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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Barbiturates retain an important place in clinical neurological practice. They are used as both diagnostic and therapeutic drugs, their most common uses being as anticonvulsant and anaesthetic agents. This article explores the current theories explaining the mechanism of action of the barbiturates, with special emphasis on their anaesthetic and anticonvulsant effects. The primary mechanism of action of barbiturates is to increase inhibition through the gamma-aminobutyric acid (GABA) system. Anaesthetic barbiturates also decrease excitation via a decrease in calcium conductance. Phenobarbital (phenobarbitone), the primary anticonvulsant barbiturate, is effective for partial, complex partial and secondarily generalised seizures. While no longer the drug of choice for all these seizure types, it remains an important and useful agent. Mysoline has been shown to be useful in the treatment of essential tremor and several other movement disorders, and as an anticonvulsant. Barbiturates are also used for their sedative-hypnotic properties. A relatively new use is in the evaluation of patients with medically intractable seizure disorders for possible surgical therapy. The roles of methohexital and amobarbital (amylobarbitone) are discussed in the section on barbiturates used as diagnostic agents. The experimental use of barbiturates is also commented on; the most important of these is perhaps the use of barbiturates in cerebral resuscitation.
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PMID:The clinical use of barbiturates in neurological disorders. 172 Mar 79

In this work we have studied in the rat the behavioral effects of the intraperitoneal (i.p.) and intrahippocampal (i.h.) administration of ruthenium red (RuR), an inorganic dye which has been shown to inhibit neurotransmitter release in synaptosomes. The i.p. injection induced initially flaccid paralysis and subsequently generalized tonic-clonic convulsions. It contrast, unilateral RuR microinjection into the CA1 area of the hippocampus produced complex seizure behavior and wet-dog shakes (WDS). The i.p. administration of the serotonin receptor antagonist ketanserin markedly inhibited the WDS induced by i.h. RuR. In contrast, the i.h. injection of ketanserin and of the gamma-aminobutyric acid (GABA) agonists 4,5,6,7-tetrahydroisoxazol[5,4-c]pyridin-3-ol(THIP) and baclofen together with RuR did not affect the frequency of WDS nor the seizure behavior. However, the i.h. injection of the GABA uptake blocker nipecotic acid, simultaneously with RuR, increased the frequency of WDS. The release of [3H]GABA, measured in synaptosomes of different cerebral structures of the rats injected i.p. with RuR, and in slices of the CA1 area after i.h. injection of the dye, was not affected. Histological observations of the injected area showed a specific and intense staining of the somas of the CA1 pyramidal neurons. It is concluded that the convulsant action induced by i.h. RuR microinjection is probably the result of an increased excitability of these CA1 neurons, which is independent of any action on GABA release.
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PMID:Convulsions and wet-dog shakes produced by systemic or intrahippocampal administration of ruthenium red in the rat. 172 73

For the majority of human epilepsy syndromes, the molecular and cellular basis for the epileptic activity remains largely conjectural. The principal hypotheses currently concern: defects in membrane ionic conductances or transport mechanisms; defects in gamma-aminobutyric acid (GABA)-mediated inhibitory processes; and enhanced or abnormal excitatory synaptic action. Substantial evidence exists in humans and animals for acquired abnormalities in excitatory amino acid neurotransmission that may participate in the abnormal patterns of neuronal discharge, and this could provide the morphological basis for a recurrent excitatory pathway sustaining seizure discharges in temporal lobe epilepsy. In practice, two approaches appear significant in the suppression of seizures. One is to act postsynaptically on receptors to decrease the excitation induced by glutamate, and the other is to decrease synaptic release of glutamate and aspartate. Agents acting upon adenosine or GABAB receptors decrease glutamate release in vitro but do not have significant anticonvulsant activity, probably because of their predominant actions at other sites. Lamotrigine blocks stimulated release of glutamate and shows anticonvulsant activity in a wide range of animal models.
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PMID:Excitatory amino acid transmitters in epilepsy. 172 42

Because previous work showed that in the newborn brain, but not in the adult brain, glutamate decarboxylase (GAD) is notably susceptible to heat, we have studied the possible involvement of GAD inhibition in febrile convulsions and the related changes in gamma-aminobutyric acid (GABA) content. Rats of different ages were subjected to hyperthermia, and GAD activity was determined in brain homogenates by measuring the release of 14CO2 from labeled glutamate and by measuring the formation of GABA. The latter method gave considerably lower values than the former in the youngest rats, and was considered more reliable. With this method, we found a 37-48% inhibition of GAD activity in rat pups 2-5 days old, which showed febrile seizures at progressively higher body temperatures, whereas in 10- and 15-day-old animals, which did not show convulsions, GAD activity was not affected by hyperthermia. Whole-brain GABA levels, however, did not change at any age. In contrast to GAD, choline acetyltransferase and lactic dehydrogenase activities were not altered by hyperthermia at any of the ages studied. These results suggest that a decreased efficiency of the inhibitory neurotransmission mediated by GABA, consequent to the inhibition of GAD activity, may be a factor related to febrile convulsions.
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PMID:Inhibition of brain glutamate decarboxylase activity is related to febrile seizures in rat pups. 172 43

The toxicity of hyperbaric oxygen in the central nervous system is expressed by clinical and electroencephalographic (EEG) manifestations resembling those of generalized tonic-clonic seizures. In the search for drugs effective against these seizures, we tested vigabatrin, an irreversible inhibitor of GABA (gamma-aminobutyric acid) transaminase. Five different doses of vigabatrin (ranging from 50 to 500 mg/kg) or vehicle were injected i.p. in rats implanted with cortical electrodes, 4 h prior to exposure to 5 ATA (0.5 MPa) oxygen. EEG and spectral analysis of the background EEG activity were monitored for the different dosages of the drug. The duration of the latent period before the appearance of electrical discharges in the EEG was used as an index of oxygen toxicity. The protective effect of vigabatrin was dose-related, and complete protection against hyperoxic-induced discharges was at 180 mg/kg. The protective effect lasted 24 h and decreased gradually disappearing completely on the third day. An increase in the low frequency bands of the EEG and a decrease in the faster activity were correlated with the vigabatrin dosage injected. Our results suggest that vigabatrin has the potential of being a useful drug in the treatment and prevention of oxygen-induced seizures during hyperbaric oxygen therapy.
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PMID:The effect of vigabatrin on central nervous system oxygen toxicity in rats. 180 44

There is evidence implicating the nigral gamma-aminobutyric acid (GABA) system in the control of seizures. Our previous studies have demonstrated that, in rat pups, intranigrally infused gamma-vinyl-GABA (GVG, 5-20 micrograms) strongly suppresses flurothyl-induced tonic but not clonic seizures. Furthermore, nigral infusions of bicuculline or muscimol abolish the anticonvulsant effect of GVG. In this study, we report that in adult rats bilateral infusions of GVG (20 micrograms) into the substantia nigra pars reticulata (SNR) significantly elevated the thresholds for both clonic and tonic seizures induced by flurothyl. Lower doses (5 and 10 micrograms) did not significantly protect adult rats against seizures, but there was a significant effect of GVG dose. Unilateral infusion of GVG (20 micrograms) in the SNR did not alter the thresholds for flurothyl-induced seizures. Intranigral infusions of bicuculline following pretreatment with GVG abolished the protective effect of GVG on flurothyl-induced seizures, indicating that the anticonvulsant effect of GVG is most likely mediated by the nigral GABAA receptor. Intranigral administration of muscimol after GVG pretreatment significantly suppressed flurothyl-induced seizures, but the combined effect of the two drugs was not as strong as that of GVG alone. The data suggest that GVG protects adult rats against flurothyl-induced seizures. In adults, however, the dose of GVG required to protect against both clonic and tonic seizures is higher than that needed in rat pup SNR.
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PMID:Effects of substantia nigra gamma-vinyl-GABA infusions on flurothyl seizures in adult rats. 181 29

The anticonvulsant profiles of two potent and orally active gamma-aminobutyric acid (GABA) uptake inhibitors, 1-(4,4-diphenyl-3-butenyl)-3-piperidine-carboxylic acid hydrochloride (SK&F 89976-A) and 1-(4,4-diphenyl-3-butenyl)-1,2,5,6-tetrahydro-3-pyridine-carboxylic acid hydrochloride (SK&F 100330-A), were determined with a battery of well-standardized tests in mice and rats and compared with the profiles of phenytoin (PHT), carbamazepine (CBZ), valproate (VPA) and clonazepam (CZP) when subjected to the same tests. ED50 values were calculated and compared with TD50 values for minimal motor impairment to provide protective indexes (PI = TD50/ED50). The anticonvulsant profiles of SK&F 89976-A and SK&F 100330-A were similar and suggest that these compounds raise the threshold for seizure initiation rather than inhibit seizure spread. Like intraperitoneal (i.p.) PHT, CBZ, VPA, and CZP, SK&F 89976-A and SK&F 100330-A inhibited seizures in corneally kindled rats. The profiles of SK&F 89976-A and SK&F 100330-A were most similar to that of CZP and virtually opposite to that of PHT. Intraperitoneal SK&F 100330-A provided complete protection against pentylenetetrazol-induced seizures [subcutaneous (s.c.) PTZ] in mice but was ineffective against seizures induced by maximal electroshock (MES) at doses slightly greater than its TD50. SK&F 100330-A provided complete protection against picrotoxin-induced seizures (s.c. Pic) and against both clonus and forelimb tonic extension induced by NMDA N-methyl-D-aspartate [intracerebral ventricular (i.c.v.)-NMDA] in mice; however, SK&F 100330-A was ineffective against seizures induced by bicuculline (s.c. Bic) and strychnine (s.c. Strych) at doses slightly greater than its TD50. SK&F 89976-A was similar but provided partial protection against NMDA-induced clonus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anticonvulsant profiles of the potent and orally active GABA uptake inhibitors SK&F 89976-A and SK&F 100330-A and four prototype antiepileptic drugs in mice and rats. 183 Nov 22

Single pyramidal cells in the rat hippocampal slice preparation were stimulated by iontophoretic application of excitatory amino acids and acetylcholine. The purine adenosine 5'-monophosphate (AMP), applied iontophoretically, readily depressed acetylcholine stimulated cell firing, was less effective on quisqualic acid stimulated cells and virtually ineffective during stimulation by N-methyl-D,L-aspartate (NMA). Inhibition could be restored if the AMP ejection current was increased 3-fold. In contrast, the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) exerted a comparable level of inhibition under all 3 neuroexcitants. These data support previously published results which suggest that purine mediated inhibition may be reduced during NMDA receptor channel activation. This may have important implications for the action of adenosine during seizures and ischaemic events as well as neuronal phenomena such as long term potentiation.
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PMID:Depression of purine induced inhibition during NMDA receptor mediated activation of hippocampal pyramidal cells--an iontophoretic study. 183 82

The mammalian central nervous system (CNS) contains an abundance of the transition metal zinc, which is highly localized in the neuronal parenchyma. Zinc is actively taken up and stored in synaptic vesicles in nerve terminals, and stimulation of nerve fibre tracts that contain large amounts of zinc, such as the hippocampal mossy fibre system, can induce its release, suggesting that it may act as a neuromodulator. The known interaction of zinc with the major excitatory and inhibitory amino-acid neurotransmitter receptors in the CNS supports this notion. That zinc has a role in CNS synaptic transmission, however, has so far not been shown. Here we report a physiological role for zinc in the young rat hippocampus (postnatal, P3-P14 days). Our results indicate that naturally occurring spontaneous giant depolarizing synaptic potentials (GDPs) in young CA3 pyramidal neurones, mediated by the release of GABA (gamma-aminobutyric acid), are induced by endogenously released zinc. These synaptic potentials are inhibited by specific zinc-chelating agents. GDPs are apparently generated by an inhibitory action of zinc on both pre- and postsynaptic GABAB receptors in the hippocampus. Our study implies that zinc modulates synaptic transmission in the immature hippocampus, a finding that may have implications for understanding benign postnatal seizures in young children suffering with acute zinc deficiency.
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PMID:A physiological role for endogenous zinc in rat hippocampal synaptic neurotransmission. 184 46

Several 1-acyl-2-pyrrolidinone derivatives were synthesized as derivatives of gamma-aminobutyric acid (GABA), and their pharmacological activities and stabilities were investigated. The derivatives showed anticonvulsant effect on picrotoxin-induced seizure at a dose of 200 mg/kg. In particular, 1-decanoyl-2-pyrrolidinone (7) and 1-dodecanoyl-2-pyrrolidinone (8) had a high activity. The anticonvulsant activity showed a dose dependency. Some of 1-acyl-2-pyrrolidinone derivatives prolonged sleeping time which was induced by sodium pentobarbital and showed a recovery from disruption of the memory of passive avoidance response, which was induced by an electroconvulsive shock. As shown by the results of the stability study of 1-acetyl-2-pyrrolidinone (1), it was degraded in an acidic buffer and an alkaline buffer although 2-pyrrolidinone was stable. 1-Acyl-2-pyrrolidinone derivatives were degraded in liver and brain homogenates of mouse and rat. They showed a degradation rate in rat plasma. Conversion of 8 to GABA in mouse liver homogenate was demonstrated. These results suggested that the pharmacological activity of 1-acyl-2-pyrrolidinone is probably due to the release of GABA by hydrolysis of derivatives although further work is necessary.
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PMID:Synthesis and anticonvulsant activity of 1-acyl-2-pyrrolidinone derivatives. 184 29


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