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)

The administration of L-alpha-amino-beta-chloropropionic acid hydroxamide (L-ACPH) to mice brought about an inhibition in GABA-T activity in the brain of the animals, a significant inhibition occurring with dosage levels as low as 0.25 mmol/kg. Minimum levels of GABA-T activity were reached 3 h after administration of the drug. Brain glutamic acid decarboxylase, DOPA decarboxylase and aspartate aminotransferase activities were not altered by the L-ACPH but alanine aminotransferase activity was totally inhibited. Slight changes in structure caused great changes in the potency of the drugs. For example, the elongation of the L-ACPH structure by one carbon, or a change in the configuration of the amino group from L- to D-, caused a significant decrease in GABA inhibition. The chloro and hydroxamide groups were necessary for inhibitory activity. The administration of L-ACPH to mice delayed the onset of drug induced seizures but had a less noticeable effect against maximal electroshock. The addition of L-ACPH to crude extracts from brain, or to preparations of semipurified GABA-T, also inhibited GABA-T activity. Again the development of the inhibition was time-dependent. Possible mechanisms of action with respect to L-ACPH induced inhibition of GABA-T activity are discussed in the light of the data presented.
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PMID:Alteration of GABA metabolism in mammalian brain by l-alpha-amino-beta-chloropropionic acid hydroxamide and related compounds. 45 23

Bilateral injection of 2-amino-7-phosphonoheptanoate (2-APH), a selective N-methyl-D-aspartate (NMDA) receptor antagonist, into substantia nigra pars reticulata (SNpr) significantly and dose-dependently suppressed tonic pentylenetetrazol (PTZ) seizures (100 mg/kg, i.p.). The results confirm the anticonvulsant effectiveness of 2-APH and the capacity of SNpr to modulate PTZ seizure activity. The anti-PTZ effect of 2-APH was significantly attenuated by muscimol, co-infused into SNpr. This result supports the hypothesis, drawn from earlier studies, that intranigral muscimol can interfere with the anti-PTZ actions of other intranigral treatments.
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PMID:Anti-pentylenetetrazol effect of intranigral 2-amino-7-phosphonoheptanoate attenuated by muscimol. 164 12

Genetically epilepsy prone rats (GEPR) are hypersensitive to various epileptogenic treatments and undergo characteristic generalized seizures when exposed to potent acoustic stimulation. We have studied the sensitivity of GEPR to high atmospheric pressure. Threshold pressures for behavioral symptoms of the high pressure neurological syndrome (HPNS) were recorded in normal Sprague-Dawley (SD) and GEPR (which originate from the SD strain) of both sexes. The threshold pressure (TP) for tremor and for convulsion was significantly lower in GEPR than in SD rats. The protective action of the NMDA receptor antagonist D-2-amino-7-phosphono-heptanoate (D-APH) was tested on both strains of rats. D-APH, 90 mg/kg ip was more protective against tremor in SD than in GEPR. Female GEPR were not protected against tremor. Protection against clonic seizures was similar in both sexes of GEPR and female SD rats while SD males were not significantly protected. None of the animals treated with D-APH developed the tonic phase of seizures. Blockade of the NMDA receptor with D-APH brought the threshold for convulsions in GEPR to a similar pressure to that obtained in SD vehicle-injected controls. This findings suggests the involvement of the excitatory amino acid system in the hypersensitivity of GEPR to high atmospheric pressure.
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PMID:The high pressure neurological syndrome in genetically epilepsy prone rats: protective effect of 2-amino-7-phosphono heptanoate. 202 31

The ability of excitatory amino acid receptor agonists, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and quisqualate to produce seizures was determined in 1-2 day old epileptic and non-epileptic (carrier) chicks. Both compounds produced prolonged clonic seizures in epileptic chicks at doses which were not convulsant in carrier chicks. Seizures produced in epileptics by AMPA were suppressed by the quisqualate antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), but were not prevented by pretreatment with competitive (2-amino-7-phosphonoheptanoic acid, APH) or non-competitive (MK-801) NMDA (N-methyl-D-aspartate) receptor antagonists. These data do not support the hypothesis that NMDA receptors work in concert with quisqualate receptors. Binding sites for [3H]AMPA were characterized in cerebral hemispheres of both epileptic and carrier chicks. Analysis of the data revealed no significant alterations in the binding affinity (KD) or the number of binding sites (Bmax) of AMPA to tissue preparations from epileptic chickens when compared to carriers. The latter data does not explain the increased susceptibility of epileptic fowl to the convulsant effects of quisqualate and AMPA.
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PMID:Quisqualate receptors in epileptic fowl: the absence of coupling between quisqualate and N-methyl-D-aspartate receptors. 215 99

The comparative effect of intracerebral injection of 2-APH, a selective antagonist for N-methyl-D-aspartate (NMDA) receptors, into the substantia innominata (SI) and the amygdala (AM) of AM-kindled rats was examined. The intra-SI injection (ipsilateral to the kindled AM) induced a transient incoordination followed by immobility with loss of the rightening reflex, beginning at about 5 min following the injection and lasting for about 3 h. When the animals were stimulated at the previously established generalized seizure triggering threshold (GST) 45 min after the injection, the kindled seizure regressed to earlier stages although the afterdischarge (AD) duration remained unchanged. At 24 h, kindled seizure was readily activated at the GST. When 2-APH was injected into the kindled AM, no behavioural change occurred but AM stimulation at the GST failed to produce AD 45 min after the injection. Kindled seizure could be elicited, however, when the stimulus intensity was increased. This elevation of the GST lasted for 1-18 days. The findings suggest that NMDA receptors in the AM and SI play a differential role in AM seizure initiation and propagation, respectively. They also provide further support to the role presumed to be played by the SI in transforming the limbic seizure into motor seizure.
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PMID:Suppression of amygdaloid kindled convulsion following unilateral injection of 2-amino-7-phosphonoheptanoic acid (2-APH) into the substantia innominata of rats. 254 69

2-APH is an antagonist of excitation due to dicarboxylic amino acids and has a protective effect against several types of experimental seizures. We have studied its effect on EEG of rats. Following either intracerebroventricular or intraperitoneal administration of 2-APH produces slow waves of high voltage in central cortex. The anticonvulsant action of this drug may be related to altered activity in neurones of this area.
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PMID:Effects of 2-amino-7-phosphonoheptanoic acid on EEG of rats. 257 3

We have used limbic convulsions induced by systemic pilocarpine in rats combined with focal intracerebral injections concurrently to study the initiation and spread of seizure activity. Protection against pilocarpine-seizure development by antagonism of excitatory or facilitation of inhibitory neurotransmission at focal sites establishes the anatomical circuits involved in the propagation of seizures. The excitatory amino acid antagonist 2-amino-7-phosphonoheptanoate (APH, selective for the NMDA preferring glutamate receptor subtype) is potently anticonvulsant after bilateral focal injections into the habenula or mediodorsal thalamus. The dose of APH required to give sustained protection against pilocarpine-induced convulsions is 10 pmol for lateral habenula and 50 pmol for mediodorsal thalamus. The GABA agonist muscimol produces a similar sustained protection following focal injections (100 pmol/side) into either the lateral habenula or the mediodorsal thalamus. An overall decrease in the efferent neurotransmission of these two brain regions results in a strong anticonvulsant effect indicating their importance in modulating limbic seizure activity.
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PMID:Decrease in excitatory transmission within the lateral habenula and the mediodorsal thalamus protects against limbic seizures in rats. 283 55

Motor limbic seizures occur following a systemic injection of pilocarpine (380 mg/kg) in rats. Focal injection of the selective N-methyl-D-aspartate receptor antagonist, (+/-)-2-amino-7-phosphonoheptanoic acid (2-APH, 5-20 pmol), bilaterally into the entopeduncular nucleus (EP) prior to pilocarine blocks these seizures. Muscimol (50 pmol), a potent gamma-aminobutyric acid receptor agonist, injected bilaterally into EP produces a similar protection against pilocarpine-induced seizures. Thus by blocking excitatory neurotransmission or facilitating inhibition within the EP, the severity of limbic seizures can be reduced.
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PMID:2-Amino-7-phosphonoheptanoic acid (2-APH) infusion into entopeduncular nucleus protects against limbic seizures in rats. 300 43

The role of excitatory synaptic activity at various brain regions in the development and spread of seizure activity has been investigated by the focal microinjection of 2-amino-7-phosphono-heptanoate (2-APH), a selective antagonist at the N-methyl-D-aspartate preferring receptor, or gamma-D-glutamyl-aminomethyl sulphonate (GAMS), a partially selective antagonist at the kainate receptor. In genetically epilepsy prone rats the seizure response to a loud sound in most effectively suppressed by focal injections of 2-APH, 0.1-1.0 nmol, in the inferior colliculus. Protection is also seen after injections of 2-APH, 25 nmoles, in the substantia nigra (pars reticulata) or the midbrain reticular formation. Motor limbic seizures induced by pilocarpine, 380 mg/kg intraperitoneally, are prevented by prior injection into the substantia nigra, pars reticulata, or the entopeduncular nucleus, of 2-APH, 10 nmol or 10 pmol, respectively. Similar protection follows the injection of 2-APH, 1-5 pmol in the piriform cortex. The convulsant effects of pilocarpine are also blocked by the focal injection of GAMS, 10 nmol in the entopeduncular nucleus. This experimental approach can indicate critical sites at which seizure activity is initiated in particular models (e.g., inferior colliculus in sound-induced seizures, and piriform cortex in limbic seizures) and the pathways controlling seizure expression, such as the basal ganglia outputs. It also identifies specific receptors at which anticonvulsant drugs may operate.
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PMID:Anti-epileptic effects of focal micro-injection of excitatory amino acid antagonists. 304 15

Pretreatment of rats with the excitatory amino acid antagonist 2-amino-7-phosphonoheptanoic acid (2-APH; 0.5 mmol/kg, i.p.) protected against insulin-induced clonic seizures. Complete protection was observed in 38% of the rats and partial protection in an additional 50%. Lesioning of the corticostriatal pathway by frontal cortical ablation caused decreases in the striatal levels of aspartate (-28%) and glutamate (-18%), an increase in striatal glutamine level (45%), and decreased high-affinity uptake of D-[3H]aspartate (-27%) in the lesioned dorsal neostriatum. Insulin-induced hypoglycemia caused a predicted sharp increase in aspartate level (165%) and decreased glutamate (-20%) and glutamine (-38%) levels in the intact striatum. Pretreatment of rats with 2-APH significantly reversed the insulin-induced changes in striatal aspartate, glutamate, and glutamine levels, especially in the intact hemisphere. In normoglycemic control rats, the "metabolic," i.e., concentration in the lesioned hemisphere, aspartate pool constituted 72% and the "synaptic," i.e., the concentration difference between the intact and lesioned hemispheres, 28% of the total striatal aspartate pool. 2-APH had no effect on the level of "metabolic" aspartate in the striata of normoglycemic rats but caused an almost complete suppression of "synaptic" aspartate. Following insulin-induced hypoglycemia, the "metabolic" aspartate pool doubled, whereas the "synaptic" aspartate pool increased 3.5-fold in the absence of 2-APH. The insulin-induced rise in "synaptic" aspartate level was almost completely blocked by 2-APH (a 5% rise instead of a 3.5-fold rise).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:2-Amino-7-phosphonoheptanoic acid inhibits insulin-induced convulsions and striatal aspartate accumulation in rats with frontal cortical ablation. 329 20


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