aconitine and Seizures

We compared analgesic activities of individual alkaloids extracted from Baikal aconite (Aconitum baikalensis): napelline, hypaconitine, songorine, mesaconitine, 12-epinapelline N-oxide. The detected analgesic activity was comparable to that of sodium metamizole. The mechanisms of analgesia were different in diterpene alkaloids of different structure. The antinociceptive effect of atisine alkaloids (12-epinapelline N-oxide, songorine) was naloxonedependent and realized via opioid receptor modulation.

Topics: Acetic Acid; Aconitine; Aconitum; Alkaloids; Analgesics; Animals; Animals, Outbred Strains; Arthritis, Experimental; Dipyrone; Freund's Adjuvant; Injections, Intraperitoneal; Mice; Pain; Plant Extracts; Rats; Seizures; Vocalization, Animal

Aconitine effects on the hippocampal slice preparation have been well documented and include acute inhibitory and prolonged excitatory effects. To date, the effect of aconitine on neocortical activity has not been investigated. The aim of this study was to characterise the acute and long term effects of aconitine on cortical local field potential activity. Neocortical slices from juvenile Sprague-Dawley rats were perfused at room temperature with aconitine in normal artificial cerebrospinal fluid (aCSF) (n=10). Spontaneous local field potential activity was recorded from the somatosensory cortex. The calcium dependence of aconitine-induced activity was investigated using low-calcium aCSF (n=8). To isolate sodium and N-methyl-d-aspartate (NMDA) channel effects, phenytoin (n=4) and 2-amino-5-phosphono-pentanoic acid (APV) (n=6) were co-administered with aconitine, respectively. Aconitine consistently induced a dramatic increase in population "spike" activity after prolonged (89.5+/-36.6 min) application in normal aCSF. This activity surge was eliminated in low-calcium aCSF and when aconitine was co-administered with phenytoin and APV. The acute effects of aconitine application were variable and included an increase in the frequency of population spikes, appearance of oscillatory seizure-like activity and prolonged bursts of multiunit activity. No acute inhibitory effects were observed. Aconitine has acute and prolonged excitatory effects on neocortical activity. The latter is effected by calcium-dependent mechanisms, in keeping with known effects of aconitine on hippocampal slices. Both sodium and NMDA channels are involved in mediating the calcium-dependent aconitine effects.

Topics: 2-Amino-5-phosphonovalerate; Aconitine; Action Potentials; Animals; Calcium; Central Nervous System Agents; Cerebrospinal Fluid; Excitatory Amino Acid Antagonists; Female; In Vitro Techniques; Male; Neocortex; Phenytoin; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures; Sodium Channel Blockers; Sodium Channels; Somatosensory Cortex; Time Factors

A series of methyllycaconitine (1a, MLA) analogs was synthesized where the (S)-2-methylsuccinimidobenzoyl group in MLA was replaced with a (R)-2-methyl, 2,2-dimethyl-, 2,3-dimethyl, 2-phenyl-, and 2-cyclohexylsuccinimidobenzoyl (1b-f) group. The analogs 1b-f were evaluated for their inhibition of [(125)I]iodo-MLA binding at rat brain alpha7 nicotinic acetylcholine receptors (nAChR). In order to determine selectivity, MLA and the analogs 1b-f were evaluated for inhibition of binding to rat brain alpha,beta nAChR using [(3)H]epibatidine. At the alpha7 nAChR, MLA showed a K(i) value of 0.87 nM, analogs 1b-e possessed K(i) values of 1.67-2.16 nM, and 1f showed a K(i) value of 26.8 nM. Surprisingly, the analog 1e containing the large phenyl substituent (K(i)=1.67 nM) possessed the highest affinity. None of the compounds possessed appreciable affinity for alpha,beta nAChRs. MLA antagonized nicotine-induced seizures with an AD(50)=2 mg/kg. None of the MLA analogs were as potent as MLA in this assay. MLA and all of the MLA analogs, with the exception of 1b, antagonized nicotine's antinociceptive effects in the tail-flick assay. Compound 1c (K(i)=1.78 nM at alpha7 nAChR) with an AD(50) value of 1.8 mg/kg was 6.7 times more potent than MLA (AD(50)=12 mg/kg) in antagonizing nicotine's antinociceptive effects but was 5-fold less potent than MLA in blocking nicotine-induced seizures. Since MLA has been reported to show neuroprotection against beta-amyloid(1-42), these new analogs which have high alpha7 nAChR affinity and good selectivity relative to alpha,beta nAChRs will be useful biological tools for studying the effects of alpha7 nAChR antagonist and neuroprotection.

Topics: Aconitine; Analgesics; Animals; Anticonvulsants; Binding, Competitive; Brain; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Data Interpretation, Statistical; In Vitro Techniques; Indicators and Reagents; Male; Mice; Mice, Inbred ICR; Nicotine; Nicotinic Agonists; Pain Measurement; Pyridines; Rats; Reaction Time; Receptors, Nicotinic; Seizures

Nicotinic acetylcholine receptors are important for maintaining optimal memory performance. In order to more fully characterize the involvement of nicotinic systems in memory, the contributions of nicotinic acetylcholine receptor subtypes were investigated. This study targeted the alpha 7 and alpha 4 beta 2 nicotinic receptors in the ventral hippocampus, an area known to be important for spatial working memory. Antagonists of alpha 7 and alpha 4 beta 2 receptors were locally infused into the ventral hippocampus of rats and the effects on memory were examined with the radial-arm maze. The subtype-specific competitive antagonists infused into separate groups of rats were methyllycaconitine citrate (an alpha 7 antagonist) and dihydro-beta-erythroidine hydrobromide (an alpha 4 beta 2 antagonist). Their effects on radial-arm maze performance were contrasted with the non-specific competitive antagonist, D-tubocurarine chloride. Significant deficits in radial-arm maze choice accuracy performance were found at 78.7 micrograms/side for methyllycaconitine and at 106.9 micrograms/side for dihydro-beta-erythroidine. Increased response latency was also seen at these doses. Tubocurarine induced seizures at doses previously reported to have no effect. Wet dog shakes were seen in most rats at 0.1 microgram/side with tubocurarine, 26.3 micrograms/side with methyllycaconitine and 106.9 micrograms/side with dihydro-beta-erythroidine. This study suggests that both alpha 7 and alpha 4 beta 2 nicotinic acetylcholine receptor subtypes are involved in working memory formation and that the hippocampus is a critical site for nicotinic cholinergic involvement in memory function, though the high doses of antagonists needed to produce the memory impairment may have had less than completely specific effects.

Topics: Aconitine; Animals; Cholinergic Antagonists; Dihydro-beta-Erythroidine; Female; Hippocampus; Maze Learning; Memory, Short-Term; Neuromuscular Blocking Agents; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Seizures; Space Perception; Tubocurarine

CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylic acid) was found to be a potent, stereospecific inhibitor of N-methyl-D-aspartate (NMDA)-evoked, but not KCl-evoked, [3H] acetylcholine release from slices of the rat striatum. The concentration-response curve to NMDA was shifted to the right by CGS 19755 (pA2 = 5.94), suggesting a competitive interaction with NMDA-type receptors. CGS 19755 inhibited the binding of [3H]-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid to NMDA-type receptors with an IC50 of 50 nM, making it the most potent NMDA-type receptor antagonist reported to date. CGS 19755 failed to interact with 23 other receptor types as assessed by receptor binding, including the quisqualate- and kainate-type excitatory amino acid receptors. In crude P2 fractions, no evidence was obtained to suggest that CGS 19755 is taken up by an active transport system. Furthermore, CGS 19755 failed to affect the uptake of L-[3H]glutamate, or to interact with aconitine-induced inhibition of L-[3H]glutamate uptake, the latter finding suggesting a lack of membrane-stabilizing or local anesthetic properties. CGS 19755 selectively antagonized the excitatory effect of iontophoretically applied NMDA in the red nucleus of the rat without affecting the excitatory effects of quisqualate. CGS 19755 blocked the harmaline-induced increase in cerebellar cyclic GMP levels at a dose of 4 mg/kg i.p. with a duration of action exceeding 2 hr. CGS 19755 inhibited convulsions elicited by maximal electroshock in rat (ED50 = 3.8 mg/kg i.p. 1 hr after administration) and in mouse (ED50 = 2.0 mg/kg i.p. 0.5 hr after administration). Likewise, convulsions elicited by picrotoxin were inhibited by CGS 19755, whereas the compound was relatively weak in protecting against convulsions elicited by pentylenetetrazole or strychnine. CGS 19755 produced retention performance deficits in a dark avoidance task. However, CGS 19755 did not show a unique propensity for learning and memory disruption compared to other anticonvulsants.

Topics: Acetylcholine; Aconitine; Animals; Anticonvulsants; Aspartic Acid; Avoidance Learning; Binding, Competitive; Darkness; Glutamates; Glutamic Acid; Male; N-Methylaspartate; Pentylenetetrazole; Picrotoxin; Pipecolic Acids; Piperidines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Structure-Activity Relationship; Tetrodotoxin