Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AHR-12245, 2-(4-chlorophenyl)-3H-imadazo[4,5-b]pyridine-3-acetamid, ethosuximide, Na valproate, phenytoin, and clonazepam were evaluated in mice and rats with a battery of well-standardized anticonvulsant test procedures. The results obtained indicate that the anticonvulsant profile of AHR-12245 is similar to that for ethosuximide and clonazepam. AHR-12245 is effective in nontoxic intraperitoneal doses in mice by the maximal electroshock seizure (MES), pentylenetatrazol (s.c. PTZ), bicuculline, and picrotoxin tests but ineffective against strychnine-induced seizures; it is effective after nontoxic oral doses in both mice and rats by the s.c. PTZ test and ineffective by the MES test. The candidate antiepileptic substance was also ineffective against seizures induced in amygdala and corneally kindled rats. The PIs for AHR-12245 by the s.c. PTZ test were 4.5 to 12 times higher than those for the prototype agents, except that for clonazepam when administered orally in mice. The in vitro studies indicate that AHR-12245 is a weak inhibitor of benzodiazepine (BDZ) receptor binding but does inhibit adenosine uptake. These results indicate that AHR-12245 is a relatively nontoxic agent with a profile of anticonvulsant action which suggests it should be useful in generalized absence seizures.
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PMID:AHR-12245: a potential anti-absence drug. 190 25

ADD 17014[1-(4-chlorophenyl)-5-(4-pyridyl) delta 2-1,2,3-triazoline], is a representative member of a hitherto unknown, structurally novel family of anticonvulsant agents. The anticonvulsant profile of ADD 17014 following intraperitoneal (i.p.) and oral administration in mice and rats was evaluated using a battery of well-standardized anticonvulsant tests and compared with phenytoin (PHT), phenobarbital (PB), ethosuximide (ESM), and valproate (VPA). The results indicate that ADD 17014 is effective in nontoxic i.p. doses in mice by the maximal electroshock seizure (MES), Metrazol (subcutaneous, s.c. Met), bicuculline (s.c. Bic) and picrotoxin (s.c. Pic) tests, but ineffective against strychnine-induced seizures; it is also effective after nontoxic oral doses in both mice and rats by the MES and s.c. Met tests. Protective indices (PI = TD50/ED50), calculated from i.p. data in mice, were highest for ADD 17014 by the s.c. Met (26.02) and s.c. Bic (93.93) tests; the PIs, after oral administration in mice and rats, were equal to or higher than those of the prototype agents. In vitro receptor binding studies of ADD 17014 and potential metabolites indicated no significant inhibitory activity except for the beta-amino alcohol, which displaced almost 93% of [3H]glutamate from the glutamate receptors, suggesting that ADD 17014 may be functioning as a prodrug and an excitatory amino acid antagonist. The overall results indicate that ADD 17014 is a relatively nontoxic agent that more closely resembles PB and VPA, with a broad and unique spectrum of anticonvulsant activity.
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PMID:Triazolines XV. Anticonvulsant profile of ADD 17014, a potentially unique 1,2,3-triazoline antiepileptic drug, in mice and rats. 337 Dec 87

Progabide (4-([(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)-methylene]amino) butanamide) is a gamma-aminobutyric acid (GABA) receptor agonist which readily enters the brain. In the body, progabide is metabolized to three active metabolites: SL 75102, gabamide and GABA. Progabide and SL 75102 readily enter the brain and GABA and gabamide are also formed within this organ. Both progabide and SL 75102 exhibit a broad spectrum of anticonvulsant activities against seizures which involve GABA-mediated events (bicuculline, picrotoxinin and pentylenetetrazol) or which are apparently independent of GABAergic mechanisms (penicillin, strychnine, electroshock and audiogenic seizures). These data support the hypothesis that direct GABA receptor stimulation is an effective means of controlling convulsions of various origins. Progabide and SL 75102 have relatively minor secondary effects in comparison to commonly used antiepileptics. Myorelaxation occurs, but only at doses higher than the ED50 values in convulsant tests. Furthermore, these compounds are not sedative. Finally, these GABA agonists have a complex action in the extrapyramidal system. Anticonvulsant doses are antagonistic to dopamine receptor-mediated behaviors, whereas much lower doses seem to facilitate the effects of dopaminergic transmission.
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PMID:gamma-Aminobutyric acid (GABA) receptor stimulation. I. Neuropharmacological profiles of progabide (SL 76002) and SL 75102, with emphasis on their anticonvulsant spectra. 627 29

A series of 2,2-diarylethylamine derivatives has been examined for potential antidepressant activity in the tetrabenazine (TBZ) test. Diethanolamine 4 (McN-4187) was one of the more potent compounds despite its polar alcohol functionalities [ED50 values of 15 mg/kg (exploratory activity) and 1.5 mg/kg (ptosis)]. Structure-activity relationships are described. Minor structural modifications of 4 were sufficient to strongly attenuate activity. For example, changing one phenyl group to a 2-thienyl, cyclohexyl, or 3,4-dimethoxyphenyl group greatly reduced activity. Replacing both phenyl groups by 4-chlorophenyl groups also dissipated activity. The bisethanol functionality was not essential for activity (q.v. 17-19 in Table I). Although 17-19 compared well with 4 in the TBZ assay, only 19 (like 4) showed a satisfactory profile in the maximal electroshock seizure threshold test.
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PMID:Structure-activity studies on antidepressant 2,2-diarylethylamines. 674 90

A novel purine, (N6-2-(4-chlorophenyl)-bicyclo 2.2.2.-octyl-(3)-adenosine) EMD 28422 increases the binding of (3H) diazepam to benzodiazepine receptors in vivo within 10 min after intraperitoneal administration. This increase in (3H) diazepam binding is due to an increase in the number of benzodiazepine receptors (Bmax) rather than an altered affinity of the radioligand for receptor (Kd), EMD 28422 protects mice against pentylenetetrazole and caffeine-induced seizures and potentiates the anticonvulsant action of subeffective doses of diazepam in a dose-dependent fashion. Furthermore, EMD 28422 also produces a significant increase in punished responding in a conflict situation (rats), and a long-lasting, dose-dependent decrease in spontaneous motor activity (mice). In contrast, neither EMD 39011 nor adenosine (the two component molecules of EMD 28422) possess anticonvulsant properties at doses up to five mole-equivalents of EMD 28422. These data indicate that the purine EMD 28422 produces a spectrum of pharmacologic effects similar to the benzodiazepines, yet in contrast to the benzodiazepines (and other purines), increases benzodiazepine receptor number. Thus, EMD 28422 may represent the prototype of a class of synthetic purines exerting a unique neurochemical effect on benzodiazepine receptors and possessing several therapeutic actions of the benzodiazepines.
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PMID:Pharmacologic and behavioral effects of EMD 28422: a novel purine which enhances (3H) diazepam binding to brain benzodiazepine receptors. 739 62

Injecting 0.5-1.0 microgram of cholera toxin into rat hippocampus induces a chronic epileptic focus which generates interictal discharges and brief epileptic seizures intermittently over the following seven to 10 days. Here we examined the electrophysiological properties of hippocampal slices prepared from these rats three to four days after injection, at the height of the epileptic syndrome. These slices generated epileptic discharges in response to electrical stimulation of afferent pathways. In many cases epileptic discharges occurred spontaneously in the CA3 subregion; these usually lasted < 200 ms, but they could last < 0.6 s. Intracellular recordings from pyramidal layer cells revealed depolarization shifts synchronous with the epileptic field potentials. These depolarization shifts had slow onsets compared with those induced by blocking inhibition with bicuculline (depolarizations started a mean of 57 ms before, and reached 5.2 mV by, the onset of the cholera toxin epileptic field potential, compared with 12 ms and 3.6 mV respectively for 70 microM bicuculline methiodide). Extracellular unit recordings showed that the slow predepolarization seen in the cholera toxin focus was associated with an acceleration of the firing of other pyramidal layer neurons. The epileptic activity in this model cannot be attributed to the loss of synaptic inhibition, because inhibitory postsynaptic potentials could be evoked when the synchronous bursts were blocked by increasing [Ca2+]o from 2 to 8 mM. Observations of monosynaptic inhibitory postsynaptic currents isolated by application of 20 microM 6-cyano-7-nitroquinoxaline-2,3-dione, 50 microM DL-2-amino-5-phosphonovaleric acid and 100-200 microM 3-amino-2-(4-chlorophenyl)-2-hydroxy-propylsulphonic acid showed a small effect of the toxin only on the time course of the inhibitory postsynaptic current. On the other hand, there were significant changes in the intrinsic properties of individual neurons. The membrane potentials of cells in the cholera toxin focus did not differ from those in slices from rats injected with vehicle solution, but their input resistances were significantly increased. Unlike the other cellular changes in this model, the increase in input resistance was not seen in slices exposed acutely to 1 micrograms/ml cholera toxin for 30 min, suggesting there may be morphological changes in the chronic focus. Action potential accommodation and the slow afterhyperpolarization were depressed in both acute and chronic epileptic tissue, indicating impairments of Ca(2+)- and/or voltage-dependent K+ currents, and we conclude that these provide the most likely basis for cholera toxin epileptogenesis.
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PMID:Epileptic focus induced in rat by intrahippocampal cholera toxin: neuronal properties in vitro. 810 80

The effects of alaproclate and GEA-857 (2-(4-chlorophenyl)-1,1-dimethylethyl 2-amino-3-methylbutanoate) on the production of cyclic GMP in the rat cerebellum in vivo induced by stimulation of N-methyl-D-aspartate (NMDA) receptors were studied. Alaproclate per se at a dose of 20 mg/kg subcutaneously, did not influence the basal cGMP level. The increase in cGMP induced by harmaline (20 mg/kg subcutaneously) was dose-dependently antagonized by alaproclate (5-40 mg/kg subcutaneously). S-(-)-Alaproclate was 2-5 times more potent than the R-(+)-enantiomer. GEA-857 which in contrast to alaproclate is a very weak 5-HT uptake inhibitor shared the ability of alaproclate to inhibit the effect of harmaline on cGMP accumulation with similar potency to S-(-)-alaproclate. Alaproclate at 15 mg/kg subcutaneously blocked the increase in cGMP in cerebellum caused by NMDA itself at 200 mg/kg subcutaneously. In contrast to alaproclate, the K+ channel antagonist, 4-aminopyridine, 5 mg/kg subcutaneously, produced per se an increase in cGMP levels in the rat cerebellum by 300% which was antagonized by the NMDA receptor antagonists, dizocilpine, phencyclidine and (+/-)-CCP, the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester and by alaproclate. Alaproclate. Alaproclate and GEA-857 antagonized seizures induced by NMDA, 200 mg/kg subcutaneously at doses similar to those antagonizing the harmaline- and NMDA-induced elevation of cerebellar cGMP. Neither alaproclate nor GEA-857 caused any behavioural effects typical for uncompetitive NMDA receptor antagonists except a slight increase in motor activity and sniffing. The effect of alaproclate on the NMDA receptor-mediated increase in cGMP in rat cerebellum in vivo might be due to blockade of the cation channel of the NMDA receptor complex previously observed in in vitro experiments and these compounds seems to belong to the group of low-affinity uncompetitive NMDA receptor antagonists that might have clinical interest.
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PMID:NMDA receptor-mediated increase in cyclic GMP in the rat cerebellum in vivo is blocked by alaproclate and GEA-857. 906 41

The compound 5-(4-chlorophenyl)-2,4-dihydro-4-ethyl-3H-1,2,4-triazol-3-one (MDL 27,192) was evaluated in a variety of rodent models to assess its anticonvulsant profile and its potential neuroprotective activity. MDL 27,192 demonstrated anticonvulsant activity in a wide range of epilepsy models that are genetically-based (audiogenic seizures in the seizure susceptible DBA/2J or Frings mouse; spike wave seizures in genetic absence epilepsy rats of Strasbourg (GAERS), electrically-based (MES seizures in mice and rats, corneally-kindled seizures in rats) and chemically-based (bicuculline, PTZ, picrotoxin, 3-mercaptopropionic acid, quinolinic acid and strychnine). When compared to valproate, orally administered MDL 27,192 was 17-48-fold more potent as an anticonvulsant and showed a safety index one to three-fold greater. Following a timed intravenous administration of PTZ to mice, MDL 27,192, but not phenytoin or carbamazepine, consistently increased the latencies to first twitch and clonus. MDL 27,192 was active in a genetic model of absence epilepsy, the GAERS rat model. These data indicate that MDL 27,192 likely exerts its anticonvulsant action by affecting seizure spread and by raising seizure threshold. MDL 27,192 did not display any signs of tolerance following subchronic (15 day) administration. In tests of neuroprotective potential, MDL 27,192 reduced infarct volume in a permanent middle cerebral artery occlusion model of focal cerebral ischemia in rats and reduced the loss of hippocampal dentate hilar neurons in an animal model of unilateral head injury. In summary, MDL 27,192 possesses a broad-spectrum anticonvulsant profile. The potential for reduced tolerance and neuroprotective activity are additional positive features of MDL 27,192's preclinical profile.
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PMID:Preclinical characterization of MDL 27,192 as a potential broad spectrum anticonvulsant agent with neuroprotective properties. 916 90

The cannabinoid CB1 receptor has been shown to be the primary site of action for cannabinoid-induced effects on the central nervous system. Activation of this receptor has proven to dampen neurotransmission and produce an overall reduction in neuronal excitability. Cannabinoid compounds like delta9-tetrahydrocannabinol and cannabidiol have been shown to be anticonvulsant in maximal electroshock, a model of partial seizure with secondary generalization. However, until now, it was unknown if these anticonvulsant effects are mediated by the cannabinoid CB1 receptor. Likewise, (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN 55,212-2), a cannabimimetic compound that has been shown to decrease hyperexcitability in cell culture models via the cannabinoid CB1 receptor, has never been evaluated for anticonvulsant activity in an animal seizure model. We first show that the cannabinoid compounds delta9-tetrahydrocannabinol (ED50 = 42 mg/kg), cannabidiol (ED50 = 80 mg/kg), and WIN 55,212-2 (ED50 = 47 mg/kg) are anticonvulsant in maximal electroshock. We further establish, using the cannabinoid CB1 receptor specific antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A) (AD50 = 2.5 mg/kg), that the anticonvulsant effects of delta9-tetrahydrocannabinol and WIN 55,212-2 are cannabinoid CB1 receptor-mediated while the anticonvulsant activity of cannabidiol is not. This study establishes a role for the cannabinoid CB1 receptor in modulating seizure activity in a whole animal model.
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PMID:Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects. 1177 37

The anticonvulsant effect of cannabinoids has been shown to be mediated through activation of the cannabinoid CB(1) receptor. This study was initiated to evaluate the effects of endogenously occurring cannabinoids (endocannabinoids) on seizure severity and threshold. The anticonvulsant effect of the endocannabinoid, arachidonylethanolamine (anandamide), was evaluated in the maximal electroshock seizure model using male CF-1 mice and was found to be a fully efficacious anticonvulsant (ED(50)=50 mg/kg i.p.). The metabolically stable analog of anandamide, (R)-(20-cyano-16,16-dimetyldocosa-cis-5,8,11,14-tetraenoyl)-1'-hydroxy-2'-propylamine (O-1812), was also determined to be a potent anticonvulsant in the maximal electroshock model (ED(50)=1.5 mg/kg i.p.). Furthermore, pretreatment with the cannabinoid CB(1) receptor specific antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A) completely abolished the anticonvulsant effect of anandamide as well as O-1812 (P< or =0.01, Fisher exact test), indicating a cannabinoid CB(1) receptor-mediated anticonvulsant mechanism for both endocannabinoid compounds. Additionally, the influence of cannabinoid CB(1) receptor endogenous tone on maximal seizure threshold was assessed using SR141716A alone. Our data show that SR141716A (10 mg/kg i.p.) significantly reduced maximal seizure threshold (CC(50)=14.27 mA) compared to vehicle-treated animals (CC(50)=17.57 mA) (potency ratio=1.23, lower confidence limit=1.06, upper confidence limit=1.43), indicating the presence of an endogenous cannabinoid tone that modulates seizure activity. These data demonstrate that anandamide and its analog, O-1812, are anticonvulsant in a whole animal model and further implicate the cannabinoid CB(1) receptor as a major endogenous site of seizure modulation.
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PMID:Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity. 1235 70


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