کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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5830475 | 1559039 | 2011 | 6 صفحه PDF | دانلود رایگان |
Dextromethorphan exhibits neuroprotective effects against inflammation-mediated neurodegeneration. However, relatively little is known regarding the molecular mechanism for this inflammation-mediated neuroprotection. Human Kv1.3 channels, one of the voltage-gated potassium channels, are widely expressed in the immune and nervous systems. Activation of human Kv1.3 channels causes neuroglia-mediated neurodegeneration. Agents that inhibit human Kv1.3 channel activity have been developed as novel drugs for immunosuppression. In the present study, we investigated the effects of dextromethorphan on human Kv1.3 or Kv1.2 channel activity heterologously expressed in Xenopus laevis oocytes. The channel currents were measured with the two-electrode voltage clamp technique. Activation of both channels induced outward peak and steady-state currents. Dextromethorphan treatment induced a slight inhibition of peak currents in human Kv1.2 and Kv1.3 channels, whereas dextromethorphan profoundly inhibited the steady-state currents of human Kv1.3 channels compared to Kv1.2 channel currents. Dextromethorphan's action on steady-state currents of human Kv1.3 channels was in a concentration-dependent manner. The half-maximal inhibitory concentration (IC50) on steady-state currents of human Kv1.3 channels was 12.8 ± 1.6 μM. Dextromethorphan also accelerated the C-type inactivation rate, increased the current decay rate, and inhibited currents in a use-dependent manner. These results indicate that dextromethorphan accelerates C-type inactivation of human Kv1.3 channels and acts as an open-channel blocker. These results further suggest the possibility that dextromethorphan-mediated acceleration of C-type inactivation of human Kv1.3 channels might be one of the cellular bases of dextromethorphan-mediated protection against inflammation-mediated neurodegeneration.
Journal: European Journal of Pharmacology - Volume 651, Issues 1â3, 25 January 2011, Pages 122-127