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

Aconitine, lappaconitine and ajacine are structurally related alkaloids occ urring in several species of the Aconitum genus. While aconitine is known t o activate the voltage-dependent sodium channel, lappaconitine has been rep orted to block this channel. To investigate a possible antagonism of the ac onitine action on neuronal activity by lappaconitine and the closely relate d 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. Wh en aconitine was applied in presence of 10 mu M lappaconitine, the concentr ation-response curve was shifted to the right. Furthermore, the complete su ppression of the population spike evoked by 100 nM aconitine was reversed b y 10 mu M lappaconitine. The action of lappaconitine was mimicked by ajacin e, however, the latter alkaloid was less potent. Both lappaconitine and aja cine shifted the input-output relationship of the presynaptic fiber spike a s function of the stimulation intensity and of the field EPSP as function o f the presynaptic fiber spike to the right. After pharmacological isolation , the presynaptic fiber spike was decreased by both compounds in a frequenc y-dependent manner indicative for a use-dependent action. Thus, electrophys iologically these alkaloids seem to inhibit predominantly the excitability of the efferent fibres and, in consequence, neurotransmission between Schaf fer 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 Mg2+ as well as spon taneously occurring epileptiform discharges in area CA3 elicited by omissio n of Mg2+ and elevation of K+. It is concluded that the inhibitory and anti epileptiform effect of ajacine and lappaconitine is mediated by a frequency -dependent inhibition of the voltage-dependent sodium channel, thereby decr easing the excitability which might be important for filtering high frequen cy bursts of action potentials characteristic for epileptiform. activity in the hippocampus. Moreover, these alkaloids are naturally occurring antagon ists of the sodium channel activator aconitine. (C) 1999 Elsevier Science B .V. All rights reserved.