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 extracellular concentration of glutamate has previously been reported to increase to more than 10-fold the basal level during seizure activity. In the present study, we tested whether localized increases in extracellular glutamate concentration influence the rhythm of epileptiform discharges in the low-magnesium epilepsy model. In hippocampal slices of guinea-pigs, epileptiform activity was induced by omission of magnesium from the bath fluid. Glutamate and its subreceptor agonists N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) were ejected into different strata of the CA3 and CA1 regions using microiontophoretic and micropressure application. Glutamate, NMDA and AMPA applied to the CA3 region, but not to the CA1 region, induced a short-lasting increase in epileptiform discharge frequency, often followed by a transient reduction. The effect was most pronounced with application into the stratum lacunosum-moleculare of the CA3 region and could only be evoked in slices exceeding 400 microns in thickness. The effects on the rhythm of epileptiform discharges induced by NMDA and AMPA were blocked by their specific receptor antagonists. They were not influenced by application of GABAA and GABAB receptor antagonists. Changes in somatic membrane potential of CA3 pyramidal neurons did not correlate with changes in the rhythm of epileptiform discharges elicited in this region. The transient suppression of epileptiform discharges that followed the increase in discharge frequency was abolished by an adenosine A1 receptor antagonist. We propose that localized increases in extracellular glutamate concentration modify the rhythm of epileptiform discharges due to changes in neuronal network activity.
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PMID:Effects of glutamate application on the rhythm of low magnesium-induced epileptiform activity in hippocampal slices of guinea-pigs. 892 5

The adenosine A3 receptor is expressed in brain, but the consequences of activation of this receptor on electrophysiological activity are unknown. We have characterized the actions of a selective adenosine A3 receptor agonist, 2-chloro-N6-(3-lodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA), and a selective A3 receptor antagonist, 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1, 4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS 1191), in brain slices from rat hippocampus. In the CA1 region, activation of A3 receptors had no direct effects on synaptically evoked excitatory responses, long-term potentiation, or synaptic facilitation. However, activation of A3 receptors with Cl-IB-MECA antagonized the adenosine A1 receptor-mediated inhibition of excitatory neurotransmission. The effects of Cl-IB-MECA were blocked by pretreatment with MRS 1191, which by itself had no effect on A1 receptor-mediated responses. The presynaptic inhibitory effects of baclofen and carbachol, mediated via GABA(B) and muscarinic receptors, respectively, were unaffected by Cl-IB-MECA. The maximal response to adenosine was unchanged, suggesting that the primary effect of Cl-IB-MECA was to reduce the affinity of adenosine for the receptor rather than to uncouple it. Similar effects could be demonstrated after brief superfusion with high concentrations of adenosine itself. Under normal conditions, endogenous adenosine in brain is unlikely to affect the sensitivity of A1 receptors via this mechanism. However, when brain concentrations of adenosine are elevated (e.g., during hypoxia, ischemia, or seizures), activation of A3 receptors and subsequent heterologous desensitization of A1 receptors could occur, which might limit the cerebroprotective effects of adenosine under these conditions.
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PMID:Activation of hippocampal adenosine A3 receptors produces a desensitization of A1 receptor-mediated responses in rat hippocampus. 898 83

The effects of repeated administration of the selective adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), the selective adenosine A2 receptor agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA), the non-selective adenosine A1/A2 receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA), the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3 dipropylxanthine (DPCPX) and the selective adenosine A2 receptor antagonist 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-(4,3-e)1,2,4-triazolo(1,5 -c)pyrimidine (SCH 58261) on the anticonvulsant activity of 3-(2-carboxypiperazine-4y)propenyl-1-phosphonic acid (CPPene), a selective N-methyl-D-aspartate receptor antagonist, were evaluated in audiogenic sensible dilute brown agouti mice DBA/2J (DBA/2). Mice were treated intraperitoneally twice daily for 7 days with CCPA 0.11 mg/kg, 2HE-NECA 0.056 mg/kg, NECA 0.11 mg/kg, DPCPX 0.5 mg/kg and SCH 58261 0.5 mg/kg followed by 2 vehicle injections (the wash-out period of 1 day) and subsequently CPPene was administered intracerebroventricularly. Audiogenic seizures were delivered 30 min after CPPene administration. Repeated treatment with CCPA significantly reduced the anticonvulsant properties of CPPene against audiogenic seizures. A weak and not significant reduction of anticonvulsant effects of CPPene was observed following repeated administration of NECA, whilst the repeated administration of 2HE-NECA did not decrease the antiseizure activity of CPPene. Conversely, repeated administration of DPCPX markedly potentiated the anticonvulsant properties of CPPene, whilst the repeated treatment with SCH 58261 did not increase the anticonvulsant activity of CPPene. The present results indicate that repeated treatment with CPPA, a selective adenosine A1 receptor agonist, decreases the anticonvulsant properties of CPPene, whilst the repeated administration of DPCPX, a selective adenosine A1 receptor antagonist, potentiates the anticonvulsant effects of CPPene. The compounds acting as selective agonists or antagonists of adenosine A2 receptors do not affect the antiseizure activity of CPPene. In conclusion, the repeated interaction of agonists or antagonists with adenosine A1 receptors seems to induce changes on anticonvulsant activity of CPPene, whereas drugs acting at adenosine A2 receptors do not.
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PMID:Repeated treatment with adenosine A1 receptor agonist and antagonist modifies the anticonvulsant properties of CPPene. 899 6

Despite its potent proconvulsant effects in vitro, the adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) does not induce seizures when administered in vivo. This contrasts with the effects of less selective adenosine antagonists such as theophylline or cyclopentlytheophylline, and led us to reexamine the nature of DPCPX-induced epileptiform activity. In the present study, we report that proconvulsant effects of bath-applied DPCPX in rat hippocampal slices are only observed after a preceding stimulus such as NMDA receptor activation or brief tetanic stimulation. While this may be due to the absence of a basal "purinergic tone", the relatively high interstitial concentrations of adenosine present in the slice suggest that access of the drug to A1 receptors may instead be prevented by tightly coupled endogenous adenosine, with the ternary adenosine-A1 receptor-G protein complex stabilised in the high-affinity conformation by a coupling cofactor. This implies that a substantial percentage of adenosine A1 receptors are inactive under physiological conditions, but that access of adenosine A1 receptor antagonists may be facilitated under pathological conditions. Once induced, DPCPX-evoked spiking persists for long periods of time. A "kindling" effect of A1 receptor blockade is unlikely, since persistent spiking is not usually observed with less selective A1 antagonists even after prolonged application. Alternatively, endogenous adenosine released during increased neuronal activity may activate A2 receptors during selective A1 blockade. The most important factor determining the duration of DPCPX-induced spiking, however, may be a persistence of the drug in the tissue and subsequent access to the A1 receptor via a membrane-delineated pathway, since DPCPX-induced spiking could be shown to decrease markedly after a transient superfusion of theophylline. This hypothesis, which implies that the apparent affinity of adenosine antagonists for the A1 receptor is in part a function of their membrane partitioning coefficient, is supported by a close correlation between alkylxanthine logP values obtained from the literature and their Ki value at A1 receptors, but not at the enzyme phosphodiesterase, whose xanthine binding site is presented to the cytosol. The implications for the therapeutic value of purinergic drugs are discussed.
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PMID:Alkylxanthine adenosine antagonists and epileptiform activity in rat hippocampal slices in vitro. 906 16

1. The effects of adenosine, the adenosine analogue, 2-chloroadenosine (2-CADO), the specific adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA) and A2 receptor agonist 5'-(N-cyclopropyl) carboxamidoadenosine (CPCA), were examined against seizures induced by acute administration of pentylenetetrazole (PTZ), 60 mg kg-1, and PTZ kindled seizures, in rats. 2. Adenosine 1000 mg kg-1, i.p., 5 min pretreatment and CPA 10 mg kg-1 i.p., 60 min pretreatment, showed significant protection against acute PTZ-induced seizures while, CPCA up to 10 mg kg-1 was ineffective. The adenosine analogue 2-CADO in a dose of 5 mg kg-1 was only partially protective and on increasing the dose to 10 mg kg-1, this protection was lost. 3. Theophylline, a non specific adenosine receptor antagonist at 50 mg kg-1 and the specific adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), at 1 mg kg-1, if administered before the maximally protective doses of adenosine and CPA, completely reversed the protection afforded by them against PTZ seizures. While, pretreatment with the adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), failed to reverse the protection. 4. Adenosine and the adenosine A1 receptor agonist in doses that protected against seizures after acute PTZ administration, offered only incomplete protection when tested against PTZ kindled seizures. 5. The effects of adenosine and adenosine receptor agonists on mean arterial pressure, heart rate and rectal temperature were studied, to rule out the possibility of their systemic effects mediating the protection of PTZ seizures. All these agents produced a fall in mean arterial pressure, heart rate and hypothermia in the doses exhibiting an anticonvulsant response. While the effect on blood pressure and heart rate was immediate i.e. seen within 5 min and, maintained throughout the observation period, the development of hypothermia lagged behind the onset of hypotension and bradycardia. However, there was no correlation between haemodynamic and hypothermic response and the anticonvulsant effect. 6. The results indicate that the adenosine mediated anticonvulsant effect is via stimulation of A1 receptors. Hypotension and hypothermia do not appear to contribute to the protection observed with adenosine and the adenosine A1 receptor agonists.
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PMID:Effect of adenosine receptor modulation on pentylenetetrazole-induced seizures in rats. 911 21

1. Recent studies have shown that fluspirilene, a dopamine D2 receptor antagonist which is a long-acting neuroleptic useful in the maintenance therapy of schizophrenic patients, also displays Ca2+ channel blocking activity. In the present study, we have investigated the effect of fluspirilene on synaptic transmission and epileptiform activity induced in slices of hippocampus and amygdala. 2. Fluspirilene reversibly suppressed the field excitatory postsynaptic potential (f-e.p.s.p) in a concentration-dependent manner in the area CA1 of the hippocampus without affecting the size and shape of fibre volley. Fluspirilene also inhibited the intracellularly recorded e.p.s.p. in amygdala neurones without affecting the resting membrane potential or neuronal input resistance. 3. Fluspirilene increased the ratio of paired-pulse facilitation suggesting a presynaptic mode of action. 4. Epileptiform activity induced in the disinhibited slices was suppessed by fluspirilene in a concentration-dependent manner. This antiepileptic effect was occluded in slices pretreated with the adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA). 5. It is concluded that fluspirilene-induced synaptic inhibition is probably due to a reduction in presynaptic Ca2+ currents. In clinical trials, the low incidence of seizures provoked by fluspirilene might be related to its intrinsic ability to inhibit synaptic transmission and epileptiform activity.
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PMID:Inhibition of synaptic transmission and epileptiform activity in central neurones by fluspirilene. 913 24

The influence of 2-chloroadenosine, a non-metabolizable adenosine A1 receptor agonist, was tested on the development of electrically kindled amygdala and on the seizure responses of fully kindled rats. Focal intra-amygdaloid injection of 2-chloroadenosine (1-10 nmol/0.5 microl) 20 min before applying the daily kindling stimulus prevented the development of the kindling process. The behavioural seizure score and the afterdischarge duration were reduced below their initial values. The antiepileptogenic effects of 1 and 10 nmol of 2-chloroadenosine were reversible 8-10 days after withdrawal of the drug. When 2-chloroadenosine was tested on fully developed stage 5 amygdala-kindled seizures, it increased the generalised seizure threshold in a dose-dependent manner. A maximum efficiency of 125% (P < 0.001) was achieved with 5 nmol and the median effective dose was 0.55 nmol. Higher doses resulted in the reduced anticonvulsant effect (P < 0.05). With the same daily stimulation, 2-chloroadenosine 5 nmol in 0.5 microl vehicle, significantly reduced the maximum seizure score by 90%, the afterdischarge duration by 88% and completely blocked the generalised seizure duration. The antiseizure activity of the drug lasted for 3 days. In conclusion, 2-chloroadenosine not only acts as an anticonvulsant against electrically induced kindled seizures as described here, and against audiogenic seizures, electroshock and a variety of chemical convulsants as described by others, it prevents the development of the epileptic state by kindling-stimulation, i.e., it is antiepileptogenic. We theorise here that this is due to its blockade of presynaptic glutamate release.
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PMID:The protective effect of 2-chloroadenosine against the development of amygdala kindling and on amygdala-kindled seizures. 917 49

We tested the effects of electrographic seizures (EGSs) elicited in a remote site (area CA3) on the induction of long-term potentiation (LTP) in area CA1 of the rat hippocampal slice. Induction of LTP was inhibited only when the LTP-inducing stimulus was delivered during the period of post-ictal depression (5-10 min period of field response depression) following an evoked EGS. It was not inhibited during the tonic firing phase of the EGS. The time course for the recovery of the ability to induce LTP after an EGS matched the recovery of field responses from post-ictal depression. Moreover, the magnitude of LTP was inversely proportional to the duration of post-ictal depression. Delaying the onset of depression with the adenosine A1 receptor antagonist 8-cyclopentyltheophylline (CPT) permitted LTP induction at a time point when it would normally be suppressed. Finally, the inhibitory effects of post-ictal depression on LTP induction were not restricted to electrically evoked EGSs, as LTP could not be induced during the depressed phase following a spontaneous EGS elicited in 10 mM K+ medium. These results demonstrate that the inhibition of LTP induction following epileptiform activity in vitro is in part a consequence of post-ictal depression of responses.
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PMID:Post-ictal depression transiently inhibits induction of LTP in area CA1 of the rat hippocampal slice. 919 85

The relationships of adenosine A1 receptor agonists and antagonists in combination with angiotensin II (AT II) and its analogue sarmesin in PTZ (pentylenetetrazol) kindling in ICR mice were studied. The occurrence of clonic and tonic seizures and the latency to their onset in PTZ kindled mice was determined. Combination of adenosinergic and AT II-ergic agents significantly reduced the incidence of clonic seizures in PTZ kindling without changing the latency. Pretreatment with 8-p-Sulfophenyl-theophylline (8-p-SPT) reversed the anti-convulsant effect of sarmesin.
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PMID:Interaction of angiotensin II and adenosine receptors in pentylenetetrazol-induced kindling in mice. 947 88

Although the selectivity and potency of adenosine amine congener (ADAC) at adenosine A1 receptors are similar to other highly selective agonists at this receptor type, the chemical structure of the N6 substituent is completely different. We now demonstrate that the characteristics of the therapeutic profile of ADAC are distinct from those observed during our previous studies of adenosine A1 receptor agonist-mediated neuroprotection. Most significantly, chronic treatment with low microgram doses of ADAC (25-100 microg/kg) protects against both mortality and neuronal damage induced by 10 min bilateral carotid occlusion in gerbils. At higher chronic doses, the statistical significance of the protective effect is lost. Acute preischemic administration of the drug at 75-200 microg/kg also results in a statistically significant reduction of postischemic mortality and morbidity. These data indicate that, contrary to other adenosine A1 receptor agonists whose chronic administration enhances postocclusive brain damage, ADAC may be a promising agent in treatment of both acute (e.g., cerebral ischemia) and chronic (seizures) disorders of the central nervous system in which adenosine A receptors appear to be involved.
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PMID:Protection against ischemic damage by adenosine amine congener, a potent and selective adenosine A1 receptor agonist. 1022 68


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