, which non-reversibly blocks NMDA receptor-mediated [Ca²⁺]i influx, imidazoline I₂ receptor antagonists, Idazoxan, and 2-(2-benzofuranyl)-2- imidazoline (2-BFI)-mediated inhibition of [Ca²⁺]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 α₂-adrenoceptors, including agmatine sulfate and yohimbine, and a ligand to the nicotinic receptor, levamisol, neither inhibited NMDA receptor-mediated [Ca²⁺]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 I₂ receptor antagonists transiently and reversibly block NMDA receptor-mediated [Ca²⁺]i influx. These compounds are leads for further development as uncompetitive antagonists to NMDA receptor-mediated excitotoxicity. |
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