Selective block of tetramethrin-modified sodium channels by (+/-)-alpha-tocopherol (vitamin E).
Pyrethroids exert their hyperexcitatory effects by prolonging the open time of individual neuronal sodium channels. Occupational exposure to pyrethroids frequently leads to abnormal skin sensation or paresthesia. Vitamin E is known to reduce the cutaneous paresthesia. However, the mechanism of action has been totally unclear. Because the sodium channel is the major target site of pyrethroids, it is possible that vitamin E interferes with pyrethroid modification of the sodium channel. Patch clamp experiments were performed using rat dorsal root ganglion neurons and cerebellar Purkinje cells. (+/-)-alpha-Tocopherol (vitamin E) selectively blocked the tetramethrin(type I pyrethroid)-modified sodium channels in a dose-dependent, but voltage-independent manner without affecting normal sodium channels. The concentration-response curves for tetramethrin modification of the sodium channels were shifted in the direction of higher concentrations by (+/-)-alpha-tocopherol in a competitive manner. Elevated depolarizing after-potential or repetitive after-discharges caused by tetramethrin were effectively blocked by (+/-)-alpha-tocopherol. (+/-)-alpha-Tocopherol did not reverse the tetramethrin-induced shift in the current-voltage curve for peak sodium current, but partially reversed the shift in the steady-state sodium channel inactivation curve. Vitamin A and its metabolic derivative, retinoic acid, slightly reduced both normal and tetramethrin-modified sodium currents. The selective block of tetramethrin-modified sodium channels by (+/-)-alpha-tocopherol is one of the important mechanisms underlying (+/-)-alpha-tocopherol alleviation of paresthesia.
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois, USA.
J H
JH
Song
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Narahashi
D000818:Animals; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007306:Insecticides / Q000494:pharmacology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D011689:Purkinje Cells / Q000187:drug effects / Q000502:physiology; D011722:Pyrethrins / Q000494:pharmacology*; D051381:Rats; D062687:Sodium Channel Agonists; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014801:Vitamin A / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology*
D007306:Insecticides; D011722:Pyrethrins; D062687:Sodium Channel Agonists; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014801:Vitamin A; D014810:Vitamin E; D013779:Tetrodotoxin; D014212:Tretinoin; C009424:tetramethrin