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)

(+-)-5-Aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d] [a,d]cyclohepten-5,10-imine (ADCI), a tricyclic compound structurally related to dizocilpine (MK-801) and carbamazepine, was a potent anticonvulsant in the mouse maximal electroshock seizure test when administered i.p. (ED50, 8.9 mg/kg) or p.o. (ED50, 23.5 mg/kg), but failed to cause motor impairment except at substantially higher doses (TD50 values, 49.2 mg/kg i.p. and 293 mg/kg p.o.). ADCI was also protective against chemically induced seizures in mice, including those produced by 4-aminopyridine (ED50, 7.1 mg/kg s.c.) and pentylenetetrazol (ED50, 37.4 mg/kg s.c.). In addition, ADCI antagonized the behavioral effects and lethality of s.c. administered N-methyl-D-aspartate (NMDA: ED50, 15.2 mg/kg), but was a weaker antagonist of kainate-induced clonic seizures (ED50, 33.0 mg/kg), indicating that the drug is a selective functional NMDA antagonist. In common with other NMDA antagonists, ADCI retarded the development of amygdaloid kindled seizures in rats, but failed to attenuate the afterdischarge duration in fully kindled animals. Whole cell voltage clamp recordings from cultured hippocampal neurons demonstrated that ADCI selectively blocks inward current responses to NMDA in a use-dependent fashion without affecting responses to kainate or quisqualate, indicating that ADCI is a selective open channel (uncompetitive) blocker of the NMDA receptor-ionophore complex. ADCI blocked NMDA-evoked inward current responses with a potency (IC50, 14 microM) similar to that with which it displaces [3H]-1-[1-(2-thienyl)-cyclohexyl]piperidine from binding to NMDA receptor channels in rat brain homogenates (IC50, 11.3 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anticonvulsant activity of the low-affinity uncompetitive N-methyl-D- aspartate antagonist (+-)-5-aminocarbonyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine (ADCI): comparison with the structural analogs dizocilpine (MK-801) and carbamazepine. 192 Jan 22

The role of nitric oxide (NO) in the genesis of motor and electrocortical seizures elicited by administration of excitatory amino acid agonists into the deep prepiriform cortex (DPC) has been evaluated. Motor and electrocortical seizures occurred in rats receiving unilateral microinjections into the DPC of either N-methyl-D-aspartate (NMDA, 5 and 10 nmol) or kainate (KA, 100 pmol). The selective NMDA receptor antagonist 2-amino-7-phosphonoheptanoate (APH), when microinjected into DPC, prevented the development of seizures induced by both NMDA and KA injected in the same site. In addition, methylene blue (20 nmol, which prevents activation of soluble guanylate cyclase) or NG-monomethyl-L-arginine (NMMA, 40 nmol; a specific inhibitor of nitric oxide synthesis), when microinjected into DPC 15 min prior to either NMDA or KA, significantly protected against seizures elicited by both excitatory amino acid agonists. These data confirm the role of excitatory amino acid transmission in the genesis of seizures elicited from the deep prepiriform cortex. They further suggest that activation of excitatory amino acid receptors within the DPC leads to the release of a substance which shares properties with EDRF/NO and contributes to the genesis of seizure activity in this area.
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PMID:Role of nitric oxide in the genesis of excitatory amino acid-induced seizures from the deep prepiriform cortex. 195 95

CNQX and DNQX are compounds that have recently been reported to show potent non-NMDA excitatory amino acid receptor antagonist activity. Effects of these compounds on seizures induced by homocysteine thiolactone and quisqualic acid were studied in order to examine the pharmacological properties of these compounds. In a dosage of 1.16 micrograms intracerebroventricularly (ICV), CNQX prolonged the latency to the onset of quisqualate-, but not homocysteine-induced seizures. DNQX was not effective when given either ICV or systemically, although a 3.78 micrograms dose of DNQX given ICV markedly increased the variability in latency to seizure onset, suggesting a combination of pro- and anticonvulsant effects. Higher dosages of both CNQX and DNQX induced seizure-like activity after ICV injection. These data confirm that CNQX has pharmacological effects corresponding to its effects on cellular responses to quisqualate and kainate agonists, but these effects are weak and may limit its usefulness as a pharmacological tool.
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PMID:A slight anticonvulsant effect of CNQX and DNQX as measured by homocysteine- and quisqualate-induced seizures. 197 50

Anticonvulsant properties of CGP 37849 and CGP 39551, two novel phosphono-amino acids which are competitive NMDA receptor antagonists, were examined in rodents. At optimal pretreatment times CGP 37849 suppressed electroshock-induced seizures in mice and rats with ED50s ranging from 8 to 22 mg/kg after oral administration, and 0.4 to 2.4 mg/kg after i.v. and i.p. injection. Relative to CGP 37849, CGP 39551 was more potent after p.o. (ED50 3.7-8.1 mg/kg), and less potent after i.v. or i.p. treatment (ED50 2.7-8.7 mg/kg). Following oral treatment, the duration of action of CGP 37849 was about 8 h, while CGP 39551 still showed good activity after 24 h (ED50 8.7 mg/kg, mouse; 21 mg/kg, rat). Both compounds were anticonvulsant at doses below those at which overt behavioural side effects were apparent. CGP 39551 delayed the development of kindling in rats at doses of 10 mg/kg p.o. and above, and showed weak anticonvulsant activity against pentylenetetrazol-evoked seizures. CGP 37849 and CGP 39551 are the first competitive NMDA antagonists to show oral anti-convulsant properties in a therapeutically-useful dose-range, and hence are interesting candidates for novel antiepileptic therapy in man.
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PMID:The competitive NMDA receptor antagonists CGP 37849 and CGP 39551 are potent, orally-active anticonvulsants in rodents. 197 33

Intrastriatal injection of the glutamate analogue N-methyl-D-aspartate (NMDA, 25 nmol) in postnatal day (PND) 7 rats provides a rapid, sensitive, and reproducible assay in which potential neuroprotective strategies against excitotoxic neuronal injury can be examined in vivo. Brain injury is quantified 5 days postinjection by comparison of the weights of the injected and contralateral cerebral hemispheres. Intraperitoneal injections (15 minutes post-NMDA) of competitive and noncompetitive NMDA receptor antagonists attenuated the severity of NMDA-induced brain injury. The rank order of neuroprotective potency of these antagonists was CGS-19755 greater than DOIPG greater than dextromethorphan greater than HA-966. Of these compounds only the competitive antagonist CGS-19755 provided complete neuroprotection. NMDA-mediated brain injury was also reduced by the specific sigma receptor ligands +PPP and haloperidol (35% reduction). In contrast, drugs that reduce presynaptic neurotransmitter release (adenosine) or enhance neuronal inhibition (baclofen) were not effective against NMDA toxicity. Although all five of the anticonvulsants tested limited NMDA-induced seizure activity, only carbamazepine reduced NMDA-mediated brain injury (36% reduction). These findings extend earlier observations that NMDA receptor antagonists can limit NMDA-induced toxicity in vivo and suggest that sigma receptors contribute to the pathophysiology of NMDA-mediated brain injury in vivo. Furthermore, NMDA-induced seizures and brain injury appear dissociable in this in vivo model. The results illustrate important practical limitations of neuroprotection in vivo vs. in vitro.
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PMID:Pharmacology of N-methyl-D-aspartate-induced brain injury in an in vivo perinatal rat model. 197 20

The protection by pyroglutamic acid (CAS 98-79-3) and derivatives Ia-i (injected i.p.) against glutamate- and NMDA (N-methyl-D-aspartate) (i.c.v.) induced seizures in mice has been studied in comparison with known antiepileptics and antagonists of excitatory aminoacids. The potency of pyroglutamic acid and some derivatives (Id,f,g,h) against glutamate-induced convulsions was similar to that shown by glutamic acid diethylester and by valproic acid. Interestingly, pyroglutamic acid did not affect NMDA-induced convulsions which were well antagonized by both 2-amino-5-phosphono valeric acid and by diazepam. Thus, pyroglutamic acid may represent the starting for synthesis of excitatory aminoacid antagonists acting at non NMDA receptors.
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PMID:Protection by pyroglutamic acid and some of its newly synthesized derivatives against glutamate-induced seizures in mice. 198 9

Quinolinic acid (QUIN), an endogenous neuroactive metabolite of tryptophan, administered i.c.v. in doses of 45, 90, 180, and 270 nmol in rabbits, demonstrated an excitatory action on the sleep-wake cycle and behaviour. Doses of 90 and 180 nmol completely abolished the paradoxical sleep phase and induced a 5-fold decrease in the duration of deep slow wave sleep (dSWS) in the first hour of the experiment. Light slow wave sleep (1SWS) duration was not altered. Sniffing behaviour was markedly activated by 180 nmol of QUIN. A dose of 270 nmol completely blocked sleep, diminished the restoration of sleep, induced panic behaviour and, in some animals, induced generalized tonic seizures. Data suggest an excitatory action of QUIN on NMDA receptors involved in the regulation of the sleep-wake cycle in the rabbit.
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PMID:Effect of quinolinic acid on wakefulness and sleep in the rabbit. 214 74

In order to determine the gamma-L-glutamyl-L-aspartate (gamma-LGLA) site of action in excitatory amino acids (EAA) systems, we studied the gamma-LGLA anticonvulsant activity against seizures induced in mice by pentylenetetrazol, picrotoxin and EAA agonists. The mice were protected against seizures induced by pentylenetetrazol (80 mg/kg s.c.) and picrotoxin (2.75 mg/kg s.c.) after intraperitoneal administration of gamma-LGLA with two significant peak effects around the doses of 0.25 and 200 mumol/kg as revealed by the dose-response curves obtained in both experiments. Use of an intracerebroventricular co-injection procedure showed that gamma-LGLA dose dependently suppressed the seizures induced by NMDA (1 nmol/mouse) with a maximal effect at 80 nmol/mouse but, at the same dose, it only slightly suppressed seizures induced by kainate (0.3 and 0.8 nmol/mouse) or by quisqualate (18.5 nmol/mouse). The anticonvulsant activity of gamma-LGLA on these chemically induced seizures is consistent with an antagonistic action of gamma-LGLA on NMDA receptor subtypes.
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PMID:NMDA antagonist properties of gamma-L-glutamyl-L-aspartate demonstrated on chemically induced seizures in mice. 214 37

NMDA-sensitive L-[3H]glutamate binding was examined in the brains of El mice, a genetic animal model of epilepsy, and in ddY mice. In whole brain, Scatchard analysis showed that both stimulated and unstimulated El mice had significantly lower Bmax values for binding than did ddY mice. In regional studies, the binding of NMDA-sensitive L-[3H]glutamate was significantly less in the cerebral cortex of both stimulated and unstimulated El mice than in that of ddY mice. These data suggest that NMDA receptors may be involved in the genetic susceptibility of El mice to seizures.
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PMID:NMDA-sensitive L-[3H]glutamate binding in cerebral cortex of El mice. 214 24

The adrenal stress hormones glucocorticoids (GCs) impair the ability of hippocampal neurons to survive neurological insults, including hypoxia-ischemia and seizure. These insults are thought to be toxic via a cascade of excessive synaptic concentrations of excitatory neurotransmitters (e.g. glutamate), activation of the NMDA receptor, and pathologic mobilization of cytosolic calcium post-synaptically. We tested whether GCs exacerbate these insults by exacerbating this 'NMDA cascade'. We sought a toxin which damaged independently of the NMDA cascade, and whose toxicity was enhanced by GCs. After testing a number of neurotoxins, we found that the antimetabolite 3-acetylpyridine (3AP) fit this requirement. We then tested if blockade of the NMDA receptor blocks the ability of GCs to enhance 3AP toxicity. Hippocampi were microinfused with 160 micrograms of 3AP. Elevating circulating GC concentrations to the range seen during major stressors for a week before and after microinfusion caused a significant increase in 3AP-induced damage (when compared to adrenalectomized rats kept GC-free for the same period). Infusing the NMDA receptor blocker APV with 3AP did not alter the toxicity in adrenalectomized rats. However, APV reduced 3AP-induced damage in GC-treated rats to levels seen in adrenalectomized rats. This suggests that GCs endanger hippocampal neurons by enhancing glutamatergic signals and/or enhancing vulnerability to such signals. As a possible explanation for this observation, GCs inhibit glucose uptake into hippocampal neurons, and numerous steps in the NMDA cascade are exacerbated when neuronal energy stores are diminished.
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PMID:Glucocorticoid endangerment of hippocampal neurons is NMDA-receptor dependent. 214 1


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