Effect of cocaine and pentylenetetrazol on cortical kindling

The effect of drug-induced convulsions on subsequent cortical kindling was studied in male Long-Evans rats. Animals experienced three intravenous infusions of physiological saline at 3 day intervals, or three convulsions induced by the infusion of cocaine or pentylenetetrazol (PTZ). Beginning eight days after the last infusion, all animals were kindled by stimulation of the anterior neocortex (area 6). PTZ-induced convulsions facilitated the development of both the behavioral convulsion and the electrographic seizure during cortical kindling, while cocaine-induced convulsions facilitated only the development of the electrographic seizure. Comparison of these results with previous research indicates that convulsions induced by these two drugs have long-lasting effects on brain function which differ both in their anatomical distribution and in the nature of the effects produced. These drugs also differed in their acute effects at subconvulsant doses on the expression of cortically kindled seizures. Cocaine (and lidocaine, another local anesthetic) substantially elevated afterdischarge (AD) threshold and inhibited the focal component of the cortically kindled seizure. PTZ had no significant effect on either of these variables but significantly increased AD duration. In addition to these drug effects, a substantial inhibitory effect on seizure expression was observed, both during kindling and afterwards, when ADs were elicited daily but not when they were separated by 3 days or more. This finding suggests that the large number of ADs typically required for cortical kindling may be due in part to daily stimulation.     

Facilitation of kindling by convulsions induced by cocaine or lidocaine but not pentylenetetrazol

The effect of drug-induced convulsions on kindling was studied in male Long-Evans rats. In Experiment 1 rats experienced a single convulsion induced by the intravenous infusion of cocaine, lidocaine, or pentylenetetrazol (PTZ), or received a control infusion of saline. Beginning eight days later all animals were kindled by daily stimulation of the olfactory bulb. Animals which had been convulsed by cocaine or lidocaine kindled significantly faster than either saline controls or PTZ-convulsed animals, which did not differ significantly. Experiment 2 was conducted to determine if an effect of PTZ on kindling could be obtained with repeated convulsions. Rats experienced three convulsions induced by cocaine or PTZ at 72 hr intervals, or control infusions of saline. Kindling began on the eighth day after the last infusion. Cocaine-convulsed animals again kindled significantly faster than saline or PTZ-convulsed animals, which did not differ significantly. The cocaine animals also had significantly longer afterdischarges than the saline group at the end of kindling and when stimulated again 21 days after kindling was completed. These results suggest that the facilitating effect of cocaine-induced convulsions is not a general property of all convulsants but is a more specific effect which is apparently shared by other local anesthetics.     

Bidirectional transfer of intracerebrally administered pentylenetetrazol and electrical kindling

Rats were kindled using electrical stimulation or the infusion of pentylenetetrazol (PTZ) in one amygdala, and subsequently rekindled using infusion of PTZ or electrical stimulation, respectively, in the contralateral amygdala. Control rats received infusions of saline into one amygdala, and were subsequently electrically kindled in the contralateral amygdala. The rats that previously had been kindled using one agent kindled significantly more rapidly and displayed significantly stronger generalized seizures when rekindled using the other agent. The results demonstrate that intracerebrally administered PTZ can effectively kindle seizures, and thus that a peripheral change in response to PTZ is not crucial for seizure development. The results also demonstrate that this form of kindling transfers bidirectionally to electrical kindling.     

Antiepileptogenic effects of the novel synthetic neuroactive steroid,ganaxolone, against pentylenetetrazol-induced kindled seizures: Comparison with diazepam and valproate

Pharmacological treatment of epilepsy is often unsatisfactory due to side effects and the lack of drugs that control the progressive epileptogenic process. Modulation of inhibitory γ-aminobutyric acid (GABA)-ergic neurotransmission by synthetic agonists of the neuroactive steroid binding site on the GABA_A receptor complex is one approach toward the identification of improved antiepileptic agents. In this study, antiepileptogenic and anticonvulsive effects of the novel synthetic neuroactive steroid, ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), were evaluated in comparison with diazepam and valproate against pentylenetetrazol (PTZ)-induced kindled seizures in mice. Kindled seizures provide a model of the progressive epileptogenic process. Successive administration of 45 mg/kg PTZ on days 1, 3, 5, 8, and 10 resulted in the rapid development of kindled seizures and significant reductions in thresholds for clonic convulsions, tonic convulsions, and lethality induced by PTZ on day 10. Ganaxolone, diazepam, and valproate dose-dependently protected against clonic convulsions induced by acute submaximal dose of PTZ (70 mg/kg). The compounds also dose-dependently suppressed fully kindled seizures and blocked the expression of kindled seizures over successive treatments with PTZ (45 mg/kg). Relative to acute anticonvulsive potencies against 70 mg/kg PTZ, however, ganaxolone was more potent than valproate or diazepam against fully kindled seizures and in blocking the expression of kindled seizures over successive treatments with PTZ. Importantly, only ganaxolone demonstrated antiepileptogenic activity by blocking the development of kindling, as evidenced when PTZ was administered in the absence of anticonvulsant treatments. Both diazepam and valproate failed to prevent development of kindled seizures even at doses that fully suppressed motor expression of seizures during kindling acquisition. Unlike diazepam and valproate, ganaxolone did not impair ambulatory activity within the dose range used in this study. These data, taken in conjunction with other findings on the unique pharmacological actions of ganaxolone, predict an improvement in the pharmacological management of epilepsy with this synthetic neuroactive steroid. Drug Dev. Res. 44:21–33, 1998. © 1998 Wiley-Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America.     

Effect of phosphamidon on convulsive behavior and biochemical parameters: modulation by progesterone and 4′-chlorodiazepam in rats

Phosphamidon (PHOS) has been shown to affect nervous system adversely. The present study was designed to explore the modulation of the effects of PHOS on convulsions by neurosteroids, progesterone (PROG), and 4′-chlorodiazepam (4′-CD), in both acute and chronic seizure models. In acute study, seizures were induced by either pentylenetetrazole (PTZ) injection or maximal electroshock seizures, while in the chronic study, kindling was induced by injecting PTZ (30 mg/kg, s.c.) on alternate days three times in a week. Oxidative stress was assessed in the brain by measuring the levels of malondialdehyde (MDA), acetylcholinesterase (AChE), and non-protein thiol (NP-SH). PROG and 4′-CD were able to modulate the PHOS-induced convulsions in acute PTZ convulsions as well as in chronic kindling model. However, they failed to reverse the derangements in oxidative stress parameters of MDA and NP-SH produced by PHOS in kindled animals. PROG significantly increased the AChE activity in untreated rats, while PROG and 4′-CD reversed the AChE activity inhibition induced by PHOS. The study indicates a possible anticonvulsive mechanism of neurosteroids, since both PROG and 4′-CD reversed PHOS-induced inhibition of AChE activity. The neurosteroids seem to play a protective role in PHOS-induced convulsions besides their antioxidant property.     

The effects of various anesthetics on amygdaloid kindled seizures

The effects of various doses of cataleptic anesthetics, gamma-butyrolactone (GBL), phencyclidine (PCP), and ketamine (KET), and the depressant anesthetics, pentobarbital (PB) and chloral hydrate (CH), on amygdaloid kindled seizures were tested in the rat. The seizure activity was monitored by behavioral observation and EEG recording. Anesthetic doses of the cataleptic anesthetics with the exception of KET had minimal effects on the afterdischarge duration (AD) and behavioral ranking (BR) of the elicited seizures. On the other hand, they were more inhibitory to the AD and BR than was the convulsant pentylenetetrazol (PTZ). The only cataleptic that induced spontaneous seizure activity at anesthetic doses was PCP, although KET induced epileptoid activity at supranesthetic doses. Ketamine, PB, and CH completely inhibited elicited seizure activity at anesthetic doses. In addition, rats were kindled by repetitive electrical stimulation during GBL-induced anesthesia or catalepsy. Although both these GBL groups averaged more stimulations to reach generalized seizures than the saline controls, GBL did not block the kindling process.     

The effects of LY-201116 [4-amino-N-(2,6-dimethylphenyl) benzamide] on the amygdala-kindled rat

The effects of LY-201116, a 4-aminobenzamide, were examined in rats using the amygdala kindling model, both during acquisition of the kindled response and in fully kindled animals. Dose-response and time-response studies for efficacy and rotorod toxicity were completed following intraperitoneal injection of the drug. Afterdischarge duration, behavioral seizure response, kindled seizure threshold and EEG recordings were used to assess efficacy and toxicity of the drug. In the acquisition trial, the drug (7.5 mg/Kg) did not significantly alter the number of stimulations required to produce the first stage 5 kindled response nor did it modify afterdischarge durations. Doses of 11.25 and 15 mg/Kg suppressed afterdischarge and diminished behavioral responses significantly in fully kindled rats, but these doses were also neurotoxic as judged by rotorod performance. The non-selective anticonvulsant effect of 11.25 mg/Kg lasted at least 90 min. A dose of 15 mg/Kg raised kindled seizure threshold and diminished afterdischarge duration. Doses of 20, 30 and 40 mg/Kg produced spontaneous EEG spikes and seizures accompanied by behavioral convulsions. The drug thus exhibited non-selective anticonvulsant effects in fully kindled rats following doses of 11.25 or 15 mg/Kg, but exhibited proconvulsant activity following doses in the range of 20-40 mg/Kg.     

5-HT1A receptor agonists modify epileptic seizures in three experimental models in rats

The effects of two serotonergic (5-HT1A) receptor agonists (8-OH-DPAT; 0.01, 0.1, 0.3, 1 mg/kg, s.c., and Indorenate; 1, 3, 10 mg/kg, i.p.) were evaluated in three type of seizures in male Wistar rats: clonic-tonic convulsions induced by pentylenetetrazol (PTZ, 60 mg/kg, i.p.), status epilepticus (SE) of limbic seizures produced by kainic acid (KA, 10 mg/kg, i.p.) and tonic-clonic seizures by amygdala kindling. 8-OH-DPAT decreased the incidence of tonic seizures and the mortality rate induced by PTZ. Indorenate increased the latency to the PTZ-induced seizures and decreased the percentage of rats showing tonic extension and death. Concerning KA, 8-OH-DPAT augmented the latency and reduced the frequency of wet-dog shake (WDS) and generalized seizure (GS). At high doses it diminished the occurrence and delayed the establishment of SE. Indorenate augmented the latency to WDS, GS and SE, and diminished the number of GS. 8-OH-DPAT and Indorenate did not alter the expression of kindled seizures. However, Indorenate enhanced the refractoriness to subsequent seizures during the postictal depression. Some effects induced by 8-OH-DPAT and Indorenate on seizures evaluated and postictal depression were fully or partially blocked by WAY100635. These results suggest that 5-HT1A receptor agonists modify epileptic activity depending on the type of seizure.     

Influence of low dietary histamine on seizure development of chemical kindling induced by pentylenetetrazol in rats

Aim: To determine the role of dietary low histamine on the seizure development of pentylenetetrazol (PTZ)-induced kindling in rats. Methods: After 14d of feeding on a low histamine diet (LH, containing 0.145μmol/g of histamine), the rats were chemically kindled by repeated intraperitoneal injection of a subconvulsant dose of PTZ (35mg/kg) once every 48h, and seizure activity of kindling was recorded for 30min. Histamine in brain samples was analyzed using a high performance liquid chromatography system with a fluorescence spectrofluorometer. Results:The LH diet induced an increase in seizure response (seizure susceptibility) to the first trial of PTZ, and resulted in facilitation of subsequent PTZ kindling process (seizure development). The histamine levels in the cortex, hippocampus, and hypothalamus of LH-treated rats decreased significantly and these changes correlated well with seizure behavior (r=0.875,0.651, and 0.796, respectively). In addition, chronic kindled seizures resulted in a significant increase of the histamine content in the cortex and hypothalamus in the LH-fed groups. Conclusion: These findings indicate that the histamine in daily food could influence the brain histaminergic function, and play an important role in regulating seizure susceptibility.     

A pharmacological study in the kindling model of epilepsy

The anticonvulsant properties of carbamazepine were evaluated in the kindled amygdaloid seizure model in rats. Carbamazepine significantly raised the threshold for seizures, reduced the duration of elicited afterdischarges and attenuated the severity of seizures in previously-kindled rats, at doses that did not cause sedation or ataxia. A similar reduction in the duration of elicited afterdischarges and severity of seizures was seen after suprathreshold stimulation (400 mu A) with doses of carbamazepine that were without obvious sedative or ataxic effects. After acute intraperitoneal injections (solvent = 2% Tween-80 and 70% propylene glycol), the maximum anticonvulsant effectiveness against suprathreshold stimulation was seen at 30 min. When administered daily (13 days) during acquisition or development of kindling, carbamazepine (25 and 50 mg/kg, i.p.) had variable effects on kindling. Neither dose consistently reduced the duration of elicited afterdischarges during the acquisition phase. Both groups tended to reduce the developing seizure, with the smaller dose of carbamazepine (25 mg/kg) resulting in a more consistent and significant reduction in severity of seizures. No significant differences in number of daily stimulations needed to reach fully kindled seizures were found. Previous studies have reported variable results with carbamazepine and the kindled amygdaloid seizure in rats. The present study provides a comprehensive evaluation of carbamazepine in this model of epilepsy and discusses the results with regard to the finding reported previously.     

Lifetime lead intoxication: influence on the amygdaloid kindling model of epileptogenesis

The nature of amygdaloid kindled seizures was studied in adult rats which were intoxicated with lead starting in neonatal life. Lactating females were exposed to lead via the drinking water (0.25% lead acetate) and the litters were continued on this level of lead after weaning at 27 days of age. When compared to controls, levels of lead in the blood and brain were significantly higher in lead-exposed rats, both at the time of weaning as well as postkindling, beyond 150 days of age. Parameters relating to amygdaloid kindled seizures, including the rate of kindling, seizure latency and seizure threshold were not significantly different in lead-treated rats than in controls. However, duration of behavioral seizures and afterdischarges was significantly longer in rats exposed to lead. Our data suggest that, although lead intoxication starting in neonatal life does not appear to affect the susceptibility to development of amygdaloid kindled seizures, it may enhance seizure severity in this model of epileptogenesis.     

Acute and chronic effects of the benzodiazepine receptor ligand FG 7142: proconvulsant properties and kindling.

The effects of the acute and chronic administration of the beta-carboline benzodiazepine receptor ligand, FG 7142 were studied in mice. On acute administration FG 7142 (at doses between 10 and 40 mg kg-1) lowered seizure thresholds to infused pentylenetetrazol (PTZ) but showed an unusual dose-response curve in that higher doses had less effect. The duration of action was considerably longer than that of other beta-carbolines, such as ethyl-beta-carboline-3-carboxylate (beta CCE). During repeated administration, doses of FG 7142 which were initially proconvulsant subsequently produced generalized seizures on average in 60% of animals after 12 once daily treatments. This seemed to be a form of chemical kindling. The effects of different drug administration regimes were studied. Once daily dosage was shown to be the optimum for kindling production, and was therefore used for subsequent experiments. Kindling lasted for at least one month after 12 single once daily doses of 40 mg kg-1 (FG 7142). The administration of the benzodiazepine antagonist Ro 15-1788 concurrent with FG 7142 prevented kindling. When Ro 15-1788 was given to kindled animals along with a challenge dose of FG 7142, it prevented the expression of kindled seizures. These data show that kindling is mediated via the benzodiazepine receptor.     

Group I metabotropic glutamate receptors interfere in different ways with pentylenetetrazole seizures,kindling, and kindling-related learning deficits

LY 367385 (mGluR1) and MPEP (mGluR5), which are group I metabotropic glutamate receptor (mGluR) antagonists, were used to investigate their effects on pentylenetetrazole (PTZ) seizures, kindling, and kindling-related learning deficits. Both substances showed anticonvulsant efficacy against seizures induced by lower doses of PTZ (40 mg/kg), but they were ineffective in counteracting seizures evoked by higher PTZ doses. When these substances were given in the course of kindling induction, LY significantly depressed the progression of kindled seizure severity. In contrast, MPEP was ineffective in this experiment. Treatment with either LY or MPEP did not modify the reaction to challenge dose of PTZ. Kindling results in a worsening of shuttle-box learning. LY improved shuttle-box learning when administered in the course of kindling development or when given prior to the learning experiment. This suggests protective and restorative effectiveness. In contrast, MPEP was only effective on the learning performance of kindled rats when given prior to the shuttle-box experiment, which demonstrates restorative effectiveness. Kindling is associated with an increase in glutamate binding. LY counteracted this increase whereas MPEP was ineffective. It was concluded that mGluR1 and mGluR5 play a specific role in the convulsive component of kindling. The beneficial action of the antagonists on kindling-induced impairments in shuttle-box learning may be associated with their effect on glutamatergic synaptic activity.     

The anticonvulsant effects of diazepam and phenobarbital in prekindled and kindled seizures in rats

The effects of various doses of diazepam (0.5–4 mg/kg) and phenobarbital (7.5–60 mg/kg) were determined on prekindled and kindled amygdaloid seizures in the same rats. Diazepam was ineffective against the prekindled focal seizures, but demonstrated profound and statistically significant control of the kindled seizures. In the kindled state, diazepam reduced the afterdischarge duration and seizure rank score to prekindled levels. Only the largest sedating dose of phenobarbital produced a reduction of both prekindled afterdischarge duration and seizure rank score. Against the kindled seizure, phenobarbital showed a marked and statistically significant increase in effectiveness in all but the smallest dose tested. The afterdischarge duration of kindled seizures was reduced to prekindled levels by 15–60 mg/kg of phenobarbital, while seizure rank score was reduced to prekindled levels by 30 and 60 mg/kg phenobarbital. The effects of two doses of diazepam (0.5 and 2.5 mg/kg) and phenobarbital (7.5 and 30 mg/kg) were tested against prekindled and kindled pentylenetetrazol (PTZ)-induced seizures. Preliminary work with 3 doses of pentylenetetrazol (30, 40 and 60 mg/kg) demonstrated that repeated doses of 30 mg/kg readily kindled seizures without the significant mortality seen with larger doses. Both diazepam and phenobarbital were less effective against seizures kindled with 30 mg/kg pentylenetetrazol compared to prekindled seizures. The comparative lack of effect that was seen with diazepam and phenobarbital against the pentylenetetrazol kindled seizure at doses associated with control of the kindled amygdaloid seizure may reflect an underlying difference in the pathogenesis of kindling between these seizure models. Further, the lack of suppression of the prekindled amygdaloid afterdischarge duration by large doses of diazepam, in contrast to large doses of phenobarbital, may also reflect differences between the mechanisms of action of these two drugs. This paradigm provides a model for testing the effectiveness of anticonvulsants during the progressive development of various epileptogenic seizures.     

Low-frequency stimulation of the external globus palladium produces anti-epileptogenic and anti-ictogenic actions in rats

Aim:

To investigate the anti-epileptic effects of deep brain stimulation targeting the external globus palladium (GPe) in rats.

Methods:

For inducing amygdala kindling and deep brain stimulation, bipolar stainless-steel electrodes were implanted in SD rats into right basolateral amygdala and right GPe, respectively. The effects of deep brain stimulation were evaluated in the amygdala kindling model, maximal electroshock model (MES) and pentylenetetrazole (PTZ) model. Moreover, the background EEGs in the amygdala and GPe were recorded.

Results:

Low-frequency stimulation (0.1 ms, 1 Hz, 15 min) at the GPe slowed the progression of seizure stages and shortened the after-discharge duration (ADD) during kindling acquisition. Furthermore, low-frequency stimulation significantly decreased the incidence of generalized seizures, suppressed the average stage, and shortened the cumulative ADD and generalized seizure duration in fully kindled rats. In addition, low-frequency stimulation significantly suppressed the average stage of MES-induced seizures and increased the latency to generalized seizures in the PTZ model. High-frequency stimulation (0.1 ms, 130 Hz, 5 min) at the GPe had no anti-epileptic effect and even aggravated epileptogenesis induced by amygdala kindling. EEG analysis showed that low-frequency stimulation at the GPe reversed the increase in delta power, whereas high-frequency stimulation at the GPe had no such effect.

Conclusion:

Low-frequency stimulation, but not high-frequency stimulation, at the GPe exerts therapeutic effect on temporal lobe epilepsy and tonic-colonic generalized seizures, which may be due to interference with delta rhythms. The results suggest that modulation of GPe activity using low-frequency stimulation or drugs may be a promising epilepsy treatment.     

Benzodiazepine receptor inverse agonist-induced kindling of rats alters learning and glutamate binding

Kindling, recognized as a model of epilepsy, can be obtained by applications of repeated nonconvulsive stimulations that finally lead to generalized seizures. Epileptics often show cognitive impairments. The present work analyzed the learning performance of male Wistar rats kindled with a convulsant inverse agonist of the GABA(A)-benzodiazepine receptor complex, methyl beta-carboline-3-carboxylate (beta-CCM). This compound is also known to have an action on learning processes. It was thus interesting to verify if beta-CCM kindling had the same impairing action on learning as other kindling agents, such as pentylenetetrazol (PTZ). A two-way active-avoidance shuttle-box learning task was chosen, because a deficit was found after PTZ kindling in this learning model. On the other hand, hippocampal glutamate binding, has previously been shown to be modified by both seizures and learning. Thus, the level of glutamate binding was also measured in the present study. Results showed that fully kindled rats had poorer learning performance after the third day of test than controls or not fully kindled animals. L-[3H] glutamate binding to hippocampal membrane fractions of the fully kindled animals was significantly higher when compared with controls, whereas L-[3H] glutamate binding of not fully kindled subjects did not differ from that of controls. Neuronal plasticity changes are a possible explanation for the correlation between kindling, learning deficits, and increased glutamate binding.     

Effect of anticonvulsants on seizures developing in the course of daily administration of pentetrazol to rats

Progressive behavioral and electroencephalographic (EEG) changes were examined following daily administration of pentetrazol (PTZ) to rats. A dose (40 mg/kg/day i.p.) of PTZ which, on the first day, induced clonic convulsions with spike and wave complexes, over several days progressively increased its effect and finally induced ‘violent convulsions’ with EEG seizures of high frequency components. In rats showing these violent convulsions, the PTZ convulsive threshold was decreased and, even after a 4- to 10-month resting period, the violent convulsion was elicited with the same dose of PTZ. Trimethadione and phenobarbital in doses blocking clonic convulsion in normal rats, did not suppress these violent convulsions. Higher doses of the two drugs were necessary to suppress the violent convulsion. Diphenylhydantoin did not suppress either type of convulsions. It is suggested that the progressive development of seizure by PTZ is a kindling effect and that a part of the neuronal mechanisms by which the violent convulsion occurs is involved in the mechanisms underlying the clonic convulsion.     

Low doses of AMPA exert anticonvulsant effects on pentylenetetrazol-kindled seizures.

Excitatory amino acids (EAAs) are critically involved in the initiation and propagation of seizures. N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors appear to be of special interest in this regard. Besides receptor binding by antagonists, the function of glutamatergic synapses can be altered via autoreceptor-mediated mechanisms or by receptor desensitisation. Therefore, the effect of AMPA (1, 10 or 100 pmol per animal, intracerebroventricular injection) was tested on acutely induced pentylenetetrazol (PTZ) seizures. The lowest dose exerted clear anticonvulsant effects. Furthermore, 1 and 10 pmol AMPA were tested for their efficacy to suppress PTZ kindling. The lower dose reduced seizure severity significantly but 10 pmol AMPA was ineffective. In reaction to a test dose of PTZ, the kindled groups pretreated with AMPA reached seizure scores similar to saline-pretreated kindled rats, suggesting that the kindled state was reached. In a further experiment, we tested the effect of cyclothiazide (CYC, which blocks AMPA receptor desensitisation) on the 1 pmol AMPA-mediated anticonvulsant effect. The AMPA response was not altered. These results suggest that autoreceptor-mediated mechanisms rather than desensitisation might contribute to the anticonvulsant effect found.     

Enhanced susceptibility of pentylenetetrazole kindled mice to quinolone effects.

The present study was designed to examine the ability of different quinolones to affect the seizure severity and the latency of development of chemical kindling produced by repeated treatment using a subconvulsant dose of pentylenetetrazole (PTZ). A group of mice (kindled control) were treated subcutaneously (s.c.) with vehicle + PTZ (30 mg/kg, three times a week) for 6 consecutive weeks and the changes in excitability associated with the kindling state were observed over the following 2 h. A second group of mice were injected intraperitoneally (i.p.) with the following quinolone derivatives, ciprofloxacin (ciprox), pefloxacin (peflox), ofloxacin (oflox), cinoxacin (cinox), nalidixic acid (nalidixic), 1-cyclopropyl-6-amino-7-tetrahydroisoquinoline-8-methyl-4-oxo-1,4-dihydr oquinoline-3-carboxylic acid (M5) and 1-cyclopropyl-7-tetrahydro-isoquinoline-8-methyl-4-oxo-1,4-dihydroquinol ine-3-carboxylic acid (MH5) at a dose of 20 mg/kg 15 min before receiving a subconvulsant dose of PTZ (30 mg/kg, s.c.). The results showed that pretreatment with some of the quinolones tested facilitated the development of kindling to PTZ-induced seizures. In particular, ciprox, peflox, oflox, M5 and MH5 derivatives variously increased the development of kindling to PTZ induced seizures, whilst cinox and nalidix did not significantly affect it. Additionally we determined whether the enhanced susceptibility of kindled mice only occurred after relatively short intervals following the last seizure or whether it was a more permanent phenomenon. For the study of the persistence of kindling, the animals were rechallenged with the kindling stimulus (PTZ 25 mg/kg, s.c.) 15 and 30 days after the last injection of the chronic treatment with PTZ (30 mg/kg, s.c.) and the behavioural changes in the kindled mice were compared with the control ones (chronically treated with vehicle). The present data demonstrated that kindling produced long-lasting alterations, substantiating that epileptogenesis initiated by kindling renders the brain more susceptible to central nervous system (CNS) side effects of quinolones. An interaction between PTZ and quinolone derivatives which involves either an inhibition of gamma-aminobutyric acid (GABA) neurotransmission or/and an increase in the function of the excitatory amino acid (EAA) system is suggested.     

吲哚醌对大鼠杏仁核点燃的抑制作用

目的：研究吲哚醌对大鼠杏仁核点燃发作的影响及其抗惊厥作用。方法：建立大鼠杏仁核点燃模型,观察发作的电生理指标和行为学变化;在小鼠最大电休克惊厥、戊四唑惊厥和氨基脲惊厥模型计数惊厥发生率。结果： ip吲哚醌50～200 mg.kg-1均可升高杏仁核点燃大鼠的局灶性后放电阈值,降低发作强度和全身性发作 (stage 5) 百分率;可剂量依赖性地对抗小鼠最大电休克发作,并能取消戊四唑惊厥和氨基脲惊厥的强直相,降低戊四唑惊厥的死亡率。结论：吲哚醌对癫痫发作有抑制作用,其机制与抑制MAO-B活性、升高发作阈值有关。