Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

U-54494A, a 1,2-diamine anticonvulsant, and U-50488H, a structurally related agonist for opiate kappa receptors, were tested for effects on spontaneous and glutamate-evoked firing rates in cerebral cortex of urethane-anesthetized male Sprague-Dawley rats. Iontophoretic application of 1,2-diamines, glutamate diethyl ether (GDEE), or procaine depressed spontaneous and amino acid-induced firing of cortical neurones. With continued ejection of 1,2-diamines or procaine, firing was silenced completely, but GDEE could maintain a partial suppression. A rapid rebound of excitation followed cessation of procaine ejections, but not of other agents. Procaine, but not U-54494A, blocked axonal conduction of rabbit sciatic nerve. Intravenous U-54494A and U-50488H significantly depressed spontaneous firing rates of cortical neurones, but only the U-50488H effects were antagonized by naloxone. It is concluded that U-54494A inhibits neuronal excitability by a mechanism independent of the analgesic kappa receptor. Biochemical and physiological studies have demonstrated that U-54494A and the kappa opioid agonist U-50488H (a structurally related diamine) (1) have anticonvulsant activity (2, 3). U-54494A lacks kappa analgesic and sedative properties, and it has been suggested that the mechanism of action of this compound may be mediated by a subtype of kappa opioid receptor (3). The effects of kappa analgesics on neuronal firing in nociceptive pathways have been described (4, 5). However, no previous electrophysiological studies on U-54494A have been done. Since U-54494A antagonizes amino acid-induced seizures (3), the interactions of this compound with glutamate are of interest. In the present study, the antagonist efficacies of U-54494A and U-50488H for inhibiting spontaneous and 1-glutamate stimulated neurons of the rat prefrontal cerebral cortex were assessed after i.v. and microiontophoretic administration of the compounds. Effects observed with these routes of administration allow the observation of neuronal changes occurring immediately after administration and take advantage of the high temporal resolution provided by the electrophysiological recording techniques of single cells. A preliminary account of portions of this work have been previously disclosed (6).
 ...
PMID:Effect of the anticonvulsant U-54494A on cortical neuron excitability: comparison to the kappa agonist U-50488H. 134 50

The effects of cis-3,4 dichloro-N-2-(1-pyrrolidinyl)cyclo-hexyl-benzamide (U-54494A), an anticonvulsant related to kappa opioids, were studied in vitro on the extracellular electrical activity of the CA1 region of slices of hippocampus in the rat. The effects of U-54494A were compared to those of the kappa opioid agonist trans-3,4 dichloro-N-2-(1-pyrrolidinyl)cyclo-hexyl benzeneacetamide methane sulphonate (U-50488H). Both U-54494A and U-50488H, in concentrations of 50 and 100 microM, respectively, reduced the magnitude of the orthodromically evoked CA1 population spikes after electrical stimulation of the stratum radiatum (100-200 microA, 70 microseconds, 0.1 Hz). Naltrexone (25 microM), or the selective kappa opiate receptor antagonist, 1-cyclopenthyl-5-(1,2,3,4,5,6-hexahydroxy-3,6,11-trimethyl-2 -6-methano-3- benzazocin)-3-pentatone methane sulphonate (WIN 44441-3) (25 microM), prevented the depressant activity of U-54494A (200 microM) on the CA1 population spikes. High calcium (+3mM) solutions prevented the depressant activity of increasing concentrations of both U-54494A and U-50488H on the amplitude of CA1 population spikes. Up to 200 microM, both drugs were ineffective in depressing the epileptiform bursting in CA1, due to 1 mM penicillin or to perfusion of the slice in absence of magnesium ions. The results demonstrate: (1) the inability of U-54494A to show antagonistic activity in two in vitro models of interictal epilepsy; (2) a depressant effect of U-54494A on basal synaptic transmission in the CA1 region of the hippocampus, which may be related to an influence on transneuronal calcium currents and which may be involved in the reported antagonism of ictal epileptic seizures by drugs.
 ...
PMID:In vitro depressant effects of U-54494A, an anticonvulsant related to kappa opioids, in the hippocampus. 165 3

Pentylenetetrazol (PTZ, 45 mg/kg, ip) impaired retention of a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. The amnestic effect of PTZ was prevented by naltrexone (0.01 or 0.10 mg/kg, ip) administered after training, but prior to PTZ-treatment. On the contrary, neither naltrexone methyl bromide (0.01, 0.10, or 10.0 mg/kg, ip), a quaternarium analog of naltrexone, nor MR2266 (0.01 or 0.10 mg/kg, ip), a putative kappa opiate receptor antagonist, modified the behavioral effects of PTZ. On the other hand, the body seizures produced by PTZ were unaffected by any of the three opiate receptor antagonists that were given before the convulsant. Taken together, these results suggest that the effects of PTZ on retention are mediated, at least in part, by opioid peptides of central origin, and rules out a possible participation of opioid peptides derived from prodynorphin-precursor molecule. Administration of beta-endorphin (0.01 or 0.10 microgram/kg, ip) 10 min prior to testing attenuate the retrograde amnesia caused by PTZ. The effect of beta-endorphin was prevented by the simultaneous administration of naltrexone (0.10 mg/kg, ip) prior to testing. Naltrexone has no effect of its own upon retrieval. These results suggest that the impairment of retention induced by PTZ is probably due, at least in part, to a release of opioid peptides in the brain during the post-training period. PTZ given after training do not affect consolidation or memory storage, as mice thus treated may retrieve the learned information when they are submitted to an appropriate neurohumoral and/or hormonal state in the test session, that is, beta-endorphin injection. Therefore, the action of PTZ would be primarily at the level of the mechanism that make stored information available for late retrieval.
 ...
PMID:The impairment of retention induced by pentylenetetrazol in mice may be mediated by a release of opioid peptides in the brain. 282 89

We have recently reported the cloning of a mouse kappa opioid receptor cDNA. Following transfection of the kappa receptor cDNA into COS-1 cells, a receptor is expressed with the pharmacological specificity of a kappa opioid receptor. To further analyse its functional properties, we have stably expressed the kappa opioid receptor in undifferentiated PC-12 cells, a pheochromocytoma clonal cell line, which do not endogenously express this receptor. We have previously shown that kappa opioid agonists selectively bind to these PC-12 membranes with high affinity. Here we show that kappa selective agonists are able to inhibit accumulation of cyclic adenosine monophosphate in a stereoselective manner. Further, the kappa agonist U-50,488 is able to inhibit an N-type calcium current in a pertussis toxin sensitive manner; this inhibition is blocked by the kappa-selective antagonist norbinaltorphimine. Inhibition of the calcium current via the kappa receptor is stereoselective as the agonist levorphanol is able to mediate inhibition whereas in the same cells dextrorphan is ineffective. This is the first demonstration that the cloned kappa opioid receptor functionally couples to a calcium current, as has been reported for kappa receptors expressed endogenously in the nervous system. Kappa opioid receptors are thought to be important in pain pathways, learning and memory deficits, and seizure activity. A major physiological action of the dynorphins, the endogenous ligands of the kappa receptor, is thought to be inhibition of neurotransmitter release at presynaptic terminals. N-type calcium channels may be important in neurotransmitter release.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The cloned kappa opioid receptor couples to an N-type calcium current in undifferentiated PC-12 cells. 770 May 8

Involvement of the kappa opioid receptor in the regulation of epileptic activity was studied in WAG/Rij rats, a genetic model of absence epilepsy. I.c.v. administration of the kappa agonists U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide), U69,593 (5 alpha, 7 alpha, 8 beta)-(-)-N-methyl-(1-pyrrolidinyl)-1- oxaspiro(4,5)dec-8-yl)benzeneacetamide) or PD117,302 ((+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzo[b]thiophene-4-acetamide), 50 and 150 micrograms/5 microliter each, dose-dependently decreased the number and mean duration of spike wave discharges (SWD). Peripheral administration of U50,488H (10 and 30 mg/kg s.c.) also attenuated the seizure activity in this model. The specific kappa opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 10 micrograms/5 microliters i.c.v., 18 h before EEG registration) moderately increased the number of SWD, which suggests that endogenous opioids acting through kappa receptors may tonically inhibit the seizure activity in these rats. In addition, the enhancement of an absence-like seizure activity induced by the specific mu opioid receptor agonist D-Ala2-N-methyl-Phe4-Gly5-ol-enkephalin (DAMGO, 0.7 microgram/5 microliters i.c.v.) was also attenuated in rats pretreated with U50,488H, U69,593 or PD117,302. These data indicate that activation of the kappa opioid receptor exerts an inhibitory effect on absence-like seizure activity in WAG/Rij rats.
 ...
PMID:Kappa opioid receptor agonists suppress absence seizures in WAG/Rij rats. 777 81

Involvement of the kappa opioid receptor in regulation of the pilocarpine-induced seizures and neurodegeneration was studied in mice. Administration of pilocarpine (400 mg/kg i.p.) resulted in a sequence of behavioral alterations including motor limbic seizures. Pretreatment of mice with the selective kappa opioid receptor agonist U69,593 (2 and 20 mg/kg i.p.) or PD117,302 (0.1 and 1 mg/kg i.p.) increased the latency of motor seizures and decreased the seizure severity and mortality. Those effects were abolished in animals pretreated with the specific kappa opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 10 mg/kg i.p.). Examination of frontal forebrain sections by light microscopy revealed widespread damage, especially within the hippocampal formation, in pilocarpine-treated mice. Both U69,593 and PD117,503 protected the integrity of hippocampal neurons, especially in the CA1 region, that effect being reversed by Nor-BNI. The above data indicate that activation of the kappa opioid receptor exerts an inhibitory effect on the pilocarpine-induced limbic seizures and neurotoxicity.
 ...
PMID:Kappa opioid receptor agonists inhibit the pilocarpine-induced seizures and toxicity in the mouse. 789 64

The anticonvulsant activity of (+-)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benz am ide monohydrochloride (U-54494A), a benzamide derivative chemically related to kappa opioid receptor agonists, was investigated in three selected seizure models of experimental epilepsy. In the maximal electroshock seizure test in mice, U-54494A (ED50 28 mg/kg i.p.) was effective, with a potency somewhat less than phenobarbital. In combination with clinically used antiepileptics, especially phenobarbital and carbamazepine, the anticonvulsant activity of the latter was significantly increased. More detailed studies with phenobarbital showed additive anticonvulsant effects. The anticonvulsant activity of U-54494A was partially antagonized by naloxone. On the other hand, this compound did not elevate the pentylenetetrazol seizure threshold (at high doses a tendency of proconvulsant action was seen). Furthermore, in unrestrained rats with chronically implanted electrodes, U-54494A (> or = 10 mg/kg) significantly reduced the duration of electrically evoked hippocampal afterdischarges. However, the focal stimulation threshold was not markedly increased. With respect to the possible mode of action, whole-cell voltage-clamp experiments on cultured neonatal rat cardiomyocytes showed that U-54494A depressed the fast sodium inward current in a concentration- and frequency-dependent manner. In summary, our results agree with earlier reports that demonstrated marked anticonvulsant effects of U-54494A in grand mal-analogous seizure tests. Moreover, in combination with some standard antiepileptics, additive effects can be found. It is suggested that, in addition to kappa opioid and excitatory amino acid receptor related effects, modulations of Na+ membrane currents may contribute to the mechanisms of action.
 ...
PMID:Anticonvulsant and related effects of U-54494A in various seizure tests. 822 43

Studies on dynorphin involvement in epilepsy are summarised in this review. Electrophysiological, biochemical and pharmacological data support the hypothesis that dynorphin is implicated in specific types of seizures. There is clear evidence that this is true for complex partial (limbic) seizures, i.e. those characteristic of temporal lobe epilepsy, because; (1) dynorphin is highly expressed in various parts of the limbic system, and particularly in the granule cells of the hippocampus; (2) dynorphin appears to be released in the hippocampus (and in other brain areas) during complex partial seizures; (3) released dynorphin inhibits excitatory neurotransmission at multiple synapses in the hippocampus via activation of kappa opioid receptors; (4) kappa opioid receptor agonists are highly effective against limbic seizures. Data on generalised tonic-clonic seizures are less straightforward. Dynorphin release appears to occur after ECS seizures and kappa agonists exert a clear anticonvulsant effect in this model. However, more uncertain biochemical data and lack of efficacy of kappa agonists in other generalised tonic-clonic seizure models argue that the involvement of dynorphin in this seizure type may not be paramount. Finally, an involvement of dynorphin in generalised absence seizures appears unlikely on the basis of available data. This may not be surprising, given the presumed origin of absence seizures in alterations of the thalamo-cortical circuit and the low representation of dynorphin in the thalamus. In conclusion, it may be suggested that dynorphin plays a role as an endogenous anticonvulsant in complex partial seizures and in some cases of tonic-clonic seizures, but most likely not in generalised absence. This pattern of effects may coincide with the antiseizure spectrum of selective kappa agonists.
 ...
PMID:Dynorphin and epilepsy. 901 27

The effects of kappa opioids on seizures and seizure-induced histopathology were investigated with the pilocarpine model of temporal lobe epilepsy. Rats treated with the kappa opioid receptor agonist U50488h before pilocarpine showed: 1) increased seizure latency; 2) decreased seizure duration; 3) decreased mossy fiber sprouting; and 4) increased hilar neuron survival when compared with rats pretreated with saline. Behavioral effects of U50488h were blocked by the kappa opioid receptor antagonist norbinaltorphimine (nBNI), whereas the changes caused by U50488h in the histological response to pilocarpine were not blocked by nBNI. Rats treated with nBNI before pilocarpine exhibited: 1) increased incidence of seizures; 2) increased mossy fiber sprouting; and 3) increased hilar neuron loss when compared with rats treated with pilocarpine alone. These changes suggest a protective role of endogenously released kappa opioids in this seizure model. The location of functional kappa opioid receptors in the rat dentate gyrus was documented electrophysiologically to enable correlation with kappa opioid effects on histopathology. The kappa selective agonist, U69593, reversibly decreased the amplitude of excitatory postsynaptic potentials in the middle molecular layer of the dentate gyrus from the ventral but not the more dorsal portion of the hippocampal formation. Thus, kappa opioids decreased the severity and incidence of behavioral seizures and secondarily decreased seizure-induced histopathology via the decreased incidence of seizures.
 ...
PMID:Administered and endogenously released kappa opioids decrease pilocarpine-induced seizures and seizure-induced histopathology. 949 77

Up to 89% of patients with herpes simplex virus type-1 (HSV-1) encephalitis can have seizures. Possibly, viruses are environmental triggers for seizures in genetically vulnerable individuals. Inherited dynorphin promoter polymorphisms are associated with temporal lobe epilepsy and febrile seizures in man. In animals, the dynorphin system in the hippocampus regulates excitability. The hypothesis that reduced dynorphin expression in dentate gyrus of hippocampus due to HSV-1 infection leads to epileptic responses was tested in a rat model of HSV-1 encephalitis using EEG recording, histopathological and neuropharmacologic probes. HSV-1 infection causes loss of dynorphin A-like immunoreactivity in hippocampus, an effect independent of direct viral interference and cell loss. A kappa opioid receptor agonist U50488 effectively blocks ictal activity, linking absence of dynorphin to propensity for epileptic activity. These findings show a vulnerability of hippocampal dynorphin during infection, suggesting a neurochemical basis for seizures that may be generalizable to other encephalitic viruses.
 ...
PMID:Viral risk factor for seizures: pathobiology of dynorphin in herpes simplex viral (HSV-1) seizures in an animal model. 1684 74


1 2 Next >>