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PubMed1991

Effects of carbamazepine on bicuculline- and pentylenetetrazol-induced seizures in developing rats.

The anticonvulsant effect of carbamazepine (CBZ) was examined in 10-, 18- and 25-day-old Wistar albino rats into which bicuculline or pentylenetetrazol had been systemically injected to induce generalized epileptic manifestations typical for the specific age of the animals. The results showed that: a) in developing rats, CBZ appears to be more effective in the pentylenetetrazol than the bicuculline model of epilepsy; b) in both models of epilepsy the efficacy of CBZ increases with the age of the animals; and c) among the various epileptic manifestations, the tonic phase is the most sensitive to the anticonvulsant effect of CBZ. These conclusions are correlated with the different levels of cerebral maturation of the animals, and are discussed with reference to the mechanisms of action of CBZ and bicuculline or pentylenetetrazol.

Animals↗

PubMed1997

The leaf essential oil of Psidium guyanensis offers protection against pentylenetetrazole-induced seizures.

The essential oil obtained from the leaves of Psidium guyanensis Pers. (Myrtaceae) was studied against lethal seizures induced by intraperitoneal injection of pentylenetetrazole (80 mg/kg), picroptoxin (6 mg/kg), and strychnine (2 mg/kg) in mice. At oral doses of 100, 200, and 400 mg/kg, the essential oil attenuated the severity of pentylenetetrazole-induced seizures and offered a dose-related protection but it was found to be ineffective against convulsions induced by picrotoxin and strychnine. The blockade of its protective effect on pentylenetetrazole lethal seizures by caffeine (10 and 50 mg/kg, i.p.) suggests a probable participation of endogenous adenosine in its mechanism. Furthermore, a peripheral mechanism also appears to be involved as the essential oil (5-20 micrograms/ml) was able to block selectively the acetylcholine (1.65 x 10(-6) M) induced contractions but not those evoked by high potassium (80 mM) or caffeine (2 x 10(-3) M) on isolated toad rectus abdominis muscle.

Animals↗

PubMed1979

Inosine, an endogenous ligand of the brain benzodiazepine receptor, antagonizes pentylenetetrazole-evoked seizures.

Partially purified extracts of bovine brain were previously found to inhibit competitively the binding of [3H]-diazepam to rat brain synaptosomal membranes. The purines inosine and hypoxanthine were subsequently identified as the compounds responsible for this inhibitory activity. Intracerebroventricular administration of inosine to mice of the C3H/HEN and NIH general purpose strains caused a dose- and time-dependent increase in the latency to clonicotonic seizures produced by intraperitoneal administration of the convulsant pentylenetetrazole. Intracerebroventricular administration of equimolar doses of 2'-deoxyinosine, which is more potent than inosine in inhibiting the binding of [3H]diazepam in vitro, significantly increased pentylenetetrazole-evoked seizure latency. In contrast, both 7-methylinosine and thymidine were ineffective in inhibiting the in vitro binding of [3H]diazepam and increasing the latency to pentylenetetrazole-induced seizures in vivo. These results suggest that endogenously occurring purines such as inosine exhibit diazepam like effects when administered intracerebroventricularly, and these effects may be related to the interaction of inosine and related compounds with benzodiazepine receptors in the central nervous system.

Animals↗

PubMedDate not supplied

Effects of antiepileptic drugs on pentylenetetrazole-induced epileptiform activity in the in vitro hippocampus.

We studied the effects of four antiepileptic drugs on pentylenetetrazole-induced burst discharges in the CA3 region of the in vitro hippocampus. Diazepam and carbamazepine abolished the bursting activity in a gradual and dose-dependent manner. Phenobarbital only decreased the burst frequency. Valproic acid was either ineffective or actually caused an increase in both burst frequency and amplitude. The findings in this model were compared with results obtained by other investigators in a penicillin-induced model of epileptiform activity in the hippocampal slice. Diazepam had a similar effect on both pentylenetetrazole- and penicillin-induced burst discharges, but phenobarbital was ineffective in the pentylenetetrazole model, indicating that these chemically induced hippocampal epileptiform activities may be differentially sensitive to antiepileptic drugs.

Animals↗

PubMedDate not supplied

Pentylenetetrazol-induced convulsion and effect of anticonvulsants in mutant inbred strain El mice.

The El mouse is an inbred strain developed from ddY mice and is very susceptible to seizure. In El mice, convulsions could be induced by 18 mg/kg of pentylenetetrazol, which is an inert dose in ddY mice. The features of the convulsions were the same as those induced by the tossing-up procedure, a common method to evoke convulsions in El mice. Phenytoin, phenobarbital, valproate sodium, and ethosuximide clearly inhibited pentylenetetrazol-induced convulsions in El mice. These findings suggest that induction of convulsions by pentylenetetrazol in the El mouse is a simple method as compared with induction of convulsions by the tossing-up procedure, and convulsions evoked by this method are a precise experimental model for the study of hereditary epilepsy and for the evaluation of anticonvulsant drugs.

Animals↗

PubMed2002

Proconvulsant effects of high doses of venlafaxine in pentylenetetrazole-convulsive rats.

Venlafaxine, an atypical antidepressant drug, has been used to treat several neurological disorders, presenting excellent efficacy and tolerability. Clinical seizures after venlafaxine treatment have occasionally been reported when the drug was used at very high doses or in combination with other medications. The aim of the present study was to investigate the convulsant effects of venlafaxine in rats under controlled laboratory conditions. Adult male Wistar rats (8 per group) receiving venlafaxine or saline at the doses of 25-150 mg/kg were subjected 30 min later to injections of pentylenetetrazole at the dose of 60 mg/kg. The animals receiving 75, 100 and 150 mg/kg venlafaxine presented increased severity of convulsion when compared to controls (P = 0.02, P = 0.04, and P = 0.0004, respectively). Indeed, an increased percentage of death was observed in these groups (50, 38, and 88%, respectively) when compared to the percentage of death in the controls (0%). The group receiving 150 mg/kg showed an reduction in death latency (999 +/- 146 s) compared to controls (1800 +/- 0 s; cut-off time). Indeed, in this group, all animals developed seizures prior to pentylenetetrazole administration. Surprisingly, the groups receiving venlafaxine at the doses of 25 and 50 mg/kg showed a tendency towards an increase in the latency to the first convulsion. These findings suggest that venlafaxine at doses of 25 and 50 mg/kg has some tendency to an anticonvulsant effect in the rat, whereas doses of 75, 100 and 150 mg/kg presented clear proconvulsant effects in rats submitted to the pentylenetetrazole injection. These findings are the first report in the literature concerning the role of venlafaxine in seizure genesis in the rat under controlled conditions.

Animals↗

PubMed1991

Acute administration of ethanol suppresses pentylenetetrazole-induced c-fos expression in rat brain.

The effect of acute ethanol administration on pentylenetetrazole-induced c-fos expression in rat brain was studied. Pentylenetetrazole induced the rapid and transient expression of c-fos mRNA in rat brain. Maximal induction at a dose of 30 mg/kg was detected within 30 min and persisted for 60 min. Thereafter c-fos gene expression decreased to control levels by 180 min. No increase in c-fos mRNA was evident at doses of pentylenetetrazole < or = 20 mg/kg, whereas maximal elevation was seen at 30 or 40 mg/kg. This action was inhibited by acute ethanol treatment (blood alcohol level > or = 100 mg/dl). Acute ethanol treatment alone had no effect on c-fos gene expression.

Animals↗

PubMed1989

Kinetics of drug action in disease states. XXXIV. Effect of experimental thyroid disorders on the pharmacodynamics of phenobarbital, ethanol and pentylenetetrazol.

To determine the effect of thyroid disorders on the concentration-activity relationship of certain drugs acting on the central nervous system, rats were made hyperthyroid by administration of L-thyroxine and hypothyroid by administration of propylthiouracil. They then received a slow i.v. infusion of phenobarbital or ethanol until they lost their righting reflex, or of pentylenetetrazol until the onset of maximal seizures. Drug concentrations in serum, brain and cerebrospinal fluid (CSF) were determined at these pharmacologic endpoints. Hyperthyroidism was associated with a statistically significant increase in the infused hypnotic dose and brain concentration of phenobarbital but had no apparent effect on concentrations of the drug in serum and CSF. The hypnotic dose of ethanol was increased significantly in hyperthyroid rats and decreased in hypothyroid animals; ethanol concentrations in serum, brain and CSF at onset of effect were generally not affected by thyroid dysfunction except for a small but statistically significant increase of serum ethanol concentrations in the hyperthyroid rats. The convulsant dose of pentylenetetrazol was reduced significantly in hypothyroid animals and unaltered in hyperthyroid rats; the concentrations of the convulsant in serum, brain and CSF were not apparently changed by the thyroid dysfunctions. In general, experimental thyroid disorders had no pronounced effect on the pharmacodynamics (concentration-effect relationship) of phenobarbital, ethanol and pentylenetetrazol in rats.

Animals↗

PubMed1998

Asymmetrical changes in blood-brain barrier permeability during pentylenetetrazol-induced seizures and in acute hypertension.

The asymmetrical breakdown of the blood-brain barrier to Evans-blue was studied in male and female rats during epileptiform seizures and in acute hypertension. The animals were divided into six groups. Group I: control female; Group II: control male; Group III: female + acute hypertension; Group IV: male + acute hypertension; Group V: female + seizure; Group VI: male + seizure. Asymmetric breakdown of the blood-brain barrier had been seen in female rats treated with pentylenetetrazol. Pentylenetetrazol-induced seizure produces less disruption of the blood-brain barrier in right cerebral hemisphere than in left cerebral hemisphere in female rats. There were no asymmetrical changes of blood-brain barrier permeability between the left and right hemispheres in acute hypertension in both sexes, and male rats treated with pentylenetetrazol.

Animals↗

PubMed1998

Altered expression of microtubule-associated protein 1B in cerebral cortical structures of pentylenetetrazole-treated rats.

Using Northern blot, immunoblotting, immunocytochemistry, and in situ hybridization, we show that a single administration of the convulsant pentylenetetrazole leads to robust, long-term changes in microtubule-associated protein 1B and its mRNA, in the adult rat brain. The first increases in MAP1B mRNA were detected at 15 hr following pentylenetetrazole administration in the temporal (Te2) and perirhinal cortex followed by increases in microtubule-associated protein 1B immunoreactivity at 72 hr postseizure. In contrast, the levels of microtubule-associated protein 1B mRNA and protein in layers I-II of the retrosplenial and parietal cortex (Par2) declined visibly by 24 hr and 72 h, respectively, post-seizure. The changes included loss of staining in layers I-II and development of structures resembling "strings-of-beads" along the fibers of projection neurons of layer V. The levels of microtubule-associated protein 1B mRNA in the entorhinal cortex peaked at later times (72 h), especially in layers II-III, and returned to control levels by 10 days. Whereas the levels of microtubule-associated protein 1B immunoreactivity in the retrosplenial and parietal cortex recovered by 5-10 days, it persisted at high levels through day 35 in layer V of the temporal cortex (Te2), layers II-III of the perirhinal cortex and layers I-II of the lateral entorhinal cortex. These results indicate that seizure activity leads to long-term upregulation of genes coding for structural elements that are characteristic of the immature brain such as microtubule-associated protein 1B.

Animals↗

PubMed1988

Suppression of pentylenetetrazol-elicited seizure activity by intraosseous propranolol in pigs.

The intraosseous (IO) route provides a rapid and effective alternative venous access in the pediatric population when the conventional intravenous (IV) route cannot be easily obtained. DL-propranolol, a beta-adrenoceptor antagonist, exhibits antiepileptic activity in various animal seizure models. This study assessed the efficacy of IO propranolol in suppressing pentylenetetrazol (PTZ)-induced seizure activity in pigs. Domestic swine (13-20 kg) were prepared for recordings of arterial blood pressure, ECG and electrocortical activity. Seizure activity was induced by pentylenetetrazol (PTZ; 100 mg/kg; IV). Sixty seconds after the onset of seizure activity, the animals either received no drug (control) or propranolol (IV or IO via an 18-gauge spinal needle placed in the right proximal tibia). A transient increase (16.3-50.0%) in the mean arterial blood pressure (MAP) was observed following PTZ administration. Both IO and IV propranolol significantly suppressed the seizure duration (SD) (sec/min interval) at 1 min following drug administration; SD control, 36.3 +/- 4.8; IV propranolol, 12.3 +/- 5.1; IO propranolol, 18.3 +/- 6.0. In addition, both IV and IO propranolol produced a maximal decrease of 32-38% in the basal heart rate; and reduced the transient increase in MAP elicited by PTZ, with no significant effect on the basal MAP. The data demonstrate that 1) propranolol possesses anticonvulsant activity against PTZ-induced seizure in the pig, and 2) the intraosseous route is a rapid and effective alternative venous access for propranolol administration in swine.

Animals↗

PubMed1975

Quantitative GLC determination of pentylenetetrazol in biological fluids.

A quantitative, sensitive, and specific GLC method was developed for the determination of pentylenetetrazol in water, plasma, and urine. The assay involves a single extraction of the sample into chloroform followed by centrifugation, evaporation, and chromatography. The method for pentylenetetrazol is reproducible, and the sensitivity limit of the assay is 0.5 mug of pentylenetetrazol/ml of biological fluid using a 2-ml sample. This method has a sensitivty sufficient to detect human plasma levels after therapeutic clinical doses and was successfully applied to monitor complete plasma level profiles of this drug in dogs. The data indicate that this drug is very rapidly absorbed following an oral dose, and the half-life of the drug in plasma is approximately 1 hr.

Administration, Oral↗

PubMed1991

Kinetics of drug action in disease states. XXXVIII: Effect of body temperature on the convulsant activity of pentylenetetrazol in rats.

The purpose of this investigation was to determine the effect of body temperature on the pharmacodynamics (convulsant activity) of pentylenetetrazol (PTZ). Rats received an iv infusion of PTZ until the onset of maximal seizures, at which time samples of cerebrospinal fluid (CSF), brain, and blood (for serum) were obtained for subsequent determination of PTZ concentrations by HPLC. The PTZ infusion caused a decrease in body temperature of approximately 4 degrees C within 20 min and onset of seizures in approximately 40 min. Compared with animals whose temperature was maintained in the normal range by heating pads, the hypothermic rats required significantly larger doses and higher serum, brain, and CSF concentrations of PTZ to produce seizures. Other rats received an injection of brewer's yeast to produce fever. Then, PTZ was infused 6, 12, or 24 h later when body temperature was elevated by an average of 1.3, 1.1, or 0.4 degrees C, respectively. Compared with control rats, whose temperature was maintained in the normal range by heating pads, moderate hyperthermia had no significant effect on the dose and concentrations of PTZ required to produce maximum seizures. Pentylenetetrazol exemplifies a drug that can produce hypothermia which, in turn, reduces the sensitivity of rats to its pharmacologic action. Unlike the central nervous system (CNS) depressants phenobarbital and ethanol, whose pharmacologic activity in rats is enhanced at elevated body temperature, the activity of the CNS stimulant PTZ is apparently not altered by fever.

Animals↗

PubMed1989

Specific suppression of pentylenetetrazol-induced epileptiform discharges in CA3 neurons (hippocampal slice, guinea pig) by the organic calcium antagonists flunarizine and verapamil.

Antiepileptic actions of the organic calcium antagonists flunarizine (cinnarizine derivate) and verapamil (papaverin derivat) on pentylenetetrazol-induced epileptic bioelectric activity were tested in CA3 neurones of hippocampal slices. In all experiments both calcium antagonists reduced the amplitudes and/or durations of paroxysmal depolarizations as well as their rate of occurrence, when the bath concentrations of flunarizine or verapamil exceeded 20 mumol/l. When they were added to the bath solution before pentylenetetrazol application, recordings of the resting membrane potential, of the membrane resistance, of action potentials and of spontaneous as well as of evoked excitatory and inhibitory postsynaptic potentials gave no indication that the antiepileptic effects of these drugs are due to unspecific depressive actions on neuronal excitability or spread of excitation.

Animals↗

PubMed1992

Opposite effects of pentylenetetrazol on self-defensive and submissive postures in the rat.

In a previous work, using the resident-intruder situation, we have shown that a benzodiazepine inverse agonist could exert a "fear-promoting" effect, in decreasing self-defensive behaviours while increasing submissive postures. To further test this hypothesis, the effects of pentylenetetrazol on different forms of defensive behaviour were examined in male intruder rats confronted with offensive residents. Administration of pentylenetetrazol (10 and 20 mg/kg, IP) increased submissive postures such as immobility and on-the-back, but reduced self-defensive postures. Other active behaviours were not reduced, thus excluding a non-specific behavioural suppression. These results suggest that self-defensive and submissive behaviours can be dissociated and that anxiogenic compounds are more likely to increase submissive behaviours than self-defensive ones.

Aggression↗

PubMed2002

Ictal brain SPET during seizures pharmacologically provoked with pentylenetetrazol: a new diagnostic procedure in drug-resistant epileptic patients.

Functional brain imaging plays an important role in seizure focus localisation. However, truly ictal single-photon emission tomography (SPET) studies are not routinely performed owing to technical problems associated with the use of tracers and methodological and logistical difficulties. In this study we tried to resolve both of these issues by means of a new procedure: technetium-99m ethyl cysteinate dimer (ECD) brain SPET performed during seizures pharmacologically provoked with pentylenetetrazol, a well-known central and respiratory stimulant. We studied 33 drug-resistant epileptic patients. All patients underwent anamnestic evaluation, neuropsychological and psychodynamic assessment, magnetic resonance imaging, interictal and ictal video-EEG monitoring, and interictal and ictal SPET with (99m)Tc-ECD. In order to obtain truly ictal SPET, 65 mg of pentylenetetrazol was injected every 2 minutes and, immediately the seizure began, 740 MBq of (99m)Tc-ECD was injected. The scintigraphic findings were considered abnormal if a single area of hyperperfusion was present and corresponded to the site of a single area of hypoperfusion at interictal SPET: the "hypo-hyperperfusion" SPET pattern. In 27 of the 33 patients (82%), interictal-ictal SPET showed the hypo-hyperperfusion SPET pattern. Video-EEG showed a single epileptogenic zone in 21/33 patients (64%), and MRI showed anatomical lesions in 19/33 patients (57%). Twenty-two of the 27 patients with hypo-hyperperfusion SPET pattern underwent ablative or palliative surgery and were seizure-free at 3 years of follow-up. No adverse effects were noted during pharmacologically provoked seizure. It is concluded that ictal brain SPET performed during pharmacologically provoked seizure provides truly ictal images because (99m)Tc-ECD is injected immediately upon seizure onset. Using this feasible procedure it is possible to localise the focus, to avoid the limitations due to the unpredictability of seizures, to avoid pitfalls due to late injection, to avoid intracranial EEG recording and to minimise costs. The clinical value of our method is confirmed by the good outcome after 3 years of follow-up in those patients submitted to ablative or palliative surgery.

Adolescent↗

PubMed1987

High-performance liquid chromatographic procedure for quantitative determination of pentylenetetrazol in serum and discrete areas of rat brain.

A precise and reproducible high-performance liquid chromatographic method for the determination of pentylenetetrazol in serum and brain tissue is described. The procedure employs reversed-phase chromatography, monitoring the eluant at 202 nm. Quantification is based on peak-height ratio of the drug to the internal standard (p-methylphenobarbital). A linear response is obtained to 100 micrograms/ml (serum) or micrograms/g (brain tissue). Within-day and between-day precision are smaller than 5%, and analytical recovery is greater than 95%. Numerous drugs tested do not interfere with the assay. The method has been used to investigate the kinetics of pentylenetetrazol distribution in serum and in discrete areas of rat brain.

Animals↗

PubMed1995

Effects of repeated administration of selective adenosine A1 and A2A receptor agonists on pentylenetetrazole-induced convulsions in the rat.

The protective effects of the selective adenosine A1 receptor agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA), the selective adenosine A2A receptor agonist, 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA), and the non-selective agonist, 5'-N-ethylcarboxamidoadenosine (NECA) were studied against lethal seizures induced by intraperitoneal (i.p.) injection of pentylenetetrazole (80 mg/kg). In acute studies there was a dose-dependent reduction of lethal seizures, as shown by the low dose's protecting 50% of animals (PD50): 0.11, 0.05 and 0.05 mg/kg i.p. for CCPA, 2HE-NECA and NECA, respectively. In the repeated administration studies the animals received either vehicle or drug i.p. twice daily for 12 days. The drug doses were twice the PD50 value: 0.3 mg/kg for CCPA or 0.1 mg/kg for both 2HE-NECA and NECA. 2HE-NECA and NECA maintained their protective activity against pentylenetetrazole-induced seizures (63% or 60% vs. 60% or 58% in acute studies, respectively). Conversely, repeated treatment with CCPA resulted in a marked decrease of its effects (67% vs. 30% in acute studies; P < 0.05). The data indicate that in addition to adenosine A1 the A2A receptors also appear to be involved in the protection from seizures. The anticonvulsant effects induced by repeated stimulation of adenosine A1 receptors are subject to tolerance, whereas effects depending on adenosine A2A receptor activation are maintained.

Adenosine↗