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

Adenosine is a ubiquitous neuromodulator that increases sleep, inhibits seizures, and promotes neuroprotection. Many of these effects are mediated by A1 receptors, but A1 receptors are expressed in most brain regions, and distinguishing the precise site of action of adenosine is challenging. To test the role of adenosine in different hippocampal regions, we have used the Cre-loxP system and an adeno-associated viral (AAV) vector to focally delete endogenous adenosine A1 receptors in the hippocampus. Microinjection of an AAV vector containing the gene for Cre recombinase induced intense, focal, neuron-specific recombination in reporter mice. In a separate line of mice with loxP sites flanking the major coding exon for the adenosine A1 receptor, this AAV-Cre markedly reduced A1 receptor mRNA and focally abolished the postsynaptic response to adenosine without any change in basic electrophysiologic properties. Adenosine inhibits signaling between CA3 and CA1 neurons, but it is unclear from pharmacologic studies whether this response is caused by presynaptic or postsynaptic effects. Deletion of A1 receptors from CA3 neurons abolished this response to adenosine, but deletion of A1 receptors from CA1 neurons had no effect, demonstrating a presynaptic site of action. This transduction knock-out technique holds enormous potential for dissecting the functions of different CNS pathways.
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PMID:Focal deletion of the adenosine A1 receptor in adult mice using an adeno-associated viral vector. 1284 80

We examined the effects of the antioxidant propolis on seizures induced by kainic acid (KA). Sprague-Dawley rats received propolis (75 and 150 mg/kg, p.o.) five times at 12 h intervals. KA (10 mg/kg, i.p.) was injected 1 h after the last propolis treatment. Pretreatment with propolis significantly attenuated KA-induced seizures and KA-induced increases in hippocampal AP-1 DNA binding activity in a dose-dependent manner. KA induced increases in the levels of malondialdehyde and protein carbonyl, and a decrease in the ratio of GSH/GSSG. These oxidative stresses and neuronal degenerations were significantly attenuated by pretreatment with propolis. The neuroprotective effects of propolis appeared to be counteracted by adenosine receptor antagonists [A1 antagonist, 8-cyclopentyl-1,3-dimethylxanthine (25 or 50 microg/kg); A2A antagonist, 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (0.5 or 1 mg/kg); and A2B antagonist, alloxazine (1.5 or 3.0 mg/kg)]. However, this counteraction was most pronounced in the presence of the A1 antagonist. Our results suggest that the protective effect of propolis against KA-induced neurotoxic oxidative damage is, at least in part, via adenosine A1 receptor modulation.
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PMID:Antioxidant propolis attenuates kainate-induced neurotoxicity via adenosine A1 receptor modulation in the rat. 1473 73

Epileptiform activity is a state often induced in vitro in order to study seizures and antiepileptic/anticonvulsant drugs. Traditional methods of evaluating drug effects have commonly relied upon measuring changes in the frequency and duration of such events. We have used a recently developed mathematical technique based on periodic orbit analysis to investigate the effect of atropine (a muscarinic antagonist) on epileptiform activity induced by soman (an irreversible acetylcholinesterase inhibitor), 4-aminopyridine (a K+ channel blocker) and 8-cyclopentyl-1,3-dipropylxanthine (an adenosine A1 receptor antagonist) in the guinea-pig hippocampal slice. This technique showed that significant changes in periodic orbits can occur without an accompanying change in burst rate. These results suggest that periodic orbit analysis may be useful in detecting and predicting novel actions of anticonvulsant drugs.
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PMID:Periodic orbit analysis reveals subtle effects of atropine on epileptiform activity in the guinea-pig hippocampal slice. 1500 80

Extracellular recording techniques have been used in the guinea pig hippocampal slice preparation to investigate the electrophysiological actions of the organophosphate (OP) anticholinesterase soman. When applied at a concentration of 100 nM, soman induced epileptiform activity in the CA1 region in approximately 75% of slices. This effect was mimicked by the anticholinesterases paraoxon (1 and 3 microM), physostigmine (30 microM), and neostigmine (30 microM), thus providing indirect evidence that the epileptiform response was mediated by elevated acetylcholine levels. Soman-induced bursting was inhibited by the muscarinic receptor antagonists atropine (concentrations tested, 0.1-10 microM), telenzepine (0.03-3 microM), AF-DX116 [11-(2-[(diethylamino)methyl]-1-piperidinyl acetyl)-5,11-dihydro-6H-pyrido 92.b-b) (1,4)-benzodiazepin-6-one] (0.3-300 microM), and biperiden (0.1-10 microM) and by the benzodiazepine anticonvulsants diazepam (3-30 microM) and midazolam (3-30 microM), but it was not inhibited by the nicotinic antagonists mecamylamine (30 microM) and methyllycaconitine (300 nM). In contrast to soman-induced epileptiform activity, bursting induced by the K(+) channel blocker 4-aminopyridine (30 microM), the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (30 nM) or perfusion with low Mg(2+) buffer was insensitive to atropine (10 microM). The ability of muscarinic antagonists and benzodiazepines to inhibit soman-induced epileptiform activity is in accordance with the in vivo pharmacology of soman-induced seizures and suggests that the guinea pig hippocampal slice preparation may provide a useful tool for the evaluation of novel anticonvulsant therapies for the treatment of seizures related to OP poisoning.
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PMID:A guinea pig hippocampal slice model of organophosphate-induced seizure activity. 1503 2

G protein-activated inwardly rectifying K+ channels (GIRK, also known as Kir3) are activated by various G protein-coupled receptors. GIRK channels play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate. Modulation of GIRK channel activity may affect many brain functions. Here, we report the inhibitory effects of various antidepressants: imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, maprotiline, and citalopram, on GIRK channels. In Xenopus oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, the various antidepressants tested, except fluvoxamine, zimelidine, and bupropion, reversibly reduced inward currents through the basal GIRK activity at micromolar concentrations. The inhibitions were concentration-dependent with various degrees of potency and effectiveness, but voltage- and time-independent. In contrast, Kir1.1 and Kir2.1 channels in other Kir channel subfamilies were insensitive to all of the drugs. Furthermore, GIRK current responses activated by the cloned A1 adenosine receptor were similarly inhibited by the tricyclic antidepressant desipramine. The inhibitory effects of desipramine were not observed when desipramine was applied intracellularly, and were not affected by extracellular pH, which changed the proportion of the uncharged to protonated desipramine, suggesting its action from the extracellular side. The GIRK currents induced by ethanol were also attenuated in the presence of desipramine. Our results suggest that inhibition of GIRK channels by the tricyclic antidepressants and maprotiline may contribute to some of the therapeutic effects and adverse side effects, especially seizures and atrial arrhythmias in overdose, observed in clinical practice.
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PMID:Inhibition of G protein-activated inwardly rectifying K+ channels by various antidepressant drugs. 1515 May 31

The role of adenosine A1 receptors in the activity of drugs and substances protecting against seizures evoked by mitochondrial toxin, 3-nitropropionic acid (3-NPA) was studied in mice. Non-selective A1/A2 adenosine receptor antagonist, aminophylline and selective A1 adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) diminished the anticonvulsive effects of diazepam, phenobarbital, valproate and gabapentin. In contrast, A1/A2 adenosine receptor antagonist, 8-(p-sulfophenyl)theophylline (8pSPT) not penetrating via blood-brain barrier was ineffective. Aminophylline and DPCPX but not 8pSPT also reversed the protective action of A1/A2 adenosine receptor agonist, 2-chloroadenosine (2-CADO) and selective A1 adenosine receptor agonist, R-N6-phenylisopropyloadenosine (R-PIA), against 3-NPA-evoked convulsions. Obtained results suggest that the central adenosine A1 receptor stimulation may play a role in the anticonvulsive potential of diazepam, phenobarbital, valproate and gabapentin in a novel model of 3-NPA-evoked seizures. Moreover, concomitant application of aminophylline with these drugs may reduce their clinical antiepileptic efficacy, especially among patients suffering from seizures related to the disturbances of mitochondrial respiratory chain.
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PMID:Adenosine A1 receptors and the anticonvulsant potential of drugs effective in the model of 3-nitropropionic acid-induced seizures in mice. 1557 77

After exposure to asphyxia, infants may develop both prolonged, clinically evident seizures and shorter, clinically silent seizures; however, their effect on cerebral tissue oxygenation is unclear. We therefore examined the hypothesis that the increase in oxygen delivery during postasphyxial seizures might be insufficient to meet the needs of increased metabolism, thus causing a fall in tissue oxygenation, in unanesthetized near-term fetal sheep in utero (gestational age 125+/-1 days). Fetuses were administered an infusion of the specific adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, followed by 10 mins of asphyxia induced by complete umbilical cord occlusion. The fetuses then recovered for 3 days. Sixty-one episodes of electrophysiologically defined seizures were identified in five fetuses. Tissue PO(2) (tPO(2)) did not change significantly during short seizures (<3.5 mins), 5.2+/-0.2 versus baseline 5.6+/-0.1 mm Hg (NS), but fell to 2.2+/-0.2 mm Hg during seizures lasting more than 3.5 mins (P<0.001). During prolonged seizures, cortical blood flow did not begin to increase until tPO(2) had begun to fall, and then rose more slowly than the increase in metabolism, with a widening of the brain to blood temperature gradient. In conclusion, in the immature brain, during prolonged, but not short seizures, there is a transient mismatch between cerebral blood flow and metabolism leading to significant cerebral deoxygenation.
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PMID:Cerebral oxygenation during postasphyxial seizures in near-term fetal sheep. 1572 87

The involvement of adenosine receptor agonists in benzodiazepine withdrawal signs was evaluated as the seizure susceptibility of mice. The concomitant administration of subthreshold dose of pentetrazole (55.0 or 60.0 mg/kg, s.c.) with flumazenil (10.0 mg/kg, i.p.) in mice chronically treated with temazepam or diazepam induced the appearance of withdrawal signs: clonic seizures, tonic convulsions and death episodes. The administration of the selective A1 (CPA-N6-cyclopentyladenosine), A2A (CGS 21680-2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride) and the non-selective A1/A2A (NECA-5'-N-ethylcarboxamidoadenosine) adenosine receptor agonists (i.p.) evoked the significant attenuation of benzodiazepine withdrawal signs, and these effects were more expressed in temazepam- than in diazepam-dependent mice. CPA has shown the most apparent and dose-dependent attenuating effect. The results confirm that adenosine A1 and A2A receptors are involved in benzodiazepine withdrawal signs, and adenosine A1 receptor plays a predominant role in this phenomenon.
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PMID:Influence of adenosine receptor agonists on benzodiazepine withdrawal signs in mice. 1622 42

This study examines the anticonvulsant profile of interactions between 2-chloro-N6-cyclopentyladenosine (CCPA, a selective adenosine A1 receptor agonist) and four conventional antiepileptic drugs (AEDs: carbamazepine--CBZ, phenobarbital, phenytoin and valproate) in the mouse maximal electroshock seizure (MES) model. Acute adverse effects produced by AEDs in combination with CCPA were determined in the chimney test (motor performance) and passive avoidance task (long-term memory). Results indicate that CCPA administered alone at 0.25 and 0.5 mg/kg significantly elevated the electroconvulsive threshold in mice. Additionally, the agent at a sub-threshold dose of 0.125 mg/kg potentiated the anticonvulsant activity of CBZ by reducing its ED50 in the MES test from 11.2 to 7.7 mg/kg (p < 0.01). In contrast, 8-cyclopentyl-1,3-dimethylxanthine (DPCPX, a selective adenosine A1 receptor antagonist at 5 mg/kg) abolished the enhanced anticonvulsant effects offered by the combination of CBZ with CCPA (0.125 mg/kg). Moreover, CCPA (0.125 mg/kg) co-administered with other tested AEDs had no significant impact on their antiseizure properties in the MES test in mice. Neither CCPA (0.125 mg/kg) administered singly, nor in combinations with conventional AEDs (at their ED50s) affected motor performance in the chimney test and long-term memory in the passive avoidance task. No pharmacokinetic alterations in brain CBZ concentrations were observed after administration of CCPA at 0.125 mg/kg. It may be concluded that CCPA, acting selectively on adenosine A1 receptors, enhances pharmacodynamically the antiseizure effect of CBZ in the MES test.
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PMID:2-Chloro-N6-cyclopentyladenosine enhances the anticonvulsant action of carbamazepine in the mouse maximal electroshock-induced seizure model. 1638 98

The aim of the present experiment was to assess the involvement of adenosine receptor antagonists in benzodiazepine (BDZ) withdrawal signs, observed as the seizure susceptibility in mice. The discontinuation of chronic treatment with temazepam or diazepam decreased seizure threshold (one of BDZ withdrawal signs). The concomitant application of subconvulsive dose of pentetrazole (55.0 mg/kg) with low dose of flumazenil (5.0 mg/kg) - a BDZ receptor antagonist, immediately induced BDZ withdrawal signs in these animals. The non-selective adenosine receptor antagonist (caffeine), and the selective adenosine A1 receptor antagonist (DPCPX), injected 15 min before the application of pentetrazole and flumazenil, were able to intensify BDZ withdrawal signs in mice. The most apparent effects were observed after administration of DPCPX, indicating that the adenosine A1 receptor may play a more important role in these effects. The obtained data demonstrate that the adenosinergic system is involved in BDZ withdrawal signs in mice, and adenosine A1 receptor plays an important role in this process.
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PMID:Adenosine receptor antagonists intensify the benzodiazepine withdrawal signs in mice. 1708 56


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