aconitine and Epilepsy

Application of choline (5 and 10 mM) to electrically stimulated (1 Hz) rat hippocampal slices evoked epileptoid activity manifested by generation of extra population spikes. Application of methyllycaconitine (10 nM), a specific agonist for α7-subunit of nicotinic acetylcholine receptors, did not prevent generation of extra population spikes. In contrast, pretreatment of slices with Mg(2+) (5 mM) or blockade of NMDA-type glutamate receptors with MK-801 (100 μM) prevented generation of the extra population spikes. It was hypothesized that elevation of choline concentration during cerebral pathology can promote activation of NMDA-receptors and provoke epileptoid activity not related to activation of α7-subunit of nicotinic acetylcholine receptor.

Topics: Aconitine; Action Potentials; Animals; CA1 Region, Hippocampal; Choline; Dizocilpine Maleate; Epilepsy; Excitatory Amino Acid Antagonists; In Vitro Techniques; Nicotinic Antagonists; Pyramidal Tracts; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic

The aim of the present study was to investigate if the plant alkaloid, mesaconitine, which has been reported to have antinociceptive effects via stimulation of the noradrenergic system, inhibits epileptiform field potentials. The experiments were performed as extracellular recordings on rat hippocampal slices. Epileptiform activity was induced by omission of Mg2+ from the bathing medium or by addition of bicuculline and stimulus-evoked population bursts were recorded in the CA1 region. Spontaneous epileptiform activity was elicited by perfusing a nominally Mg2+-free bathing medium with high K+ concentration (5 mM). Both stimulus-triggered and spontaneous epileptiform activity was attenuated in a concentration-dependent manner by mesaconitine (30 nM-1 microM). The inhibitory effect was rather variable in appearance when lower concentrations (30 and 100 nM) of mesaconitine were applied. Pretreatment of the slices with the alpha-adrenoceptor antagonist yohimbine (1 microM) prevented the effect of mesaconitine. It is concluded that the inhibitory action of mesaconitine at low concentration is mediated via alpha-adrenoceptors.

Topics: Aconitine; Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Animals; Anticonvulsants; Bicuculline; Electric Stimulation; Epilepsy; GABA Antagonists; Hippocampus; In Vitro Techniques; Magnesium; Male; Potassium Chloride; Rats; Rats, Wistar; Timolol; Yohimbine

In the present study the effects of the two Aconitum alkaloids 14-benzoyltalitasamine and talitasamine on neuronal activity were investigated in order to obtain further insight into structure-dependent effects of this group of alkaloids on central nervous activity. Both alkaloids are closely related to aconitine, the main alkaloid of plants of Aconitum species. However, they have shortened side chains at position C3 and C8 of the molecule. The experiments were performed as extracellular recordings of orthodromically and antidromically evoked population spikes as well as of field excitatory potentials (EPSPs) from the CA1 region of rat hippocampal slices. 14-Benzoyltalitasamine exerted a reversible inhibition of the field potentials in a concentration-dependent manner. The orthodromic population spike was attenuated at concentrations higher than 1 microM, while the field EPSP was already affected at a concentration of at least 0.3 microM. Both responses were completely blocked at a concentration of 30 microM. The alkaloid failed to affect the presynaptic fiber spike at concentrations less than 10 microM. There was only a up to 30% decrease in the antidromic population spike (10-100 microM). The inhibition of the antidromic spike was increased by using a higher stimulus frequency. In contrast to 14-benzoyltalitasamine, the alkaloid talitasamine which is lacking the benzoylester side chain was a less effective inhibitor of the orthodromic population spike and even failed to affect the antidromic spike. Furthermore, the effects of the alkaloids on experimentally induced epileptiform activity was examined. While talitasamine was lacking any significant effect at concentrations less than 100 microM, 14-benzoyltalitasamine reversibly reduced both stimulus-triggered epileptiform activity in area CA1 elicited by omission of Mg2+ from the bathing medium as well as spontaneously occurring epileptiform activity in CA3 elicited by omission of Mg2+ and elevation of K+ to 5 or 8 mM. The antiepileptiform efficacy of this compound was concentration-dependent (0.3-10 microM) and manifested itself as a decrease in burst frequency as well as in burst amplitude and was significantly increased by the higher K+ concentration.

Topics: Aconitine; Alkaloids; Animals; Depression, Chemical; Electric Stimulation; Electrophysiology; Epilepsy; Evoked Potentials; Excitatory Postsynaptic Potentials; Hippocampus; In Vitro Techniques; Magnesium; Male; Plants; Potassium Chloride; Rats; Rats, Wistar

The effects of the Aconitum alkaloid 3-acetylaconitine on neuronal activity were investigated in the slice preparation and on cultivated neurons of rat hippocampus by extracellular and patch-clamp recordings, respectively. 3-Acetylaconitine (0.01-1 microM) diminished the orthodromic and antidromic population spike in a concentration-dependent manner. The inhibitory action of the drug was preceded by a transiently enhanced excitability. The latency of onset of the inhibition was accelerated by increased stimulation frequency, whereas recovery during washout of the alkaloid was accelerated by decreased stimulation frequency. Moreover, the inhibitory effect of 3-acetylaconitine was evaluated in two different models of epileptiform activity induced either by blockade of GABA receptors by bicuculline (10 microM) or by a nominal Mg(2+)-free bathing medium. In accordance with the activity-dependent mode of action, this compound abolished the synaptically evoked population spikes in the presence of bicuculline or nominal Mg(2+)-free bathing medium, respectively. Whole-cell patch-clamp recordings revealed an interaction of 3-acetylaconitine with the voltage-dependent sodium channel. At a concentration of 1 microM, 3-acetylaconitine did not affect the peak amplitude of the sodium current, but shifted the current-voltage relationship in the hyperpolarized direction such that sodium currents were already activated at the resting potential.

Topics: Aconitine; Animals; Depression, Chemical; Dose-Response Relationship, Drug; Epilepsy; Evoked Potentials; Hippocampus; In Vitro Techniques; Ion Channel Gating; Male; Neurons; Patch-Clamp Techniques; Rats; Rats, Wistar; Sodium Channels

Alkaloids of Aconitum spec. (Ranunculaceae) are employed in traditional Chinese folk medicine as analgesics. The present study was designed in order to investigate the effects of the structurally related alkaloids aconitine, lappaconitine, and 6-benzoylheteratisine on experimentally induced epileptiform activity. Experiments were performed as extracellular recordings of stimulus evoked population spikes in rat hippocampal slices. Epileptiform activity was induced by bicuculline. All three alkaloids exerted an inhibitory action on excitability of hippocampal pyramidal cells in a frequency-dependent manner. The onset of inhibition was accelerated by increasing the frequency of electrical stimulation. Aconitine (1 microM) evoked a complete suppression of both normal and epileptiform activity, whereas lappaconitine (10 microM) and 6-benzoylheteratisine (10 microM) selectively diminished the epileptiform afterdischarges and the duration of the bursts, but spared the normal activity. The present findings suggest that the structurally related Aconitum alkaloids aconitine, lappaconitine, and 6-benzoylheteratisine possess an anticonvulsive potential. The predominant effect of these alkaloids is to suppress the spread of seizure activity, and they may therefore tend to distort epileptic events. However, despite their similar structure, they exert qualitatively and quantitatively different inhibitory effects.

Topics: Aconitine; Alkaloids; Animals; Bicuculline; Epilepsy; Hippocampus; In Vitro Techniques; Male; Medicine, Chinese Traditional; Plants, Medicinal; Rats; Rats, Wistar

Alkaloids of different Aconitum species are employed as analgesics in traditional Chinese folk medicine. The present study was designed in order to investigate the effects of the structurally related alkaloids 6-benzoylheteratisine and heteratisine on neuronal activity in rat hippocampus. Experiments were performed as extracellular recordings of stimulus evoked population spikes in rat hippocampal slices. 6-Benzoylheteratisine (0.01-10 microM) inhibited the ortho- and antidromic population spike as well as the field EPSP in a concentration- and frequency-dependent manner. Heteratisine (1-100 microM) was a less potent inhibitor. It exerted a depression of the orthodromic spike, but failed to affect the antidromic population spike. 6-Benzoylheteratisine (10 microM) diminished epileptiform activity induced by bicuculline. In hippocampal neurons, this compound reduced the peak amplitude of the sodium current. There was no effect of heteratisine on the sodium current in concentrations up to 100 microM. It is concluded that the frequency-dependent action of 6-benzoylheteratisine suggests an inhibition of neuronal activity which underlies epileptiform burst discharges. The predominant effect is a suppression of neuronal activity due to a blockade of sodium channels.

Topics: Aconitine; Action Potentials; Alkaloids; Analgesics; Animals; Bicuculline; Convulsants; Depression, Chemical; Drugs, Chinese Herbal; Epilepsy; GABA Antagonists; Hippocampus; In Vitro Techniques; Male; Neurons; Rats; Rats, Wistar; Sodium Channels

The effects of the two structurally related Aconitum alkaloids, 1-benzoylnapelline and napelline, were investigated by extracellular recording of the stimulus-evoked population spike in the CA1 region of rat hippocampal slices in vitro. 1-Benzoylnapelline (1-100 microM) exerted a depressant action on the orthodromic as well as on the antidromic population spike. Napelline failed to evoke a significant effect at concentrations up to 100 microM. The inhibitory action induced by 1-benzoylnapelline was enhanced when the frequency of electrical stimulation was increased. In contrast, reversal of the inhibitory effect was accelerated when stimulation frequency was decreased. The activity-dependent mode of action of 1-benzoylnapelline raised the question of whether the drug is effective to suppress epileptiform activity. The results obtained from experiments on epileptiform hippocampal slices revealed a reduction of the burst duration and of the number of spikes in the burst as well as attenuation of the amplitude of the population spikes. These data support the conclusion that 1-benzoylnapelline, in contrast to the structurally related compound, napelline, has an activity-dependent inhibitory action on central neurons.

Topics: Aconitine; Aconitum; Action Potentials; Animals; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Electric Stimulation; Epilepsy; Hippocampus; In Vitro Techniques; Male; Rats; Rats, Wistar; Structure-Activity Relationship

Lappaconitine, a C19 diterpenoid alkaloid from Aconitum sinomontanum has been reported to possess analgesic and antiinflammatory properties in vivo and to inhibit neuronal activity in brain slices. In the present study the effect of lappaconitine has been compared with the effects of its main metabolite N-desacetyllappaconitine and the structurally related alkaloid lappaconidine. For comparison of drug effects population spikes and field excitatory postsynaptic potentials (EPSPs) evoked by stimulation of stratum radiatum or the alveus were studied in normal rat hippocampal slices and in slices treated with low Mg2+-medium. At concentrations of 3-100 microM, both lappaconitine and N-desacetyllappaconitine inhibited population spikes elicited by stratum radiatum and alvear stimulation as well as the field EPSP recorded in CA1 stratum radiatum. The drug-induced depression of field potential responses was increased with rising stimulus frequency, indicating an activity-dependent mode of action. The effect of N-desacetyllappaconitine on each parameter investigated was significantly stronger than the effect of lappaconitine. Despite the structural relationship, lappaconidine failed to affect neuronal excitability in concentration below 100 microM, and an increase in stimulus frequency did not potentiate its effect. Moreover, lappaconitine and N-desacetyllappaconitine suppressed epileptiform activity induced by bicuculline or by omission of Mg2+ from the bathing medium.

Topics: Aconitine; Action Potentials; Alkaloids; Animals; Electric Stimulation; Epilepsy; Evoked Potentials; Excitatory Postsynaptic Potentials; Hippocampus; In Vitro Techniques; Male; Rats; Rats, Wistar; Structure-Activity Relationship

1. Extracellular recording of the stimulus-evoked population spike in the CA1 region of rat hippocampal slices in vitro was performed in order to investigate whether lappaconitine affects neuronal excitability. Lappaconitine is a diterpene alkaloid of plants of the Aconitum genus and has analgesic properties. 2. The results reveal an inhibitory action of lappaconitine (10 microM) manifested in a slow attenuation of the orthodromic and antidromic population spike. 3. The lappaconitine-induced inhibitory action was activity-dependent, that is, it was potentiated when frequency of electrical stimulation was increased. In contrast, washout of the neurotoxin was accelerated when stimulation frequency was decreased. 4. The activity-dependent action of lappaconitine raised the question of whether the drug is effective in suppressing the aberrant neuronal activity that occurs during an epileptic seizure. The results obtained from experiments on epileptic hippocampal slices demonstrated a selective reduction of the later spikes in the bursts with less effect on normal neuronal activity. 5. These data support the conclusion that lappaconitine, in addition to its antinociceptive effect, also has antiepileptic potency due to its highly activity-dependent mode of action.

Topics: Aconitine; Animals; Electric Stimulation; Epilepsy; Evoked Potentials; Hippocampus; In Vitro Techniques; Male; Rats; Rats, Wistar; Time Factors

The effect of aconitine, an alkaloid neurotoxin known to bind at site 2 of the sodium channel, was investigated on epileptiform activity in hippocampal slices by use of extracellular recordings in CA1 pyramidal cell layer. Epileptiform activity was induced by bicuculline, picrotoxin, penicillin, pentylenetetrazol or by omission of magnesium from the bathing medium, respectively. In every case aconitine (0.1 and 1 microM) blocked the multiple population spikes representing the epileptiform activity. The onset of inhibition was shorter by use of an increased concentration of the epileptogenic drug. Epileptiform activity evoked by pentylenetetrazol and low magnesium was first increased by aconitine followed by a rapid inhibition, while the bicuculline-, picrotoxin-, and penicillin-induced epileptiform discharges were immediately abolished.

Topics: Aconitine; Action Potentials; Animals; Epilepsy; Hippocampus; In Vitro Techniques; Male; Rats; Rats, Wistar

The structurally related Aconitum alkaloids aconitine, lappaconitine, and 6-benzoylheteratisine inhibited the orthodromic and antidromic population spike in hippocampal CA1 area in a frequency-dependent manner. Aconitine (1 microM) completely suppressed epileptiform activity induced by omission of Mg2+ as well as normal neuronal activity, whereas lappaconitine (10 microM) and 6-benzoylheteratisine (10 microM) diminished epileptiform activity by sparing normal neuronal activity.

Topics: Aconitine; Action Potentials; Alkaloids; Animals; Electric Stimulation; Electrophysiology; Epilepsy; Hippocampus; In Vitro Techniques; Magnesium; Neural Inhibition; Neurons; Rats