Antagonism of the aconitine-induced inexcitability by the structurally related Aconitum alkaloids, lappaconitine and ajacine

Abstract

Aconitine, lappaconitine and ajacine are structurally related alkaloids occurring in several species of the Aconitum genus. While aconitine is known to activate the voltage-dependent sodium channel, lappaconitine has been reported to block this channel. To investigate a possible antagonism of the aconitine action on neuronal activity by lappaconitine and the closely related alkaloid ajacine, we have performed extracellular recordings of stimulus evoked population spikes and field excitatory postsynaptic potential (EPSP) in rat hippocampal slices. Aconitine (10–100 nM) diminished the amplitude of the orthodromic population spike in a concentration-dependent manner. When aconitine was applied in presence of 10 μM lappaconitine, the concentration–response curve was shifted to the right. Furthermore, the complete suppression of the population spike evoked by 100 nM aconitine was reversed by 10 μM lappaconitine. The action of lappaconitine was mimicked by ajacine, however, the latter alkaloid was less potent. Both lappaconitine and ajacine shifted the input–output relationship of the presynaptic fiber spike as function of the stimulation intensity and of the field EPSP as function of the presynaptic fiber spike to the right. After pharmacological isolation, the presynaptic fiber spike was decreased by both compounds in a frequency-dependent manner indicative for a use-dependent action. Thus, electrophysiologically these alkaloids seem to inhibit predominantly the excitability of the afferent fibres and, in consequence, neurotransmission between Schaffer collaterals and the CA1 neurons, thereby suppressing the firing of the latter. Ajacine and lappaconitine inhibited stimulus-triggered epileptiform population bursts in area CA1 elicited by omission of Mg 2+ as well as spontaneously occurring epileptiform discharges in area CA3 elicited by omission of Mg 2+ and elevation of K +. It is concluded that the inhibitory and antiepileptiform effect of ajacine and lappaconitine is mediated by a frequency-dependent inhibition of the voltage-dependent sodium channel, thereby decreasing the excitability which might be important for filtering high frequency bursts of action potentials characteristic for epileptiform activity in the hippocampus. Moreover, these alkaloids are naturally occurring antagonists of the sodium channel activator aconitine.