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Vol. 295, Issue 2, 524-530, November 2000

Effects of Tetraethylammonium Analogs on Apoptosis and Membrane Currents in Cultured Cortical Neurons1

Xin Wang, Ai Ying Xiao, Tomomi Ichinose and Shan Ping Yu

Department of Neurology, Center for the Study of Nervous System Injury, School of Medicine, Washington University, St. Louis, Missouri

Tetraethylammonium (TEA), the quaternary ammonium ion and nonselective K+ channel blocker, is protective against neuronal apoptosis. We now tested two TEA analogs, tetrapentylammonium (TPeA) and tetrahexylammonium (THA), for their effects on apoptotic neuronal death and for their pharmacological profiles on membrane currents in cultured mouse cortical neurons. TPeA and THA (0.1-1.0 µM) attenuated staurosporine-induced caspase-3 activation and neuronal apoptosis. TPeA and THA blocked the outward delayed rectifier K+ (IK) current in concentration-dependent manners with IC50 values of 2.7 and 1.9 µM, respectively. IK was blocked by TPeA in a use-dependent manner, whereas THA blocked IK regardless of activation state of the channel. TPeA at 1 µM inhibited the high voltage-activated (HVA) Ca2+ current and the A-type K+ current (IA). TPeA (1-10 µM) also blocked the fast inactivating Na+ current. The ligand-gated N-methyl-D-aspartate (NMDA) receptor current was not affected by up to 20 µM TPeA. THA at 1 µM showed inhibitory effects on IA, HVA Ca2+, and Na+ currents. THA (10 µM) suppressed NMDA currents. The data suggest that, as K+ channel blockers and apoptosis antagonists, TPeA and THA are much more potent than TEA; however, they have nonspecific actions on several voltage-gated or ligand-gated channels.

1 This work was supported by research grants from American Heart Association (9950207N), National Science Foundation (IBN-9817151), and National Institutes of Health (3257ADRC16).

0022-3565/00/2952-0524$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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