Strychnine Convulsions Research Articles

EFFECT OF GAMMA-AMINOBUTYRIC ACID UPON STRYCHNINE CONVULSIONS.

Journal Article Effect of γ-aminobutyric acid upon strychnine convulsions Get access Heinz Sorer, Heinz Sorer Hazleton Laboratories, Inc. P.O. Box 30 Falls Church, Virginia, USA Search for other works by this author on: Oxford Academic Google Scholar Olavi Pylkkö Olavi Pylkkö Hazleton Laboratories, Inc. P.O. Box 30 Falls Church, Virginia, USA Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 17, Issue 2, February 1965, Pages 122–123, https://doi.org/10.1111/j.2042-7158.1965.tb07627.x Published: 12 April 2011 Article history Received: 22 December 1964 Published: 12 April 2011

Anticonvulsant activity of bioflavonoid gossypin

The anticonvulsant activity of gossypin was investigated by studying the effects on seizures induced by pentelentetrazole, strychnine and maximal electroshock convulsive methods in mice. Gossypin (10 and 20 mg/kg) significantly reduced the duration of convulsion in tonic seizure induced by pentelenetetrazole (95 mg/kg, intraperitoneally). Gossypin (20 mg/kg p.o) significantly reduced the tonic extensor convulsion induced by strychnine and maximum electroshock-induced convulsions. The data obtained suggest that gossypin have anticonvulsant property and may probably be affecting both GABA aminergic and glycine inhibitory mechanism.

Systemically administered glycine protects against strychnine convulsions, but not the behavioural effects of high pressure, in mice.

1. The effects of intraperitoneal administration of glycine were studied on the behavioural effects of raised ambient pressure in mice, compared with the effects of such administration on the actions of chemical convulsants. 2. Glycine did not alter the onset pressures for the occurrence of tremor, myoclonic jerks or clonic convulsions, when the ambient pressure was raised using helium. 3. Glycine showed a protective action against the convulsant effects of strychnine. 4. No protective action of glycine was found against the convulsant actions of pentylenetetrazol or bicuculline. 5. It is suggested that the results provide evidence that the high pressure neurological syndrome and strychnine convulsions have different neurophysiological origins.

Investigations into the origin of the high pressure neurological syndrome: the interaction between pressure, strychnine and 1,2-propandiols in the mouse.

1. The effects of a variety of structural isomers of the centrally acting muscle relaxant mephenesin on the high pressure neurological syndrome have been investigated. Threshold pressures for the onset of the behavioural signs, tremors and convulsions, were established. The effects of these compounds on the response to pressure were also compared with their ability to antagonize the convulsive action of strychnine. 2. The dose-response relationships for strychnine and picrotoxin were investigated at fixed pressures. Additionally, the dose-response relationship of strychnine, in the presence of mephenesin, at pressure was investigated. 3. All the isomers of mephenesin protected against the effects of both pressure and strychnine. The relative potency was found to be identical with respect to both. Mephenesin was clearly the most effective; it raised the threshold pressure for tremors by 2.5 times, that for convulsions elicited by pressure by 1.5 and the ED50 for strychnine convulsions by 1.6 times. Strychnine was found to be strictly additive with pressure whereas picrotoxin exhibited gross deviations from additivity. Mephenesin ameliorated the combined effects of pressure and strychnine equally. 4. The marked dependence on structure of the anticonvulsant activity of the mephenesin isomers can be interpreted as evidence that pressure acts not by some general perturbation of the membranes of excitable cells but rather via some specific interaction. The finding that strychnine and pressure are strictly additive supports the idea of specificity and also indicates that they may share a common mechanism in the production of convulsions. By analogy with the established mechanism of action of strychnine, it is suggested that the hyperexcitability associated with pressure might arise from an action on glycine-mediated inhibitory processes.

Anticonvulsant profile of the dihydropyridine calcium channel antagonists, nitredipine and nimodipine

The effects of the dihydropyridine calcium channel antagonists, nitredipine and nimodipine, on convulsions produced by different mechanisms have been studied in rats. Nitrendine and nimodipine significantly raised the thresholds to pentyleneterazzol for up to six hours after their injection. The calcium channel agonist, BAY K 8644, lowered the convulsion threshold to pentylenetetrazol and antagonised the effects of nitrendipine. In contrast, the severity of seizures produced by N-methyl-dl-aspartate (NMA) was increased by nitrendipine. BAY K 8644 also slightly increased the effects of NMA. Nimodipine and nitredipine caused small, but significant, increases in the threshold pressures for the convulsions caused by raising the atmospheric pressure with helium gas. The compounds had no effect on strychnine convulsions. The conclusion is that the calcium channel antagonists are anticonvulsant against only certain types of convulsions, such as pentylenetetrazol and high pressure (and ethanol withdrawal, reported previously). Others may be increased, such as NMA seizures, or unaffected, such as strychnine-induced convulsions.

Evidence for an involvement of GABA in the mediation of the cerebellar cGMP decrease and the anticonvulsant action of diazepam

Subcutaneous injections of isoniazid or picrotoxin increase the cerebellar content of 3',5'-cyclic guanosine monophosphate (cGMP) without changing the 3',5'-cyclic adenosine monophosphate cAMP. This increase was dose dependent and the threshold for the cGMP increase was lower than that for convulsions. In cerebellum the increase of cGMP content elicited by isoniazid but not that caused by picrotoxin was paralleled by a decrease of GABA content. Diazepam doses starting from 1.74 mumol/kg intraperitoneally produced a dose dependent decrease of cerebellar cGMP concentration without changing cAMP or GABA content. Smaller doses of diazepam (0.5 mumol/kg i.p.)failed to decrease the basal cerebellar content of cGMP. However, this dose of diazepam antagonized the increase of cGMP produced by isoniazid but not that produced by picrotoxin. Higher doses of diazepam were necessary to block the increase of cerebellar cGMP elicited by picrotoxin. Low doses of diazepam (0.14 mumol/kg) antagonized the convulsions in 50% of the rats injected with 3.3 mmol/kg of isoniazid. The doses of diazepam required to block picrotoxin, pentylenetetrazol or strychnine convulsions were 7, 25 and 40 times higher than those required to block isoniazid convulsions, respectively. Desmethyldiazepam, chloridiazepoxide, oxazepam were also several times more potent in antagonizing isoniazid than picrotoxin, pentylenetetrazol, or strychnine convulsions. In contrast, barbiturates were equipotent against all the convulsants studied. These experiments suggest that diazepam may act in the CNS either by altering the disposition of endogenous GABA or by mimicking the action of GABA at specific synaptic receptors.

1-Hydroxy-3-amino-pyrrolidone-2(HA-966): a new GABA-like compound, with potential use in extrapyramidal diseases.

1. The drug HA-966 (1-hydroxy-3-amino-pyrrolidone-2), which chemically resembles the cyclic form of GABA, has been studied for neuro-pharmacological properties and for effects on the catecholamine content of the corpus striatum.2. The acute effects on spontaneous behaviour of rodents included flaccid catalepsy and reversible tranquillization in doses which were 5% or less of the lethal dose. Long lasting depression of the CNS, followed by complete recovery, was produced in the cat and the dog. In the monkey HA-966 caused periodical sleeping episodes.3. The exploratory behaviour and the amphetamine-induced motor activity in mice were blocked by HA-966. The toxicity of amphetamine in aggregated mice was only moderately reduced, suggesting that HA-966 differs from neuroleptics.4. Tremors induced by chemical agents (nicotine, zinc and tremorine) were markedly inhibited by HA-966. The muscarinic effects of tremorine were not reduced by HA-966, indicating a selective central antitremor effect.5. HA-966 elevated the threshold to strychnine convulsions and abolished the ipsilateral flexor reflex, while not having motor endplate blocking properties. It is suggested that HA-966 depresses central internuncial neurones.6. In rats and rabbits HA-966 produced synchronous EEG and inhibited the sensory arousal in doses not causing sedation. In the monkey the drug caused a periodical dissociation between ;sleep-EEG' and behaviour.7. In rat brain, HA-966 selectively elevated the dopamine content in the corpus striatum, while no changes in noradrenaline and 5-hydroxytryptamine contents could be demonstrated. The effect was still present when dopa synthesis was inhibited with alpha-methyl-p-tyrosine.8. Several effects of intravenously administered HA-966 became manifest after an appreciable delay and in hepatectomized mice the effects were much reduced. It is postulated that HA-966 is converted to a pharmacologically active metabolite.9. The results are discussed in the light of current views on drug therapy in extrapyramidal conditions and a GABA-related hypothesis as to the mode of action of HA-966 is presented.

Propylene glycol as a drug solvent in pharmacologic studies

Pharmacologic activity of propylene glycol (PG) was evaluated, using several procedures commonly employed in drug screening. Acute pretreatment of mice with 2.08 g/kg of PG (equivalent to administration of 0.01 ml/g of a 20% solution) produced a significant elevation in initial clonic seizure threshold to iv infusion of pentylenetetrazol, not apparent with this dose when a single CD99 dose of convulsant was used. Parallel results were obtained at higher doses of PG vs. strychnine convulsions. Potentiation of hexobarbital sleeping time was observed at doses of PG below the TD50 of 5.77 g/kg. Higher doses decreased spontaneous motor activity. Subchronic administration of PG did not alter hexobarbital sleeping time subsequently determined, but did diminish diphenylhydantoin anti-MES (maximal electroshock seizure) activity. Thus, at cosolvent concentrations which might be employed in animal experiments, PG exhibits weak but significant CNS depressant activity as well as strychnine, pentylenetetrazol, tremorine, and oxotremorine antagonist action. There-fore, use of PG as an “inert” cosolvent in pharmacologic studies cannot be recommended when the ip route is employed.

Spinal shock and strychnine convulsions in intact and spinal amphibians and reptiles

1. 1. Spinal shock was measured in amphibians and reptiles and compared with the time to convulsions : strychnine dose response curves of intact and spinal animals. 2. 2. These dose response curves were interpreted in terms of relative amounts of supraspinal inhibition and facilitation of spinal motor activity. 3. 3. The degree of encephalization could then be assigned as due predominantly to supraspinal facilitation, supraspinal inhibition involving inhibition of spinal inhibitory interneurons or supraspinal inhibition of hyperactive spinal reflexes.

Some observations on the experimental production of acute neuroaxonal and synaptosomal dystrophy.

Fluorocitrate, and fluoroacetate block the Krebs cycle in neural tissue, cause convulsive seizures, and produce interesting neuropathological lesions, notably a swelling of neuronal and glial mitochondria and neuroaxonal and synaptosomal dystrophy. Axonal ballooning is a consequence of convulsive seizures coupled with inhibition of the Krebs cycle. Mg++ suppresses the convulsive seizures produced by fluorocitrate and prevents axonal ballooning. Strychnine convulsions do not cause neuroaxonal dystrophy. However, Mg++ does not prevent mitochondrial swelling or axonal dystrophy. Fluorouracil produces similar neuropathological lesions, apparently because it is degraded partly to fluoroacetate. Numerous agents with diverse biological actions also produce dystrophic changes in axons and nerve endings. These include: cyanide, arsenious oxide, ouabain, puromycin, parabenzoquinone, malonate, succinate, 3-acetylpyridine, desoxypyridoxine, methionine sulfoximine, antimycin A, iminodiproprionitrile, plasmocide, pyrathiamine, cupric sulfate, Trypan blue. Electron microscopic examination showed that the following agents also caused mitochondrial swelling: cyanide, iminodiproprionitrile, plasmocide, 3-acetylpyridine, methione sulfoximine, puromycin and Trypan blue. It is proposed that a swelling of perikaryal mitochondria is the common basis for the increased disgorgement of lysosomes, mitochondria and other cytoplasmic constituents occurring in neuroaxonal and synaptosomal dystrophy.

Susceptibility to strychnine convulsions in maturing rats.

Chez le rat ce n'est pas la permeabilite du systeme nerveux central, mais le metabolisme du foie qui joue le rOle principal dans la susceptibilite a la strychnine inoculee par voie intraperitoneale.

Substance P and antistrychnine activity.

The administration to mice of crude substance P prepared from bovine brain inhibited strychnine convulsions. After alumina column chromatography, this antistrychnine activity was observed mainly in the fraction which was not adsorbed, while those fractions containing substance P or its satellite polypeptides (Zetler, 1963) were found ineffective. The regional distribution of such an antistrychnine activity in bovine brain was also found to be different from that of substance P. Experiments in which inactivation with proteases and dialysis were investigated suggested that the component or components bearing the antistrychine activity were of a polypeptide nature.

Carbamazepine for epilepsy

Carbamazepine (Tegretol - Geigy) gives considerable relief from pain in trigeminal neuralgia in the majority of patients.1 Although it was initially introduced as an anticonvulsant, it is only recently that the manufacturers have advocated its use, either alone or in addition to other anticonvulsants, in the treatment of ‘grand mal’ and temporal lobe epilepsy. The drug is an iminodibenzyl derivative and is chemically related to the antidepressant imipramine. It raises the threshold for electrical and strychnine convulsions in animals.2

An electron microscopic study of the effects of tetanus toxin on motoneurons of the rat spinal cord

In this electron microscopic study tetanus toxin was chosen as the convulsive agent for determining whether hyperactivity resulted in discernible morphological changes in motoneurons of the spinal cord. Alterations in the motoneurons were evident 19 hours after 10,000 LD50, 32 hours after 1000 LD50 and 51 hours after 100 LD50 of tetanus toxin. These changes were manifested as an increase in the numbers of ribosomes and, after a 100 LD50 injection of toxin, in alterations in the amount and form of the endoplasmic reticulum which were comparable to those noted in a previous study following strychnine convulsions. No striking morphological differences were observed after tetanus convulsions created by an injection of either 50 or 25 LD50 of toxin. These observations offer some morphological basis for the postulate that strychnine and tetanus toxin may operate in a similar manner in the central nervous system.

Seizure Activity Due to Intravenous Strychnine

The controversy concerning the site of action of strychnine as well as its mode of action has yet to be resolved. In 1933, Dusser de Barenne 1 reviewed this field and presented his own experiments pointing to a primary neuronal effect of strychnine. With the increased resolution afforded by electron microscopy, it is now feasible to examine the nervous system during strychnine convulsions in an attempt to demonstrate any accompanying morphologic alterations. Materials and Methods Rabbits weighing 1.5 to 2.0 kg were etherized and a craniotomy and tracheotomy performed. A small polyethylene tube was inserted through the femoral vein into the vena cava. Animals then were allowed to blow off the ether and under 3 mg per kilogram of gallamine triethiodide (Flaxedil) were maintained by artificial respiration. One pair of calomel electrodes recorded transcortically from the frontal granular cortex and another between the surface of the cerebellar vermis and its

Anticonvulsant action of some new skeletal muscle relaxants on strychnine convulsions in mice.

Anticonvulsant action of some new skeletal muscle relaxants on strychnine convulsions in mice.

Central effects produced by injection of 48/80 into the cerebral ventricles of mice.

Injections of 20 to 30 mug. of 48/80 into the cerebral ventricular spaces of mice produced a condition of motor excitement termed "delirium ambulatorium." This condition was aggravated by previous intraperitoneal injection of tranquillizers, atropine, and promethazine, not affected by previous injection of mepyramine and abolished by a previous injection of pentobarbitone. When an intraperitoneal injection of strychnine was followed by an intraventricular injection of 48/80, the strychnine convulsions became more violent, but the pattern of delirium ambulatorium was not produced.

Some Anticonvulsant, Skeletal Muscle Relaxing, and Toxic Properties of a Series of Substituted Cyclohexanones

A series of substituted cyclohexanones was screened for anticonvulsant, skeletal muscle relaxing and toxic properties in mice, and for those compounds that were selected for further study, ED 50 , PD 50 , and LD 50 values were determined. Although the series in general, possesses low water solubility, individual members are rapidly absorbed following intraperitoneal injection of suspensions of the compounds. 2-( o -Methylphenyl)cyclohexanone was one of the most active compounds in the series, both as an anticonvulsant and as a muscle relaxant. Because its action resembled that of mephenesin, a comparison of the two compounds was made. The effect of the ortho-isomer on strychnine convulsions was also studied.

Clinical evaluation of the effect of mephenesin on anxiety.

The drug which is now known officially as Mephenesin (“Myanesin,” “Tolserol”) was introduced by Berger and Bradley (1946), who showed that it antagonizes strychnine convulsions, counteracts pre-narcotic excitement, and increases the duration of barbiturate anaesthesia. Small doses depress the reflex excitability of the spinal cord, and larger doses have an ascending depressant action on the central nervous system. When Berger (1947) found that doses with little effect on voluntary power restored deranged reciprocal innervation to normal, he suggested that mephenesin might be useful in spastic and hypertonic conditions.

Observations on the effect of myanesin (3 orthotoloxy-1,2 propaneidol or tolserol) on epileptic thresholds and some psychiatric conditions.

Myanesin was first investigated in animal experiments by Berger and Bradley (1946) and found to have a curare-like muscle relaxing effect. This they thought was mainly due to action on the spinal cord, because strychnine convulsions were inhibited by the drug. Smaller doses were more effective for this than for the reduction of Metrazol convulsions. Hunter and Waterfall (1948) reported an immediate disappearance of epileptic seizures in man after intravenous administration of.4-1 gm. of Myanesin. Gammon and Churchill (1948) found that the spike and dome pattern of the E.E.G. in cases of petit mal disappears following Myanesin, whereas E.E.G. alterations associated with grand mal seizures were uninfluenced. Higher doses might, however, abolish these changes. Geer (1949) used the drug (in doses up to 3 1/2 gm.) in conjunction with electric convulsive therapy (E.C.T.) for mental disorders and found it of no demonstrable value because it apparently tended to make convulsions more severe, although it slightly increased the voltage time stimulus necessary to produce a convulsion. Unna and Kaplan (1949) examined the anticonvulsive properties of Myanesin in mice. Metrazol seizures of mice treated with Myanesin were seen to be at least as severe as controls and often prolonged. The tonic extensor phase was, however, eliminated. The death in Myanesin-treated animals was delayed as compared with controls. Electroshock also caused a seizure in 89 per cent. of the Myanesin treated mice, but no deaths occurred, whereas controls without Myanesin had a mortality of 33 per cent. Here, again, Myanesin appeared to abolish the tonic phase of the fit and only more violent clonic convulsions occurred. Schlau and Unna (1949) reported that the pattern and duration of seizures in E.C.T. in man were not changed following 2 gm. of Myanesin four times daily by mouth. They did, however, observe a shortening of the period of apnoea following the convulsion.