Mechanisms of the tetrahydroaminoacridine effect on action potential and ion currents in myelinated axons.
9-Amino-1,2,3,4-tetrahydroacridine (THA) in the range of 10-300 microM was shown to prolong the action potential in myelinated nerve fibres of Xenopus laevis. Voltage-clamp experiments showed that THA, besides reducing the Na+ and the K+ current, modified the Na+ current inactivation and the K+ current activation. The effects were frequency dependent. Quantitative models were developed and used in computer simulations of the THA effect on the action potential. The computations showed that the observed effects on the ion currents were sufficient to explain the observed prolongation of the action potential. The models further suggest that THA binds to Na+ channels in an open state and from the axoplasmic side while it binds to K+ channels in a closed state. The findings suggest an explanation to some aspects of the clinical effects of THA on Alzheimer patients.
Nobel Institute for Neurophysiology, Karolinska Institutet, Stockholm, Sweden.
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D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001369:Axons / Q000187:drug effects*; D003198:Computer Simulation; D004553:Electric Conductivity; D004558:Electric Stimulation; D006801:Humans; D009413:Nerve Fibers, Myelinated / Q000187:drug effects*; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D013619:Tacrine / Q000494:pharmacology*; D014982:Xenopus laevis
D013619:Tacrine; D012964:Sodium; D011188:Potassium