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.     

Anticonvulsant and proconvulsant effects of inhibitors of GABA degradation in the amygdala-kindling model

The effects of three drugs, namely gamma-vinyl GABA (vigabatrin), gamma-acetylenic GABA, and aminooxyacetic acid, which increase brain GABA concentrations by irreversible inhibition of GABA degradation, were studied in amygdala-kindled rats. Vigabatrin 800 or 1,200 mg/kg i.p. 4 h after its administration, caused prolongation of behavioural seizures and electrographic afterdischarges recorded from the stimulated amygdala. One to three days after administration it dose dependently reduced seizure severity, seizure duration and afterdischarge duration in most animals. Determination of GABA levels in synaptosomes isolated from 12 brain regions of kindled rats 4 or 48 h after injection of 1,200 mg/kg vigabatrin indicated that the variable effects of this drug at different times after its administration could be related to differences in the time course of nerve terminal GABA increases in selective brain regions such as amygdala and corpus striatum. In contrast to vigabatrin, gamma-acetylenic GABA, 100 mg/kg i.p., reduced seizure severity in kindled rats as early as 4 h after its administration but afterdischarge duration increased significantly on subsequent days. Similar late increases in afterdischarge duration (and limbic seizure activity) after the time of maximum anticonvulsant effect had elapsed were also observed with vigabatrin, which could suggest that the anticonvulsant effect of such drugs is followed by withdrawal hyperexcitability. Aminooxyacetic acid, 20 mg/kg i.p., exerted no significant anticonvulsant effect in kindled rats but prolonged afterdischarge duration in several of the animals studied. The data suggest that GABA-T inhibitors, such as vigabatrin, differ from most antiepileptic drugs previously tested in the kindling model in that they may produce both anticonvulsant and proconvulsant effects at the same dose in the same animal as a function of time after administration.     

The effect of the NMDA receptor antagonist, MK-801, on the course and outcome of kindling

A rapid kindling procedure was used to distinguish between the anticonvulsant activity of drugs and their ability to retard the kindling process. MK-801 is a specific ligand at the phencyclidine (PCP) recognition site, and acts as a noncompetitive antagonist of NMDA-type glutamate/aspartate receptors. Intraperitoneal injections of MK-801 (0.5-4.0 mg/kg IP) significantly reduced the cumulated effect of 12 2-hr kindling stimulations, as determined from behavioral measures of seizure activity in immediately ensuing 24-hr drug-free kindling sessions; however, the corresponding electrographic effects did not reach significance. MK-801 also showed significant anticonvulsant activity when injected in fully kindled rats. Higher doses tested were accompanied by locomotor and postural effects. The anticonvulsant benzodiazepine, clonazepam, formulated with a proprietary diluent (as Rivotril, Roche), injected in anticonvulsant doses during the first 12 kindling sessions (0.64 mg/kg IP, repeated after 9 hr) did not significantly affect the course of subsequent sessions of drug-free kindling. Systemic injections of kynurenic acid (300-600 mg/kg IP 4 hours), a nonspecific antagonist of glutamate receptors in vitro, were without significant anticonvulsant or antikindling activity. Activity of NMDA-sensitive glutamate/aspartate receptors associated with the PCP recognition site may induce lasting facilitation of neural transmission; this facilitation may be responsible for the remote propagation and progressive enhancement of seizure activity kindled in the amygdala. The facilitatory process appears to be antagonised by MK-801.     

Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy

1. The centrally acting analgesic tramadol has recently been reported to cause seizures at re-commended dosages in patients, whereas animal experiments had indicated that seizures only occur in high, toxic doses. Tramadol has a dual mechanism of action that includes weak agonistic effects at the mu-opioid receptor as well as inhibition of monoamine (serotonin, norepinephrine) re-uptake. Its major (M1) metabolite mono-O:-desmethyltramadol, which is rapidly formed in vivo, has a markedly higher affinity for mu receptors and may thus contribute to the effects of the parent compound. Furthermore, the pharmacological effects of tramadol appear to be related to the different, but complementary and interactive pharmacologies of its enantiomers. In the present study, we evaluated (+/-)-tramadol, its enantiomers, and its M1 metabolite ((+)-enantiomer) in the amygdala kindling model of epilepsy in rats. Adverse effects determined in kindled rats were compared to those in nonkindled rats. 2. At doses within the analgesic range, (+/-)-tramadol and its enantiomers induced anticonvulsant effects in kindled rats. However, at only slightly higher doses seizures occurred. With (+/-)-tramadol, generalized seizures were observed at 30 mg kg(-1) in most kindled but not in nonkindled rats. The (-)-enantiomer induced myoclonic seizures at 30 mg kg(-1) in most kindled but not in nonkindled rats, although myoclonic seizure activity was observed in some nonkindled rats at 10 or 20 mg kg(-1). Seizures were also observed after the (+)-enantiomer and the (+)-enantiomer of the M1 metabolite, but experiments with higher doses of these compounds were limited by marked respiratory depression. 3. The data demonstrate that kindling enhances the susceptibility of rats to convulsant adverse effects of tramadol and its enantiomers, indicating that a preexisting lowered seizure threshold increases the risk of tramadol-induced seizures.     

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.     

Effects of YM90K, a selective AMPA receptor antagonist, on amygdala-kindling and long-term hippocampal potentiation in the rat.

To investigate the role of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) type glutamate receptors in epileptic seizures, we examined the antiepileptogenic and anticonvulsant effects of YM90K [6-(1H-imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione hydrochloride], a potent and selective new AMPA receptor antagonist, in the rat amygdala-kindling model of epilepsy. Pretreatment with YM90K (7.5-30 mg/kg i.p.) markedly retarded the evolution of kindling. Once kindling was established, administration of YM90K (7.5-30 mg/kg i.p.) significantly and dose-dependently suppressed fully kindled seizures. The maximal effects were observed 15-30 min after injection. When the intensity of electrical stimulation was increased to twice the generalized seizure-triggering threshold, the anticonvulsant effects of YM90K were reversed, suggesting that they were due to elevation of the generalized seizure-triggering threshold. Furthermore, an anticonvulsant dose (15 mg/kg) of YM90K affected neither field potentials nor long-term potentiation in the hippocampus in vivo. These results indicate that AMPA receptors play an important role in the seizure expression mechanism and the development of kindling-induced epileptogenesis, and suggest the possible clinical usefulness of AMPA receptor antagonists as antiepileptic drugs.     

Comparison of the anticonvulsant effects of two novel GABA uptake inhibitors and diazepam in amygdaloid kindled rats

Summary Two novel, specific inhibitors of GABA uptake, namely SKF 89976-A (N-[4,4-diphenyl-3-butenyl]-nipecotic acid) and SKF 100330-A (N-[4,4-diphenyl-3-butenyl]-guvacine) were tested for anticonvulsant effects in amygdaloid kindled female rats. The anticonvulsant effectiveness of the compounds was compared with that of diazepam. SKF 89976-A and SKF 100330-A produced dosedependent anticonvulsant effects on all seizure parameters measured in fully kindled rats, i.e. they inhibited seizure severity, increased seizure latency, and decreased the duration of motor seizures and EEG afterdischarges. ED 50s for inhibition of seizure severity were 4.6 and 15.1 mg/kg (0.014 and 0.045 mmol/kg) i.p. for SKF 100330-A and SKF 89976-A, respectively. For comparison, the ED 50 of diazepam was 1.9 mg/kg (0.0067 mmol/kg) i.p. Observation of behaviour indicated that the novel GABA uptake blockers exerted no side-effects in anticonvulsant doses, whereas diazepam produced sedative effects at all active dosage levels. The data demonstrate that SKF 100330-A and SKF 89976-A are potent, non-sedative anticonvulsant drugs in the kindling model of epilepsy, and these compounds thus may deserve interest as potential antiepileptic drugs with a very selective mechanism of action.     

利多卡因对电点燃模型的作用

目的研究利多卡因对电点燃模型的作用。方法采用腹腔注射的给药途径,观察杏仁核点燃大鼠的行为表现,以Racine分级作为评价标准。结果利多卡因0.5～25.0mg/kg腹腔注射可依赖性抑制大鼠杏仁核点燃作用,提高阈值,降低Rcine分级(P<0.01)。利多卡因剂量>30mg/kg,有明显的兴奋作用(P<0.05)。结论利多卡因对大鼠杏仁核点燃有兴奋和抵制双重作用。     

Kindled rats are more sensitive than non-kindled rats to the behavioural effects of combined treatment with MK-801 and valproate.

The effects of combined treatment with low doses (0.025-0.05 mg/kg i.p.) of the non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), and the antiepileptic drug, valproate, were studied in amygdala-kindled and non-kindled rats. MK-801, 0.05 mg/kg, did not exert anticonvulsant effects in fully kindled rats but increased the anticonvulsant potency of valproate, 100 mg/kg i.p. However, the increase in anticonvulsant activity was paralleled by a marked increase in adverse effects such as motor impairment and hyperactivity, resulting in a considerable reduction of the therapeutic index of the combined treatment compared to valproate alone. Furthermore, MK-801 potentiated the adverse effects but not the anticonvulsant activity of 50 mg/kg valproate. Combined treatment with MK-801 and valproate induced much less marked adverse effects in non-kindled rats than in kindled rats. The competitive NMDA receptor antagonist, CGP 37849 1 mg/kg i.p., did not alter the effects of valproate in kindled rats. The data on combined treatment with MK-801 and valproate substantiate the conclusion that kindling alters the susceptibility to manipulations of NMDA receptor-mediated events.     

The effect of a glycine derivative (CP 1552-S) on kindled seizures in rats

The effects of the glycine derivative, CP 1552-S (2-N-pentylaminoacetamide hydrochloride) were evaluated for potential anticonvulsant activity in rats which were cortically- or amygdaloid-kindled. Large doses (300-600 mg/kg, i.p.) of CP 1552 given 30 min before stimulation resulted in significant reductions in duration of afterdischarge after both partially-developed and fully-developed cortically-kindled seizures. The largest dose tested (600 mg/kg, i.p.) markedly reduced the duration of the elicited afterdischarge and the severity of seizure. This dose was associated with prestimulation sedation and a 50% incidence of post-afterdischarge spontaneous, electrical seizure activity. Against kindled amygdaloid seizures, CP 1552-S significantly reduced the duration of afterdischarge at 300 mg/kg (i.p.) without modifying the seizure and without prestimulation behavioral or electrical effects. The largest dose tested (600 mg/kg, i.p.) resulted in a significant reduction of the elicited duration of afterdischarge but was associated with a 25% incidence of prestimulation spontaneous electrical seizure activity and a 45% incidence of post-afterdischarge electrical seizure activity. When CP 1552-S (30-300 mg/kg, i.p.) was administered daily, prior to the amygdaloid kindling stimulus, no difference was noted in the rate of acquisition of the kindled amygdaloid response. It is concluded that the glycine derivative CP 1552-S, has little anticonvulsant activity against the acquisition or development of kindled amygdaloid seizures. It appears to have significant anticonvulsant effects against both cortically- and amygdaloid-kindled afterdischarges with little effect on the behavioral severity of the seizure. Further, large doses of CP 1552-S appeared to result in paradoxical post-afterdischarge and possibly prestimulation electrical seizure activity.     

A characterization of chemical kindling with the pesticide endosulfan.

In a companion article (see this issue), the proconvulsant properties of the pesticide endosulfan in electrical kindling of the amygdala are described. In the present report, an evaluation of the chemical kindling properties of endosulfan is presented. Repeated administration (3 times per week for a total of 21 doses) of endosulfan (5 and 10 mg/kg in corn oil, PO) was found to induce behavioral seizures in rats. Behavioral seizure development was most apparent in the high dose group (10 mg/kg). Heightened seizure responsiveness to a challenge dose was maintained following a two-week, drug-free period, arguing against cumulative toxicity as a mechanism for seizure induction. Electrical kindling induced by once daily stimulation of the amygdala began approximately 4 weeks after the final dose of endosulfan. In the absence of further dosing, a significant facilitation in the rate of kindling development was evident as a function of prior treatment with endosulfan. An enhancement in the rate of kindling was also evident in the low dose group (5 mg/kg) in the absence of clonic seizure development during dosing. A history of endosulfan treatment failed to affect threshold for inducing an afterdischarge (AD) and had equivocal effects on the development of AD with repeated stimulation. Pretreatment with a single high dose of endosulfan 2 weeks prior to electrical kindling was without effect on the development of the kindled response. Endosulfan has been reported to decrease binding of gamma-amino-butyric acid (GABA). Chemical kindling with endosulfan may result from the interaction of this pesticide with GABA-mediated neurotransmission in the central nervous system (CNS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological studies with a GABA uptake inhibitor in rats with kindled seizures in the amygdala

The anticonvulsant effects of the inhibitor of the uptake of GABA, SKF 89976-A (N-[4,4-diphenyl-3-butenyl]-nipecotic acid), were investigated using the amygdala kindling seizure model in rats. The time course of activity of the racemic mixture, given orally, and the relative potencies of its d- and l-isomers, when given intraperitoneally, were tested. The drug SKF 89976-A was active, when given orally with anticonvulsant effects lasting 2-4 hr when given at 15 mg/kg, and 4-6 hr when given at 30 mg/kg. Peak inhibition of severity of seizures occurred at 1 hr after administration with an ED50 of 17.8 mg/kg. The d-isomer of SKF 89976-A was significantly more potent than the l-isomer and inhibited various parameters of kindled seizure activity in a dose-dependent manner. The l-isomer had significant effects on kindled seizures only at the largest dose (20 mg/kg). The ED50 of the d-isomer for inhibition of severity of seizures measured 0.5 hr after intraperitoneal injection, was 11.2 mg/kg and the antiseizure effects of the d-isomer lasted for 2-3 hr. Side effects of SKF 89976-A, such as sedation, abdominal muscle relaxation, rear limb splaying and ataxia, were seen at 30 mg/kg; there was a marked suppression of seizure activity with no side effects at smaller doses. The characterization of a biphasic kindled seizure allows for speculation regarding the role of GABAergic mechanisms in its pathogenesis and of the mechanism of action of SKF 89976-A.     

Effects of competitive and noncompetitive NMDA receptor antagonists on kindling and LTP

In the present study, comparative studies of the effects of competitive and noncompetitive antagonists of NMDA receptors (CPP, CGS19755 and MK-801) on two models of neuronal plasticity, kindling and long-term potentiation (LTP), were performed in rats. Systemic administration of CPP (5, 10 mg/kg), CGS19755 (5, 10 mg/kg) or MK-801 (1, 2 mg/kg) strongly retarded kindling development from the amygdala (AM), in which the early stage of kindled seizures and the growth of afterdischarges (ADs) recorded from the AM were significantly suppressed. After establishment of kindling, however, these compounds only reduced the previously AM-kindled seizure stage without shortening the AD duration. These NMDA receptor antagonists with the same dose sufficient for suppressing AM kindling almost completely blocked LTP of the synaptic component in the hippocampal dentate gyrus following high-frequency trains of the perforant path in urethane-anesthetized rats. These results further support the hypothesis that neuronal plasticity is induced by activation of the NMDA receptor complex and one of the basic neuronal mechanisms underlying kindling may be a long-lasting increase in synaptic transmission.     

The interaction of cannabinoids and opioids on pentylenetetrazole-induced seizure threshold in mice

Cannabinoid and opioid receptor agonists show functional interactions in a number of their physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study examined the possibility of a functional interaction between these receptors. We used acute systemic administration of cannabinoid selective CB(1) receptor agonist (ACPA) and antagonist (AM251) and opioid receptor agonist (morphine) and antagonists (naltrexone and norbinaltorphimine) in a model of clonic seizure induced by pentylenetetrazole (PTZ). Acute administration of ACPA (1.5-2 mg/kg) increased the PTZ-induced seizure threshold. In contrast, AM251 (0.5-2 mg/kg) dose-dependently decreased the seizure threshold. Low dose of AM251 (0.5 mg/kg), which did not alter seizure threshold by itself, reversed the anticonvulsant effect of ACPA (2 mg/kg), showing a CB(1) receptor-mediated mechanism. Naltrexone (1 or 10 mg/kg) but not specific kappa-opioid receptor antagonist norbinaltorphimine (5 mg/kg) completely reversed the anticonvulsant effect of ACPA (2 mg/kg). Moreover, the combination of the lower doses of AM251 (0.5 mg/kg) and naltrexone (0.3 mg/kg) had an additive effect in blocking the anticonvulsant effect of ACPA. In accordance with previous reports, morphine exerted biphasic effects on clonic seizure threshold with anticonvulsant effect at lower (0.5-1 mg/kg) and proconvulsant effect at a higher (30 mg/kg) doses. The pretreatment with AM251 blocked the anticonvulsant effect of morphine at 1 mg/kg, while pretreatment with ACPA (1 mg/kg) potentiated the anticonvulsant effect of morphine at 0.5 mg/kg. The proconvulsant effect of morphine at 30 mg/kg was also inhibited by AM251 (2 mg/kg). A similar interaction between cannabinoids and opioids was also detected on their anticonvulsant effects against the generalized tonic-clonic model of seizure. In conclusion, cannabinoids and opioids show functional interactions on modulation of seizure susceptibility.     

The development of tolerance to the anticonvulsant effects of clonazepam, but not sodium valproate, in the amygdaloid kindled rat

The effects of chronic treatment with clonazepam and sodium valproate were studied on kindled amygdaloid seizures in rats. Fully kindled rats were given an intraperitoneal (i.p.) injection of either vehicle (1.0 ml/kg), clonazepam (0.3 mg/kg) or sodium valproate (200 mg/kg) twice daily for 12 days. Each rat was stimulated through an amygdaloid electrode 30 min after the morning dose. While both drugs initially blocked and kindled seizure (P less than 0.01), the results showed a significant trend (P less than 0.02) in the development of tolerance to the anticonvulsant action of clonazepam but no significant tolerance to the action of valproate.     

琥珀酸对大鼠化学性点燃和杏仁核电刺激性点燃的抑制作用

目的:研究琥珀酸对大鼠戊四哇化学性点燃(kindling)发作及杏仁核电刺激点燃发作的影响及作用机制.方法:建立大鼠戊四唑化学性点燃模型和杏仁核电刺激点燃癫痫模型,测定琥珀酸对点燃发作的脑电活动及行为变化指标的影响.测定琥珀酸对GABA_A受体拮抗剂印防己毒素诱发小鼠惊厥的影响.结果:琥珀酸(100-400 mg/kg,iP)对两种点燃模型有显著抑制作用,降低发作强度和全身性发作百分率(P<0.05,P<0.01),可升高杏仁核电刺激点燃大鼠的局灶性后放电阈值(P<0.05,P<0.01),以上反应呈剂量效应关系。琥珀酸可延长印防己毒素诱发小鼠惊厥的潜伏期(P<0.05,P<0.01).结论:琥珀酸对大鼠戊四唑化学性点燃和脑杏仁核电刺激点燃发作有抑制作用,其机制可能与增强GABA_A受体功能有关.     

The effects of pentylenetetrazol, bicuculline and strychnine on the development of kindled seizures

Modification of the rate of acquisition of the kindled amygdaloid seizure by the convulsants pentylenetetrazol, bicuculline and strychnine was studied. Injections of saline, 25 mg/kg of pentylenetetrazol, 2 mg/kg of bicuculline or 1 mg/kg of strychnine were given 15 min prior to the daily electrical stimulation of the amygdala. The drug doses selected were capable of producing some behavioral and electrical epileptoid activity prior to stimulation without inducing generalized seizures. To determine whether pentylenetetrazol or bicuculline accelerated the rate of development of the kindled amygdaloid seizure or merely augmented the expression of each seizure, a crossover design was implemented. The crossover studies involved switching animals during the acquisition phase (between stimulations 3–6) from prestimulation saline to drug or drug to saline injections. It was found that pentylenetetrazol markedly augmented the expression of seizures during kindling development but the results of the crossover studies showed a less dramatic acceleration in the actual rate of the development of the fully generalized kindled amygdaloid seizure. The bicuculline-treated animals showed little augmentation in the expression of seizures during the kindling acquisition phase and in the actual rate of development of the kindled amygdaloid seizure. The strychnine treated animals showed no augmentation in expression of the seizures nor in the rate of development. The effects of prestimulation injections of bicuculline (1, 2 and 3 mg/kg) and strychnine (0.5, 1 and 2 mg/kg) on fully developed kindled amygdaloid seizures were also evaluated. Pretreatment with bicuculline minimally increased seizure afterdischarge duration at the highest dose. When fully kindled animals were pretreated with strychnine, a paradoxical decrease in afterdischarge length and an increase in severity (tonic hindlimb extension) was seen with the largest dose tested. This study emphasizes the potential importance of crossover studies in evaluating pharmacological manipulations of the rate of acquisition of the kindled seizure.     

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.     

The effect of clonidine and yohimbine on audiogenic seizures (AGS) in rats

Clonidine in high doses (0.5,1.0 mg/kg) significantly increased the latency for audiogenic seizures (AGS) in rats and reduced seizure severity. At a dose (0.05 mg/kg) which acts more specifically on presynaptic alpha 2-receptors, clonidine did not affect seizure latency, but showed a slight proconvulsant action. Yohimbine tended to decrease seizure-latency at all doses, but statistical significance (p less than 0.05) was only reached at 10 mg/kg. Smaller doses of yohimbine (0.5 and 1.0 mg/kg) showed a proconvulsant effect, while a high dose (10 mg/kg) markedly reduced the severity of AGS. The effect of clonidine on seizure-latency was only antagonized by high-dose yohimbine (10 mg/kg), the combination of these drugs being of marked anticonvulsant efficacy. From these results it can be concluded that the anticonvulsant effect of clonidine does not seem to be mediated through presynaptic alpha 2-receptors. Action on other central noradrenergic receptors, and influences on other transmitters must be taken into account when interpreting the effect of clonidine and yohimbine on AGS in rats.     

Preclinical evaluation of CHF3381 as a novel antiepileptic agent

CHF3381 [n-(2-indanyl)-glycinamide hydrochloride] has been selected on the basis of a screening program as the compound displaying the highest anticonvulsant activity in the maximal electroshock seizure (MES) test and the best therapeutic index with reference to the rotarod test in mice and rats. In this study, the antiepileptic activity and the behavioural toxicity of CHF3381 were characterised in multiple model systems. CHF3381 effectively prevented MES-induced convulsions when administered i.p. (ED50, 24 mg/kg and 7.5 mg/kg) or p.o. (ED50, 21 mg/kg and 21 mg/kg) in both mice and rats, respectively. The time course of oral anti-MES activity in the rat was related to the brain concentration profile of unchanged CHF3381. Interestingly, the brain drug levels were about 4-5 times higher than in plasma. CHF3381 was very effective in mice against picrotoxin-, and i.c.v. N-methyl-D-aspartate (NMDA)-induced hind limb tonic extension (ED50 Approximately/=10 mg/kg), but was a weaker antagonist of 4-amynopyridine- and bicuculline-induced tonic seizures (ED50 approximately/=100 mg/kg), and ineffective against pentylentetrazole- and picrotoxin-induced clonic seizures. CHF3381 antagonised the behavioural effects and lethality of i.p. administered NMDA (ED50 = 57 mg/kg p.o.), indicating that the compound may act as a functional NMDA antagonist. In keeping with this idea, CHF3381 weakly displaced [(3)H]-TCP from binding to NMDA receptor channels (Ki, 8.8 microM). In the rat amygdala kindling model, CHF3381 was more efficient against kindling development than against kindled seizures (minimally active dose = 80 vs. 120 mg/kg i.p). Furthermore, it significantly increased the seizure threshold in kindled rats at relatively low doses (40 mg/kg i.p.). In contrast with MK-801-induced hyperactivity, CHF3381 moderately reduced the spontaneous locomotor activity in mice at anticonvulsant doses. Toxic effects on motor performance (rotarod test) were found at high doses only (TD50 approximately/= 300 mg/kg p.o., congruent with 100 mg/kg i.p. in both mice and rats). Furthermore, CHF3381 did not impair passive avoidance and Morris water maze responding in the therapeutic range of doses. Finally, the development of tolerance after repeated doses was negligible. These data indicate that CHF3381 exerts anticonvulsant and antiepileptogenic effects in various seizure models and possesses good therapeutic window, with scarce propensity to cause neurological side-effects.