Pentylenetetrazole-induced convulsions

This laboratory has utilized two approaches to define further the anticonvulsant properties of PCP. One approach involved a relatively simple convulsant model, pentylenetetrazol-induced convulsions. In this model, the administration of ketamine alone, or in combination with several known anticonvulsants, was tested. Ketamine, as a structural analog of PCP, shares many of the pharmacological properties associated with PCP. The second approach involved a more complex model, hippocampal-kindled seizures. 

Inhibitory effect of a mixture of herbal drugs (TJ-960, SK) on pentylenetetrazol-induced convulsion in EL mice. Epilepsy Res 1988 2(5) 337-339. 

Phenobarbitone raises the threshold of electro-shock seizures and modifies maximal electro-shock seizures and abolish the tonic phase thus useful in the treatment of grandmal epilepsy. The threshold of pentylenetetrazol induced convulsion is slightly raised and has less usefulness in the treatment of petitmal epilepsy. 

It is a new anticonvulsant drug and is a structural analogue of GABA. It increases the release of GABA by unknown mechanism. It modifies maximal electroshock as well as inhibits pentylenetetrazol induced convulsions. 

Diazepam (2b) was completely effective against penicillin-induced convulsions in rabbits.26 The hydroxyamino compounds 2g were generally less active as anticonvulsants than their nitro analogs in mice.27 Compound 6 was ca. as potent as diazepam (2b) against metrazole included convulsions28 in mice and the pyrrolobenzodiazepines such as Z were effective against pentylenetetrazole induced convulsions.29... 

Several piperazinoimines with anticonvulsant activity such as 3380 in light sensitive baboons, 3481 and 358" against tetrazoles, and 36 against electroshock, were reported. Structurally related imines such as 37 exhibited inhibition of pentylenetetrazole induced convulsions.84... 

The effect of substitution on the activity of some thirty variously substituted 4-pregnen-3,20-diones (XIX) and 53-pregnanediones (XX) as antagonists of pentylenetetrazole-induced convulsions in the mouse showed... 

Inhalation of the essential oil of a Chinese antiepileptic storax pill (SuHeXiang Wan) delayed the onset of pentylenetetrazole-induced convulsions in mice. This is an indication of a CNS mechanism involving GABAergic neuromodulation, which is supported by the prolonged pentobarbital-induced sleeping time and inhibition of brain lipid peroxidation observed in the same study. ... 

A benzodiazepinone CT 510 ( ) was considerably less protective than chlordiazepoxide versus electroshock-induced convulsions in mice. nie benzodiazeplndiones were ineffective as antagonists of pentylenetetrazol-induced convulsions in rats. In humans, ORF 8063 (2 ) elicited electrophysiological and behavioral changes similar to those produced by diazepam. The pyrazolodiazepine Cl 683 (25) had clinical anti-anxiety activity. In rats, it counteracted conflict-induced depression and antagonized pentylenetetrazol-induced convulsions. ... 

Research in rodents has provided evidence of solvent withdrawal. Continuous exposure to toluene for 4 days and subsequent cessation produced an increase in handling-induced convulsions for at least 2 hours after cessation (Wiley et al. 2003). A similar pattern of trichloroethane administration to rodents produced pronounced withdrawal, which was worsened by the administration of the proconvulsant drug pentylenetetrazole and attenuated by reexposure to 2,000 ppm of toluene or the administration of alcohol, pentobarbital, or midazolam (Evans and Balster 1993). 

The anticonvulsant activity of diazepam, assessed by its protection against pentylenetetrazole-induced tonic convulsions, was strongly reduced in ai-(HIOIR) mice compared to wild-type animals (Rudolph et al. 1999). Sodium phenobarbital remained fully effective as anticonvulsant in ai(HlOlR) mice. Thus, the anticonvulsant activity of benzodiazepines is partially but not fuUy mediated by ai receptors. The anticonvulsant action of zolpidem is exclusively mediated by ai receptors, since its anticonvulsant action is completely absent in ai(HlOlR) mice (Crestani et al. 2000). 

Bilobalide, a main constituent of the terpene fraction of the EGb, possesses anticonvulsant activity against convulsions induced by pentylenetetrazol, isoniazid, 4-0-methylpyridoxine, and electroshock. Reduced durations of convulsions and prolonged onset time of convulsions induced by chemical convulsants and electroshock were observed in mice treated orally with bilobalide (30 mg/kg/day, for 4 days). However, bilobalide has no protective effect against bicuculline- and strychnine-induced convulsions [99,100]. 

In addition to locomotor activity, delta opioid agonists produce convulsions in mice [41,43], rats [34,35], and monkeys [44 46], In the past, chemical-induced convulsions induced by camphor or pentylenetetrazol (Metrazol) were used as treatments for depression today, however, ECT is the only convulsant therapy used because the treatment-induced effects are less unpleasant than those produced by chemical convulsants [47]. ECS was demonstrated to have antidepressant-like effects in the forced swim test in rats [3], and ECT is a very effective treatment for depression in humans. Based on these observations, it was proposed that delta opioid agonists produce antidepressant-like effects tough a convulsive- or electroconvulsive shock (ECS)-like mechanism of action [41]. 

Inhibition of pentylenetetrazol-induced seizures is used as an indication of hypnotic, tranquilizer, or anticonvulsive activity. Mice or rats are given the test drug, and after 30 min a dose of pentylenetetrazol, which will cause 50% of the animals to convulse (CD50), is administered intramuscularly. A drug that increases the CD 50 may have activity of the type mentioned above. 

The hydantoins have a 5-membered ring structure containing two nitrogens in an ureide configuration (Fig. 20.4) and were tested as antiepileptics by Merritt and Putnam (23,24). These drugs suppressed electrically induced convulsions in animals but were ineffective against convulsions induced by pentylenetetrazole, picrotoxin, or bicuculline. The structures for the clinically available hydantoins are listed in Figure 20.5. 

In mice, PCP is effective in antagonizing electroshock- or pentylenetetrazol (PTZ)-induced tonic extensor convulsions and audiogenic seizures (Chen et al. 1959 Chen and Bohner 1961). In dogs,... 

Nonphysiological compounds have also been described as influencing the overall metabolism of sialic acid. Administration of ethanol (2 g/kg) to rats significantly decreases the sialic acid content of brain tissue.246 Convulsions induced by pentylenetetrazole (6,7,8,9-tetrahy-dro-5/f-tetrazoloazepine) are accompanied by a diminution in the rate of biosynthesis of polysialogangliosicles GT, and GQn, in rat brain.227 Such ManNAc analogs as 2-acetamido-l,3,4,6-tetra-0-acetyl-2-deoxy-D-mannopyranose or the 2-(trifluoroacetamido) derivative lead to a marked lowering of the incorporation of radioactivity from labelled ManNAc into glycoconjugate sialic acids of murine, erythroleukemia (Friend) cells.247... 

Whereas the genetic and kindling models have been widely used to investigate possible neurotransmitter defects that cause different types of epilepsy, rodent models in which seizures are induced by electroshock, or by convulsant drugs such as pentylenetetrazol (also called pentetrazol, leptazol), picrotoxin or bicuculline, are mainly used in screening procedures to identify potential anticonvulsants. 

Many studies have shown that kava extract and the kavalactones present in it have anticonvulsant effects in mice with experimentally induced tonic-extensor convulsions, produced by maximal electroshock, strychnine, pentylenetetrazol, bemegride, and picrotoxin (Klohs 1959 Meyer, 1964 Kretzschmar 1969 Kretzschmar and Meyer, 1969) Methysticin and dihydromethysticin proved to be the most effective in this respect. As kavalactones are poorly absorbed in the gut, the oral administration of unsaturated kavalactones required a dosage that was ten-fold higher than that required by intravenous administration. Mixtures of yangonin or desmethoxyyangonin with... 

The preclinical investigation of a newly proposed antiepileptic in experimental animals typically involves the use of electrical stimulation (electroshock) to induce maximal generalized seizures (MES), and the systemic administration of convulsant drugs (e.g., pentylenetetrazole) to elicit minimal seizures. The use of animals genetically susceptible to seizures caused by light or specific noise is also prevalent [175]. The efficacy of the antiepileptic is then tested against the seizures induced. (For leading references see [175].)... 

The barbiturates are substituted pyrimidine derivatives with an ureide configuration (Fig. 20.4). They are lipophilic weak acids (pKa 7-8) that are weii distributed into brain (see Appendix A for the respective pKa values). Although many barbiturates dispiay sedative-hypnotic activity (see Chapter 19), oniy a few have antiseizure properties. Paradoxically, many barbiturates cause convulsions at larger doses. The barbiturates clinically useful as AEDs are phenobarbital, mephobarbital, and primidone (Fig. 20.8). In laboratory animals, phenobarbital is effective by several tests in nontoxic doses. It is active against electrically induced seizures (MES), and it elevates the threshold for pentylenetetrazole stimulation. The mechanism of antiseizure action for the barbiturates... 

Experimental models for seizures can be broadly divided into two groups models for acute seizures and for chronic focal epilepsy. The acute models are responsible for much of our understanding of the mechanisms of epilepsy. They involve the administration of drugs such as picrotoxin, bicuculline, pentylenetetrazol (PTZ), and 4-aminopyridine to previously healthy animals. Since they are models of convulsions rather than epilepsy, they relate to seizures induced by drugs or by metabolic derangements in humans. 

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