CNS Neuroscience & Therapeutics 2015-01-01

Local anesthetic lidocaine inhibits TRPM7 current and TRPM7-mediated zinc toxicity.

Tian-Dong Leng, Jun Lin, Hua-Wei Sun, Zhao Zeng, Zaven O'Bryant, Koichi Inoue, Zhi-Gang Xiong

Index: CNS Neurosci. Ther. 21(1) , 32-9, (2014)

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Abstract

Previous study demonstrated that overstimulation of TRPM7 substantially contributes to zinc-mediated neuronal toxicity. Inhibition of TRPM7 activity and TRPM7-mediated intracellular Zn(2+) accumulation may represent a promising strategy in the treatment of stroke.To investigate whether local anesthetics lidocaine could inhibit TRPM7 channel and TRPM7-mediated zinc toxicity.Whole-cell patch-clamp technique was used to investigate the effect of local anesthetics on TRPM7 currents in cultured mouse cortical neurons and TRPM7-overexpressed HEK293 cells. Fluorescent Zn(2+) imaging technique was used to study the effect of lidocaine on TRPM7-mediated intracellular Zn(2+) accumulation. TRPM7-mediated zinc toxicity in neurons was used to evaluate the neuroprotective effect of lidocaine.(1) Lidocaine dose dependently inhibits TRPM7-like currents, with an IC50 of 11.55 and 11.06 mM in cultured mouse cortical neurons and TRPM7-overexpressed HEK293 cells, respectively; (2) Lidocaine inhibits TRPM7 currents in a use/frequency-dependent manner; (3) Lidocaine inhibits TRPM7-mediated intracellular Zn(2+) accumulation in both cortical neurons and TRPM7-overexpressed HEK293 cells; (4) TRPM7-mediated Zn(2+) toxicity is ameliorated by lidocaine in cortical neurons; (5) QX-314 has a similar inhibitory effect as lidocaine on TRPM7 currents when applied extracellularly; (6) Procaine also shows potent inhibitory effect on the TRPM7 currents in cortical neurons.Our data provide the first evidence that local anesthetic lidocaine inhibits TRPM7 channel and TRPM7-mediated zinc toxicity.© 2014 John Wiley & Sons Ltd.