Electroshock Seizures In Mice Research Articles

Influence of methadone on the anticonvulsant efficacy of valproate sodium gabapentin against maximal electroshock seizure in mice by regulation of brain MDA TNF-α.

Methadone is the most frequently used opioid therapy worldwide, with controversial effects on oxidative stress homeostasis. This study investigated the effects of intraperitoneal (i.p.) co-administration of methadone (0.1, 0.3, 1, and 3 mg/kg) and valproate sodium (300 mg/kg) or gabapentin (50 mg/kg) in the mice maximal electroshock (MES)-induced seizure model. The adverse effect of drugs was assessed using the chimney test. The levels of tumor necrosis factor-alpha (TNF-α) and malondialdehyde (MDA) contents were measured in mice brains after a single seizure. Administration of methadone alone resulted in a significant reduction in the duration of hind limb extension (HLE) than that in the control group. Methadone pretreatment at doses of 0.1 and 0.3 mg/kg i.p. decreased, and at doses of 1 and 3 mg/kg i.p. had an increasing effect on anticonvulsant efficacy of gabapentin. Pretreatment with all doses of methadone significantly decreased the valproate anticonvulsive efficacy. At doses of 1 and 3 mg/kg i.p. methadone per se increased brain MDA levels after MES-induced seizure. Administration of methadone (0.3 mg/kg i.p.) enhanced and at 3 mg/kg decreased gabapentin effect on brain MDA level, but their co-treatment did not lead to further increase in MDA. Methadone at 0.3–3 mg/kg enhanced the effect of sodium valproate on MDA levels in the brain, but at all doses significantly potentiated its effect on brain TNF-α levels. The drugs did not produce any side effects on motor coordination in experimental animals. In conclusion, methadone showed different effects on anticonvulsant actions of gabapentin and valproate through regulation of brain levels of MDA and TNF-α.

Synthesis, structure–activity relationships, and anticonvulsant activities of 2-amino-4H-pyrido[3,2-e][1,3]thiazin-4-one derivatives as orally active AMPA receptor antagonists

As part of a program aimed at discovering orally active 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonists, we screened our compound library and identified 2-[allyl(4-methylphenyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (7) as a lead compound that inhibited kainate-induced neurotoxicity mediated by AMPA receptors in rat hippocampal cultures. Structure–activity relationship studies of a series of 2-amino-4H-pyrido[3,2-e][1,3]thiazin-4-one derivatives revealed that substituents on the phenyl ring attached to the 2-amino group and the 4H-pyrido[3,2-e][1,3]thiazin-4-one ring system play an important role in inhibitory activity against kainate-induced neurotoxicity. Several analogs bearing a phenyl group with a 4-substituent or five- or six-membered ring fused at the 3,4-positions exhibited potent inhibitory activity against kainate-induced neurotoxicity. Further, some of these compounds exhibited significant suppression of maximal electroshock seizure in mice following oral administration. Of these compounds, 2-[(4-chlorophenyl)(methyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (16i) (YM928) demonstrated the most potent inhibitory effect with an ED50 value of 7.4mg/kg.

Citrus aurantium increases seizure latency to PTZ induced seizures in zebrafish thru NMDA and mGluR's I and II.

Epilepsy is a serious neurological condition and pharmacotherapy is not effective for all patients and causes serious adverse effects and pharmacokinetic and pharmacodynamic interactions. Natural products and ethnobotanical resources can help develop new therapeutic options for conditions like epilepsy. In Puerto Rico, ethnobotanical resources highlight the anxiolytic properties of a tea like preparation made from the leaves of the Citrus aurantium tree or bitter orange. Studies performed with essential oils from the peel of the fruit have shown to increase seizure latency to pentylenetetrazole (PTZ) and maximal electroshock seizure in mice. We characterized the extract composition, and used a model of PTZ induces seizures in the zebrafish and a receptor-ligand binding assay to determine if this preparation has anticonvulsant properties and its mechanism of action. We determined that the aqueous extract made from the leaves of the C. aurantium tree contains hesperidin, neohesperidin, and neohesperidin dihydrochalcone. Using our zebrafish model, we determined that exposure to the C. aurantium 28 mg/mL extract in aquarium water increases seizure latency by 119% compared to controls. We ruled out a mechanism involving GABAA receptors using the selective antagonist gabazine. We used two approaches to study the role of glutamate in the mechanism of the C. aurantium extract. The ligand binding assay revealed C. aurantium extracts at concentrations of 0.42 to 5.6 mg/mL significantly reduced [3H]Glu binding indicating an interaction with glutamate receptors, in particular with NMDA receptors and mGluR II. This interaction was confirmed with our animal model using selective receptor antagonists and we identified an interaction with mGluR I, not observed in the ligand binding experiment. These study provide evidence of the anticonvulsant properties of the aqueous extract made from the leaves of the C. aurantium tree and a mechanism involving NMDA and mGluR's I and II.

Supraadditive effect of hydroethanolic extract of Valeriana wallichii (Indian valerian) root and phenobarbitone against maximal electroshock seizure in mice.

There was a drastic increase in use of herbal preparations in recent years which raise concerns about their toxic and interactive propensity with concomitant diseases and other drugs consumed. Valerian is one of the most widely used herbal medicines in the world. This study analyzed the interaction of Valeriana wallichii (Indian valerian) and Phenobarbitone on anticonvulsant activity using maximal electroshock seizures (MES) in Swiss albino mice. Valeriana wallichii hydroethanolic extract reduced the duration of HLTE with a dose dependant increase in potency at 450 and 900 mg/kg given as intra-peritonial injections. Combination analysis show synergistic interaction between VwHE extract and Phenobarbitone at 50:50, and 25:75 (Vw: PBT) dose ratios, and antagonistic interaction at 75:25 (Vw: PBT) dose ratio in anticonvulsant activity, as indicated by the reduction in duration of HLTE phase of Maximal electroshock seizure model in mice. Phytochemical profile of Valeriana wallichii suggests many active constituents with more than one possible mechanism of action. The interaction could be pharmacokinetic or pharmacodynamic. Large scale studies at various dose ratios and with more parameters including the adverse effect profile of the combination at preclinical and clinical level are required to explore potential therapeutic applications of the combination.

Isovaleramida, principio anticonvulsivo aislado de Valeriana pavonii

Fractioning of an extract of Valeriana pavonii, a native species used in Colombian folk medicine as tranquilizer, led to the isolation and identification of isovaleramide, one of the active constituents responsible for its central nervous system activity as anticonvulsant. Description of the isolation and identification of isovaleramide, an active principle on central nervous system from Valeriana pavonii. The purification of isovaleramide was carried out by chromatographic techniques. Its structural elucidation was determined by nuclear magnetic resonance and mass spectrometry. Maximal electroshock seizure was used as in vivo pharmacological test, additionally in vitro GABA-A/BDZ-binding site studies were performed. Isovaleramide was isolated from the most active fraction of Valeriana pavonii. This compound, at 100 mg/Kg, p.o, evidenced a 90% index protection against the maximal electroshock seizure in mice (MES), comparable to the reference agent: sodium phenytoin (20 mg/kg, p.o, 100%). In the in vitro assay, isovaleramide (300 µM) exhibited a 42% of inhibition of the binding of ³H-FNZ to its sites. Isovaleramide is one of the active anticonvulsant constituents of Valeriana pavonii, for the first time reported in this species. These results support the traditional use of Valeriana pavonii and its interest as a therapeutic source.

Anticonvulsant properties of saponins from Ficus platyphylla stem bark

Preparations of Ficus platyphylla have been used in Nigerian traditional medicine for the management of epilepsy for many years and their efficacy is widely acclaimed among the Hausa communities of northern Nigeria. The anticonvulsant properties of the saponin rich fraction (SFG) obtained from the methanol extract of F. platyphylla stem bark were studied on pentylenetetrazole-, strychnine- and maximal electroshock seizures in mice. Effects of SFG were also examined in murine models for neurological disease and on relevant in vitro targets for anticonvulsant drugs. SFG protected mice against pentylenetetrazole- and strychnine-induced seizures; and significantly delayed the onset of myoclonic jerks and tonic seizures. SFG failed to protect mice against maximal electroshock seizures at doses tested. SFG neither abolished the spontaneous discharges induced by 4-aminopyridine in a neonatal rat brain slice model of tonic–clonic epilepsy nor could it modulate chloride currents through GABA A receptor channel complex in cultured cortical cells. However, it was able to non-selectively suppress excitatory and inhibitory synaptic traffic, blocked sustained repetitive firing (SRF) and spontaneous action potential firing in these cultured cells. Our results provide scientific evidence that F. platyphylla stem bark may contain psychoactive principles with potential anticonvulsant properties. SFG impaired membrane excitability; a property shared by most anticonvulsants particularly the voltage-gated sodium channel (VGSC) blocking drugs, thus supporting the isolation and development of the saponin components of this plant as anticonvulsant agents.

Curcumin has anticonvulsant activity on increasing current electroshock seizures in mice

Epilepsy is one of the most common serious disorders of the brain. Several experimental studies have reported neuroprotective and antioxidant activity of certain natural products like curcumin, an active ingredient of turmeric. The present study was designed to explore the effect of acute administration of curcumin at doses 50, 100 and 200 mg/kg, orally (p.o.) and its chronic (x 21 days) administration in 100 mg/kg, p.o. on increasing current electroshock (ICES) test, elevated plus maze and actophotometer in mice. Curcumin in a dose of 100 mg/kg significantly increased the seizure threshold in ICES test on both acute and chronic administration. The same dose of 100 mg/kg on acute administration showed anxiogenic effect on elevated plus maze and actophotometer test. However, this anxiogenic effect of curcumin disappeared on chronic administration. These results suggest that curcumin appears to possess anticonvulsant activity in mice.

The effects of compound 45/80, morphine, and mast cell depletion on electroshock seizure in mice

The effects of compound 48/80 (C48/80), morphine, and mast cell depletion on maximal electroshock seizure (MES) were studied in Swiss albino mice. An electrical current (60Hz, 0.2 msec) inducing convulsions in 50% of the animals (CC50) was assessed as 46 mA. Compound 48/80 (5 mg/kg) and morphine (100mg/kg) were administered subcutaneously. CC50 was applied separately to electroshock-unexposed animal groups at 15, 30, 60, 120, and 240 min after the onset of the experiment. In untreated controls, the percent of seizure induced by CC50 and percent of death among mice having convulsions were 50 and 20, respectively. After C48/80, a significant increase in rates of seizure at 60th and 120th min and death beyond 60th min (p < .0001) indicates a pro-convulsive action of the drug, probably caused by a reduction in MES threshold. In contrast, rate of seizure tended to decrease following mast-cell depletion, which was readily reversed by C48/80 at the 60th min (p < .0001). Mast-cell depletion, alone or plus morphine, significantly increased the death percentage of convulsions. Morphine alone reduced the percentage of seizure induced by the application of CC50 in the mast-cell depleted animals (anticonvulsive action) but increased the percent of dying animals by as much as 100% at the 30th and 60th min (p < .0001). Combined morphine + C48/80 not only augmented the anticonvulsive effect of morphine at the 30th min but also nullified the rate of death among mice having convulsions. We concluded that compound 48/80 (1) penetrates into the central nervous system to produce a central effect; (2) acts as pro-convulsive, and (3) paradoxically augments the anticonvulsive action of morphine, likely caused by the ability of the compound to increase the permeability of blood-brain barrier for morphine or by the release of histamine from mast cells in the brain, acting as anticonvulsant through the stimulation of H1 receptors or both. The precise mechanism of the increased death rate by C48/80 or morphine in intact and in mast-cell-depleted mice appears to involve pro-convulsive effects, cardiovascular impairment, and respiratory depression. The nullification of morphine-induced lethal toxicity by C48/80 could be due to the antagonistic interaction of the drug with opiate receptors in the brain.

Development and Characterization of Liposome‐Based Formulation of Amiloride Hydrochloride

Amiloride hydrochloride, a generally used diuretic recently has been found effective in the treatment of epilepsy. The side effects of the drug, such as hyperkalemia, hypertension, and hyperaldosteronism were controlled by reducing the dose and targeting the drug to the brain. The objective of this study was to determine the factors influencing encapsulation of amiloride hydrochloride in liposomes and to demonstrate the anti‐epileptic potential of liposomal drug. A series of liposomal formulations of amiloride hydrochloride were prepared by varying the compositions of the formulations. The optimized formulation consisted of 10 mg/mL of amiloride hydrochloride, L‐phosphatidyl choline, lecithin, cholesterol, and butylated hydroxy toulene. The percentage entrapment efficiency in the optimized formulation was 44%. The drug to lipids ratio and L‐phosphatidyl choline: lecithin: cholesterol: butylated hydroxy toulene ratios were 2.0:3.0 and 5:5:5:2, respectively. The formulation showed an in vitro release of 98.17% in 8 hours, and the best fit kinetic model was Peppas model. Treatment with amiloride hydrochloride liposomes resulted in a significant increase in seizure threshold as compared to free drug in increasing current electroshock seizures in mice, which indicated an increase in CNS uptake of drug in liposome formulation.

Synthesis and Anticonvulsant Activity of Some N‐Phenyl‐2‐phtalimidoethanesulfonamide Derivatives

In this study, inspired by the structures of the taltrimide, 2-phthalimidoethanesulphonamide, and the anilide pharmacophore known to be synthetically produced anticonvulsant compounds, fifteen N-phenyl-2-phtalimidoethanesulfonamide derivatives bearing substituents with diverse electronic and hydrophobic features on N-phenyl ring were synthesized. The structural confirmation of the title compounds was achieved by interpretation of spectral and analytical data. The anticonvulsant activity of the title compounds was determined against maximal electroshock seizure in mice at a dose level of 100 mg/kg. The preliminary screening results indicated that the exchange of the N-isopropyl moiety for an N-phenyl ring in the taltrimide molecule abolished the anticonvulsant activity. However, introducing certain substituents, such as nitro, methyl, and chloro, into the N-phenyl ring lead to more active compounds in comparison to the unsubstituted derivatives.

Anticonvulsant effect of wogonin isolated from Scutellaria baicalensis

In previous studies, we identified sedative effects of Scutellaria baicalensis extracts and found that these extracts or their constituents may also have anticonvulsive effects. Wogonin is a natural product isolated from S. baicalensis, which possesses central nervous system effects such as anxiolytic and neuroprotective activities. In this study, we investigated the effects of wogonin on convulsion related behaviors, such as myorelaxation, motor coordination, and anticonvulsant effects of wogonin on chemical induced seizure and electroshock seizure in mice or rats. The effect of wogonin on membrane potential was also observed. Wogonin was intraperitoneally injected into mice or rats 30 min prior to testing. Animals treated with wogonin did not change locomotor activities as well as endurance times on the rota-rod, which indicates that wogonin did not cause a sedative and myorelaxation effect. Wogonin significantly blocked convulsion induced by pentylenetetrazole and electroshock but not convulsion induced by strychnine. Wogonin also significantly reduced the electrogenic response score, but flumazenil treatment reversed this decrease to the level of the control group. The wogonin treatment increased Cl(-)influx into the intracellular area as dose increased. Flumazenil and bicuculline treatment, however, inhibited the Cl(-) influx induced by wogonin. These results indicate that the anticonvulsive effects produced by wogonin were mediated by the GABAergic neuron.

A ketogenic diet and knockout of the norepinephrine transporter both reduce seizure severity in mice

Ketogenic diets (KD) have been known to be effective against epilepsy for more than 80 years, yet the mechanism(s) responsible for this action remain unknown. Norepinephrine (NE) has been shown to have anti-ictal effects against a wide variety of pro-convulsants and in animal models of epilepsy. Loss of noradrenergic activity is also associated with loss of the seizure protection seen following consumption of ketogenic diets. By contrast, knockout of the NE transporter (NET) gene, which elevates synaptic levels of norepinephrine, decreases seizure severity in mice fed normal diets. The purpose of this study was to compare the severity of maximal electroshock seizures in mice lacking the NET (NET KO) with that of wild type (WT) mice fed either a normal or a KD. In general, NET KO mice and mice fed a KD had a similar reduction in seizure severity, and the anticonvulsant effects of the genetic deletion of NET and the ketogenic diet were additive. These observations suggest that, while the noradrenergic system is required for the anti-seizure effects of the KD, additional mechanisms are involved.

Activity profile of pregabalin in rodent models of epilepsy and ataxia

Pregabalin (Lyrica™) is a novel amino acid compound that binds with high affinity to the alpha 2–delta (α 2–δ) auxiliary protein of voltage-gated calcium channels. In vivo, it potently prevents seizures, pain-related behaviors and has anxiolytic-like activity in rodent models. The present studies were performed to determine the profile of pregabalin anticonvulsant activity in a variety of mouse and rat models. In the high-intensity electroshock test, pregabalin potently inhibited tonic extensor seizures in rats (ED 50 = 1.8 mg/kg, PO), and low-intensity electroshock seizures in mice. It prevented tonic extensor seizures in the DBA/2 audiogenic mouse model (ED 50 = 2.7 mg/kg, PO). Its time course of action against electroshock induced seizures in rats roughly followed the pharmacokinetics of radiolabeled drug in the brain compartment. At higher dosages (ED 50 = 31 mg/kg, PO), pregabalin prevented clonic seizures from pentylenetetrazole in mice. In a kindled rat model of partial seizures, pregabalin prevented stages 4–5 behavioral seizures (lowest effective dose = 10 mg/kg, IP), and also reduced the duration of electrographic seizures. Pregabalin was not active to prevent spontaneous absence-like seizures in the Genetic Absence Epilepsy in Rats from Strasbourg (GAERS) inbred Wistar rat strain. Pregabalin caused ataxia and decreased spontaneous locomotor activity at dosages 10–30-fold higher than those active to prevent seizures. These findings suggest that pregabalin has an anticonvulsant mechanism different from the prototype antiepileptic drugs and similar to that of gabapentin except with increased potency and bioavailability. In summary, our results show that pregabalin has several properties that favor treatment of partial seizures in humans.

Anticonvulsant profile and mechanism of action of propranolol and its two enantiomers

The anticonvulsant properties of the ß-adrenoceptor antagonist propranolol and its two enantiomers were examined in various screening tests in order to characterize the anticonvulsant profile as well as the possible molecular mechanism of action. These compounds dose-dependently raised the threshold for tonic electroshock seizures in mice and were effective in the traditional maximal electroshock test (ED 50s 15– 20 mg kg −1i.p.). In combination with clinically used antiepileptics, the anticonvulsant effectiveness of the latter was significantly increased. In the pentylenetetrazol (85 mg kg −1s.c.) seizure threshold test, ( ±)- and ( +)-propranolol were not effective in preventing clonic seizures. In unrestrained rats with chronically implanted electrodes in the dorsal hippocampus, propranolol and its ( +)-enantiomer equieffectively reduced the duration of electrically-evoked hippocampal afterdischarges (10 and 20 mg kg −1i.p.) and raised the focal stimulation threshold (20 mg kg −1i.p.). In amygdala-kindled rats, both drugs ( ≥ 10 mg kg−1 i.p.) reduced the seizure severity from stage 5 (generalized clonic–tonic) to stage 3 (unilateral forelimb) seizures. Furthermore, whole-cell patch-clamp experiments showed that ( +)- as well as ( −)-propranolol ( 10−6to 10−4M) depressed the fast inward sodium current in a concentration- and use-dependent manner in cultured rat cardiomyocytes and inhibited picrotoxin-induced burst firing activity of mouse spinal cord neurones in culture. In conclusion, propranolol and its two enantiomers have anticonvulsant effects in models for generalized tonic–clonic and complex partial seizures which may be accounted for by the sodium channel blocking and not by the ß-adrenoceptor blocking activity.

The Effect of Isradipine on Maximal Electroshock Seizures in Mice

1. The aim of this study was to investigate the possible anticonvulsant effect of a dihydropyridine calcium antagonist, isradipine, which easily crosses the blood–brain barrier displaying high affinity and specificity for the brain L-type voltage-sensitive calcium channel, on maximal electroshock seizures in mice. 2. Isradipine at IP doses of 2.5 mg/kg and 5.0 mg/kg was found to cause a statistically significant increase in the convulsion threshold of maximal electroshock seizures in a dose-dependent manner ( P=0.047 and P=0.022, respectively). 3. It was concluded that the mode of action of the anticonvulsant effect of isradipine is related to blockade of the intraneuronal calcium currents, which play an important role in epileptic activity.

Chinese herb constituent β-eudesmol alleviated the electroshock seizures in mice and electrographic seizures in rat hippocampal slices

We have found that β-eudesmol, a sesquiterpenol constituent of Chinese herb antagonized organophosphate-induced lethal toxicity by reversing the neuromuscular failure and reducing the occurrence of convulsions. Its possible antiepileptic action was further explored in electroshock seizure mice in vivo and in high potassium treated rat hippocampal slices in vitro. At a dose with little effect on the motor activity, β-eudesmol prevented the convulsions and lethality induced by maximal electroshock but not those by pentylenetetrazol or picrotoxin. At subeffective doses, β-eudesmol and phenytoin showed additive effect in preventing electroshock seizures. Extracellular recording of field potentials in CA1 pyramidal layer of hippocampal slices showed that β-eudesmol reduced the high potassium (8.5 μM)-induced electrographic seizure activity. The potential of β-eudesmol to serve as an antiepileptic or a conjuvant in phenytoin therapy is suggested.

Research and development of zonisamide, a new type of antiepileptic drug

Zonisamide (1,2-benzisoxazole-3-methanesulfonamide, AD-810) is a broad spectrum antiepileptic drug which has been launched in Japan and South Korea. It lacks the ureide structure included in most of the existing antiepileptic drugs. Zonisamide was synthesized by the sulfonation and the successive amination of 1,2-benzisoxazole-3-acetic acid in a very poor yield. After several efforts to optimize the compound, zonisamide was selected based on the balance of the efficacy and safety. The yield was greatly improved by the development of new synthetic routes. Zonisamide suppressed maximal electroshock seizures in mice, rats, rabbits and dogs. Its therapeutic plasma concentration range between anticonvulsant and neurotoxic effects was much wider than that of the existing antiepileptic drugs. In electroencephalographic studies on animal models of epilepsy, zonisamide, like phenytoin and carbamazepine, restricted the spread or propagation of seizures and, like sodium valproate, it suppressed the epileptogenic focus activity. Zonisamide was effective in several kindling models. In clinical studies, zonisamide exerted the efficacy against partial seizures (simple, complex, secondarily generalized seizures) and some generalized seizures (tonic-clonic, tonic, atypical absence seizures) that were comparable to that of carbamazepine and sodium valproate, respectively. Zonisamide was also effective in monotherapy. The adverse effects related with zonisamide were mainly drowsiness, ataxia, loss of appetite and gastrointestinal symptoms. Serious adverse effects which may be life-threatening have not been reported.

Selective antagonism of the anticonvulsant effects of felbamate by glycine

Glycine blocked the anticonvulsant effects of felbamate on electroshock- and NMDA-induced seizures in mice. In contrast to its effects on felbamate, glycine either potentiated or had no effect on the anticonvulsant actions of phenytoin, valproate, carbamazepine and phenobarbital on electroshock seizures in mice. The data support that the glycine-felbamate blockade is a specific interaction. Felbamate is likely to be the first clinically available anticonvulsant drug that acts through this unique mechanism.

Dose-response relationships with nimodipine against electroshock seizures in mice.

The anticonvulsant effect of the dihydropyridine calcium channel blocker, nimodipine (NMD) was evaluated against electroshock-induced seizures in mice. At 1 h postdosing, NMD elicited a dose-dependent reduction in the occurrence of tonic hindlimb extension (THE) after maximal electroshock (MES). The calculated ED50 for NMD was 87 mg/kg. A single dose of NMD (75 mg/kg) produced a significant (p < 0.05) reduction in occurrence of THE for < or = 12 h postdosing. NMD was detectable for < or = 6 h, and plasma and brain drug concentrations correlated well (r = 0.677, p < 0.01) for that period. At 1 h postdose, a single dose of NMD (75 mg/kg) produced a 40% increase (p < 0.001) in the threshold for tonic seizures as determined by minimal electroshock (Min-ES). NMD is an effective anticonvulsant against experimental seizures induced by electroshock. The pharmacodynamic effect of NMD appears to extend beyond the time anticipated from the pharmacokinetic profile.

Potent and stereospecific anticonvulsant activity of 3-isobutyl GABA relates to in vitro binding at a novel site labeled by tritiated gabapentin

3-Isobutyl GABA is a derivative of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and is also structurally related to the novel anticonvulsant gabapentin. The S(+) enantiomer of 3-isobutyl GABA blocks maximal electroshock seizures in mice and also potently displaces tritiated gabapentin from a novel high-affinity binding site in rat brain membrane fractions. The R(−) enantiomer is much less active in both assays, suggesting that the gabapentin binding site is involved in the anticonvulsant activity of 3-isobutyl GABA.