The Experts below are selected from a list of 3141 Experts worldwide ranked by ideXlab platform
Wolfgang Löscher - One of the best experts on this subject based on the ideXlab platform.
-
Polymorphic variants of the multidrug resistance gene Mdr1a and response to antiepileptic drug treatment in the Kindling Model of epilepsy.
European journal of pharmacology, 2006Co-Authors: Cordula Baars, Wolfgang Löscher, Tosso Leeb, Albert Becker, Heidrun PotschkaAbstract:Allelic variants of the human P-glycoprotein encoding gene MDR1 (ABCB1) are discussed to be associated with different clinical conditions including pharmacoresistance of epilepsy. However, conflicting data have been reported with regard to the functional relevance of MDR1 allelic variants for the response to antiepileptic drugs. To our knowledge, it is not known whether functionally relevant genetic polymorphisms also occur in the two genes (Mdr1a/Abcb1a, Mdr1b/Abcb1b) coding for P-glycoprotein in the brain of rodents. Therefore, we have started to search for polymorphisms in the Mdr1a gene, which governs the expression of P-glycoprotein in brain capillary endothelial cells in rats. In the Kindling Model of temporal lobe epilepsy, subgroups of phenytoin-sensitive and phenytoin-resistant rats were selected in repeated drug trials. Sequencing of the Mdr1a gene coding sequence in the subgroups revealed no general differences between drug-resistant and drug-sensitive rats of the Wistar outbred strain. A comparison between different inbred and outbred rat strains also gave no evidence for polymorphisms in the Mdr1a coding sequence. However, in exon-flanking intron sequences, four genetic variants were identified by comparison between these rats strains. In conclusion, the finding that Wistar rats vary in their response to phenytoin, while having the same genetic background, argues against a major impact of Mdr1a genetics on pharmacosensitivity to antiepileptic drugs in the amygdala Kindling Model.
-
AWD 140-190: a potent anticonvulsant in the amygdala-Kindling Model of partial epilepsy.
Epilepsia, 2001Co-Authors: Christine Tober, Wolfgang Löscher, Dagmar Hönack, Reni BartschAbstract:Summary: Purpose: Evaluation of the effect of the new anticonvulsant drug, AWD 140-190 [4-(p-bromophenyl)-3-morpholino-1H-pyrrole-2-carboxylic acid methyl ester] on focally induced seizures and on epileptogenesis in the Kindling Model. Methods: Effects of AWD 140-190 were studied in amygdala kindled rats after oral and intraperitoneal administration. In addition, the effect on Kindling development was evaluated. In all experiments, behavioral changes in the rats in response to AWD 140-190 were monitored closely. Results: AWD 140-190 exerted potent anticonvulsant activity against focal seizures. After intraperitoneal and oral administration in fully kindled rats, the substance dose-dependently increased the threshold for induction of afterdischarges starting at 15 mg/kg. AWD 140-190 only weakly influenced the seizure severity of the animals after stimulation at the elevated afterdischarge threshold current. No adverse effects were observed up to 30 mg/kg after intraperitoneal and oral administration in the open field and in the rotarod test. No differences were found between kindled and nonkindled rats when comparing neurotoxicity of AWD 140-190. Prolonged treatment with AWD 140-190 during Kindling acquisition did not prevent Kindling, but significantly retarded the development of fully kindled seizures during the treatment. Conclusions: This study demonstrates that AWD 140-190 has anticonvulsant effects in the amygdala Kindling Model in rats, suggesting that the substance is particularly effective against partial seizures. AWD 140-190 is orally active and devoid of neurotoxic effects in anticonvulsant doses, thus indicating that this compound has potential for antiepileptic therapy. AWD 140-190 retards the Kindling development during the treatment. This effect could be explained by the acute anticonvulsant effect of the substance.
-
anticonvulsant and proconvulsant effects of tramadol its enantiomers and its m1 metabolite in the rat Kindling Model of epilepsy
British Journal of Pharmacology, 2000Co-Authors: Heidrun Potschka, Elmar Friderichs, Wolfgang LöscherAbstract:The centrally acting analgesic tramadol has recently been reported to cause seizures at re-commended dosages in patients, whereas animal experiments had indicated that seizures only occur in high, toxic doses. Tramadol has a dual mechanism of action that includes weak agonistic effects at the mu-opioid receptor as well as inhibition of monoamine (serotonin, norepinephrine) re-uptake. Its major (M1) metabolite mono-O-desmethyltramadol, which is rapidly formed in vivo, has a markedly higher affinity for mu receptors and may thus contribute to the effects of the parent compound. Furthermore, the pharmacological effects of tramadol appear to be related to the different, but complementary and interactive pharmacologies of its enantiomers. In the present study, we evaluated (±)-tramadol, its enantiomers, and its M1 metabolite ((+)-enantiomer) in the amygdala Kindling Model of epilepsy in rats. Adverse effects determined in kindled rats were compared to those in nonkindled rats. At doses within the analgesic range, (±)-tramadol and its enantiomers induced anticonvulsant effects in kindled rats. However, at only slightly higher doses seizures occurred. With (±)-tramadol, generalized seizures were observed at 30 mg kg−1 in most kindled but not in nonkindled rats. The (−)-enantiomer induced myoclonic seizures at 30 mg kg−1 in most kindled but not in nonkindled rats, although myoclonic seizure activity was observed in some nonkindled rats at 10 or 20 mg kg−1. Seizures were also observed after the (+)-enantiomer and the (+)-enantiomer of the M1 metabolite, but experiments with higher doses of these compounds were limited by marked respiratory depression. The data demonstrate that Kindling enhances the susceptibility of rats to convulsant adverse effects of tramadol and its enantiomers, indicating that a preexisting lowered seizure threshold increases the risk of tramadol-induced seizures. Keywords: Opioids, analgesics, seizures, noradrenaline, serotonin Introduction The centrally acting analgesic tramadol possesses weak opioid agonist properties and inhibits norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) uptake (Dayer et al., 1994; Raffa et al., 1995; Lewis & Han, 1997). Tramadol is an effective and relative safe analgesic that has been prescribed for almost two decades in Europe, and was approved for marketing in the United States in 1995 for the treatment of moderate to moderately severe pain (Lee et al., 1993; Gibson, 1996; Lewis & Han, 1997; Bamigbade & Langford, 1998). However, in the years after its release in the United States, an increased risk of seizures associated with tramadol was reported (Kahn et al., 1997). This adverse drug effect occurred at recommended dosages, although an overdose may increase the risk of tramadol-related seizures (Kahn et al., 1997). It is long known that opioid analgesics such as morphine and related drugs can produce convulsions, but with most opioids convulsions occur only in doses far in excess of those required to produce profound analgesia (c.f., Frenk, 1983). With respect to tramadol, animal experiments also indicated that convulsions only occur in high, toxic doses (Friderichs et al., 1978; Osterloh et al., 1978; Matthiesen et al., 1998). This apparent paradox between preclinical data and the risk of seizures associated with tramadol in patients may be related to the fact that most clinical reports were from patients receiving concomitant treatment with other drugs which may increase the risk of tramadol-related seizures (Khan et al., 1997; Jick et al., 1998). In the present study, we used the Kindling Model of temporal lobe epilepsy to evaluate the proconvulsant activity of tramadol in more detail. Because a recent study indicated that tramadol exerts anticonvulsant effects in the maximal electroshock seizure (MES) test in mice (Manocha et al., 1998), we also assessed whether tramadol possesses anticonvulsant activity in the Kindling Model. In view of our previous finding that Kindling-induced epileptogenesis may enhance the adverse effect potential of drugs (Loscher & Honack, 1991; Honack & Loscher, 1995; Loscher, 1998; Wlaz & Loscher, 1998), adverse effects of tramadol in kindled rats were compared to those in nonkindled rats. Tramadol is a racemic 1:1 mixture of two enantiomers, (+)-tramadol and (−)-tramadol which differ in their potencies at opioid receptors and monoamine uptake sites (Raffa et al., 1993). Furthermore, (±)-tramadol is rapidly metabolized to mono-O-desmethyltramadol (M1 metabolite; see Figure 1) which also binds to opioid receptors (Raffa et al., 1995; Gibson, 1996). In addition to testing tramadol, we therefore evaluated the extent to which the enantiomers and the M1 metabolite contribute to tramadol's anticonvulsant and proconvulsant effects in rats. Figure 1 Stereochemistry of tramadol and metabolic activation to the M1-metabolite O-desmethyltramadol. Methods Animals Female Wistar rats (Harlan-Winkelmann, Borchen, Germany), weighing 200–300 g, were used. The animals were purchased from the breeder at a body weight of 180–220 g. Following arrival in the animal colony, the rats were kept under controlled environmental conditions (ambient temperature 24–25°C, humidity 50–60%, 12/12 h light/dark cycle, light on at 0700) for at least 1 week before being used in the experiments. Standard laboratory chow (Altromin 1324 standard diet) and tap water were allowed ad libitum. All animal care and handling was conducted in compliance with the German Animal Welfare Act and was approved by the responsible governmental agency in Hannover. With respect to the use of females, it is important to note that we previously showed that neither seizure susceptibility nor anticonvulsant drug effects are affected by the estrous cycle in fully kindled female rats as used in the present study (Rundfeldt et al., 1990; Wahnschaffe & Loscher, 1992).
-
INHIBITION OF MONOAMINE OXIDASE TYPE A, BUT NOT TYPE B, IS AN EFFECTIVE MEANS OF INDUCING ANTICONVULSANT ACTIVITY IN THE Kindling Model OF EPILEPSY
The Journal of pharmacology and experimental therapeutics, 1999Co-Authors: Wolfgang Löscher, Holger Lehmann, Hans-jurgen Teschendorf, Martin Dr. Traut, Gerhard GrossAbstract:The anticonvulsant activity of inhibitors of monoamine oxidase (MAO) was reported early after the development of irreversible MAO inhibitors such as tranylcypromine, but was never clinically used because of the adverse effects of these compounds. The more recently developed reversible MAO inhibitors with selectivity for either the MAO-A or MAO-B isoenzyme forms have not been studied extensively in animal Models of epilepsy, so it is not known which type of MAO inhibitor is particularly effective in this respect. We compared the following drugs in the Kindling Model of epilepsy: 1) l-deprenyl (selegiline), i.e., an irreversible inhibitor of MAO-B, which, however, also inhibits MAO-A at higher doses, 2) the novel reversible MAO-B inhibitor LU 53439 (3,4-dimethyl-7-(2-isopropyl-1,3,4-thiadiazol-5-yl)-methoxy-coumarin), which is much more selective for MAO-B than l-deprenyl, 3) the novel reversible and highly selective MAO-A inhibitor LU 43839 (esuprone; 7-hydroxy-3,4-dimethylcoumarin ethanesulfonate), and 4) the irreversible nonselective MAO inhibitor tranylcypromine. Esuprone proved to be an effective anticonvulsant in the Kindling Model with a similar potency as l-deprenyl. In contrast to esuprone and l-deprenyl, the selective MAO-B inhibitor LU 53439 was not effective in the Kindling Model; this substantiates the previous notion that the anticonvulsant activity ofl-deprenyl is not related to MAO-B inhibition, but to other effects of this drug, such as inhibition of MAO-A. Drugs inhibiting both MAO-A and MAO-B to a similar extent (tranylcypromine) or combinations of selective MAO-A and MAO-B inhibitors (esuprone plus LU 53439) had no advantage over MAO-A inhibition alone, but were less well tolerated. The data thus suggest that selective MAO-A inhibitors such as esuprone may be an interesting new approach for the treatment of epilepsy.
-
A new pyrrolyl-quinoxalinedione series of non-NMDA glutamate receptor antagonists: pharmacological characterization and comparison with NBQX and valproate in the Kindling Model of epilepsy
The European journal of neuroscience, 1999Co-Authors: Wolfgang Löscher, H. Lehmann, Berthold Behl, D. Seemann, H. J. Teschendorf, H. P. Hofmann, W. Lubisch, T. Höger, H. G. Lemaire, G. GroßAbstract:Antagonists at the ionotropic non-NMDA [AMPA (amino-methyl proprionic acid)/kainate] type of glutamate receptors have been suggested to possess several advantages compared to NMDA (N-methyl-D-aspartate) receptor antagonists, particularly in terms of risk/benefit ratio, but the non-NMDA receptor antagonists available so far have not fulfilled this promise. From a large series of pyrrolyl-quinoxalinedione derivatives, we selected six new competitive non-NMDA receptor antagonists. The basis of selection was high potency and selectivity for AMPA and/or kainate receptors, high in vivo potency after systemic administration, and an acceptable ratio between neuroprotective or anticonvulsant effects and adverse effects. Pharmacological characteristics of these novel compounds are described in this study with special emphasis on their effects in the Kindling Model of temporal lobe epilepsy, the most common type of epilepsy in humans. In most experiments, NBQX and the major antiepileptic drug valproate were used for comparison with the novel compounds. The novel non-NMDA receptor antagonists markedly differed in their AMPA and kainate receptor affinities from NBQX. Thus, while NBQX essentially did not bind to kainate receptors at relevant concentrations, several of the novel compounds exhibited affinity to rat brain kainate receptors or recombinant kainate receptor subtypes in addition to AMPA receptors. One compound, LU 97175, bound to native high affinity kainate receptors and rat GluR5-GluR7 subunits, i.e. low affinity kainate binding sites, with much higher affinities than to AMPA receptors. All compounds potently blocked AMPA-induced cell death in vitro and, except LU 97175, AMPA-induced convulsions in vivo. In the Kindling Model, compounds with a high affinity for GluR7 (LU 97175) or compounds (LU 115455, LU 136541) which potently bind to AMPA receptors and low affinity kainate receptor subunits were potent anticonvulsants in the Kindling Model, whereas the AMPA receptor-selective LU 112313 was the least selective compound in this Model, indicating that non-NMDA antagonists acting at both AMPA and kainate receptors are more effective in this Model than AMPA receptor-selective drugs. Three of the novel compounds, i.e. LU 97175, LU 115455 and LU 136541, exerted potent anticonvulsant effects without inducing motor impairment in the rotarod test. This combination of actions is thought to be a prerequisite for selective anticonvulsant drug action.
James O Mcnamara - One of the best experts on this subject based on the ideXlab platform.
-
vagus nerve stimulation elevates seizure threshold in the Kindling Model
Epilepsia, 2012Co-Authors: Georgia M Alexander, James O McnamaraAbstract:Summary Purpose: Vagus nerve stimulation (VNS) provides partial relief of medically refractory partial seizures in a subset of patients. The optimal pattern of stimulation and the mechanism of the antiseizure effects are uncertain. Establishing the efficacy of VNS in an animal Model of epilepsy would provide an experimental preparation with which to address these questions. We sought to determine whether VNS exerted antiseizure effects in the Kindling Model of epilepsy. Methods: We implanted adult rats with bipolar stimulating electrodes in the right amygdala and VNS devices around the left vagus nerve. Following induction of Kindling, electrographic seizure threshold (EST) was determined by quantifying the amygdala electrode current required to evoke a seizure. Once stable ESTs were established, VNS devices were programmed to deliver U.S. Food and Drug Administration (FDA)–approved, clinically used (standard) or an experimental (microburst) pattern of stimulation of variable intensity. VNS devices were programmed identically in control animals except that no current was delivered. EST was examined at 60 min and 1 week in the control and vagus nerve stimulated groups. Key Findings: Significant reductions of EST values were detected in control animals when tested both 60 min and 1 week following device programming. Both clinically used and experimental patterns of VNS prevented the reduction of EST evident in control animals when tested either 60 min or 1 week after device programming. Significance: These findings establish an experimental preparation with which to elucidate the antiseizure mechanisms of VNS and to determine patterns of VNS most effective at elevating seizure threshold.
-
Reduction of TrkB expression de novo in the adult mouse impairs epileptogenesis in the Kindling Model.
Hippocampus, 2010Co-Authors: Robert Kotloski, James O McnamaraAbstract:Elucidating the mechanisms of epileptogenesis in molecular terms can identify targets for therapies aimed at preventing epileptogenesis or limiting its progression. Genetic perturbations have implicated signaling by the neurotrophin, BDNF, and its receptor, TrkB, in limbic epileptogenesis. Whether this signaling is critical to epileptogenesis in the adult brain is unclear. We sought to determine whether reduced expression of TrkB de novo in the mature brain is sufficient to impair epileptogenesis in the Kindling Model. Treatment of adult Act-CreER TrkBflox/flox mice with tamoxifen resulted in modest reductions of TrkB protein expression de novo in the adult that were detected in hippocampus but not other brain regions. Modest reduction of hippocampal TrkB content inhibited epileptogenesis induced by stimulation of hippocampus or amygdala. The data support the conclusion that reduction of TrkB expression in hippocampus de novo in the mature brain impairs epileptogenesis in the Kindling Model. These findings advance TrkB and its downstream signaling pathways as attractive targets for limiting the progression of epileptogenesis. © 2009 Wiley-Liss, Inc.
-
The tyrosine receptor kinase B ligand, neurotrophin-4, is not required for either epileptogenesis or tyrosine receptor kinase B activation in the Kindling Model.
Neuroscience, 2006Co-Authors: Linda S. Butler, Xin Liu, James O McnamaraAbstract:The Kindling Model of epilepsy is a form of neuronal plasticity induced by repeated induction of pathological activity in the form of focal seizures. A causal role for the neurotrophin receptor, tyrosine receptor kinase B, in epileptogenesis is supported by multiple studies of the Kindling Model. Not only is tyrosine receptor kinase B required for epileptogenesis in this Model but enhanced activation of tyrosine receptor kinase B has been identified in the hippocampus in multiple Models of limbic epileptogenesis. The neurotrophin ligand mediating tyrosine receptor kinase B activation during limbic epileptogenesis is unknown. We hypothesized that neurotrophin-4 (NT4) activates tyrosine receptor kinase B in the hippocampus during epileptogenesis and that NT4-mediated activation of tyrosine receptor kinase B promotes limbic epileptogenesis. We tested these hypotheses in NT4-deficient mice with a targeted deletion of NT4 gene using the Kindling Model. The development and persistence of amygdala Kindling were examined in wild type (+/+) and NT4 null mutant (-/-) mice. No differences were found between +/+ and -/- mice with respect to any facet of the development or persistence of Kindling. Despite the absence of NT4, activation of the tyrosine receptor kinase B receptor in the mossy fiber pathway as assessed by phospho-trk immunohistochemistry was equivalent to that of +/+ mice. Together these findings demonstrate that NT4 is not required for limbic epileptogenesis nor is it required for activation of tyrosine receptor kinase B in hippocampus during limbic epileptogenesis.
-
conditional deletion of trkb but not bdnf prevents epileptogenesis in the Kindling Model
Neuron, 2004Co-Authors: Xiaoping He, Robert Kotloski, Bryan W Luikart, Luis F Parada, James O McnamaraAbstract:Abstract Epileptogenesis is the process whereby a normal brain becomes epileptic. We hypothesized that the neurotrophin brain-derived neurotrophic factor (BDNF) activates its receptor, TrkB, in the hippocampus during epileptogenesis and that BDNF-mediated activation of TrkB is required for epileptogenesis. We tested these hypotheses in Synapsin-Cre conditional BDNF −/− and TrkB −/− mice using the Kindling Model. Despite marked reductions of BDNF expression, only a modest impairment of epileptogenesis and increased hippocampal TrkB activation were detected in BDNF −/− mice. In contrast, reductions of electrophysiological measures and no behavioral evidence of epileptogenesis were detected in TrkB −/− mice. Importantly, TrkB −/− mice exhibited behavioral endpoints of epileptogenesis, tonic-clonic seizures. Whereas TrkB can be activated, and epileptogenesis develops in BDNF −/− mice, the plasticity of epileptogenesis is eliminated in TrkB −/− mice. Its requirement for epileptogenesis in Kindling implicates TrkB and downstream signaling pathways as attractive molecular targets for drugs for preventing epilepsy.
-
antiepileptogenic effects of conventional anticonvulsants in the Kindling Model of epilepsy
Annals of Neurology, 1991Co-Authors: Jon M Silver, Cheolsu Shin, James O McnamaraAbstract:We sought to determine whether the clinically effective anticonvulsant drug valproate exhibited antiepileptogenic properties in the Kindling Model (we use the term anticonvulsant to mean suppression of seizure, and antiepileptogenic to mean suppression of development of epilepsy). We compared and contrasted valproate with two other anticonvulsant drugs, phenobarbital and carbamazepine. We investigated the effects of these drugs on the development of Kindling, that is, the number of stimulation-induced afterdischarges required to induce enhanced seizure susceptibility in rats. Valproate exhibited powerful antiepileptogenic effects as evident in a dose-dependent increase in the number of afterdischarges required to induce Kindling. These effects were not due to retained valproate or an active metabolite merely masking the expression of kindled seizures. By contrast, carbamazepine was devoid of any antiepieptogenic effects despite exhibiting marked anticonvulsant effects. Like valproate, phenobarbital exhibited both antiepileptogenic and anticonvulsant properties, but its antiepileptogenic properties were significantly less pronounced. The antiepileptogenic effects of valproate and phenobarbital strengthen the candidacy of these agents for the clinical studies needed to investigate pharmacological prevention of the development of epilepsy in high-risk groups.
Heidrun Potschka - One of the best experts on this subject based on the ideXlab platform.
-
synergism of perampanel and zonisamide in the rat amygdala Kindling Model of temporal lobe epilepsy
Epilepsia, 2016Co-Authors: Vera Russmann, Josephine D Salvamoser, Maruja L Rettenbeck, Takafumi Komori, Heidrun PotschkaAbstract:Objective: Anticonvulsive monotherapy fails to be effective in one third of patients with epilepsy resulting in the need for polytherapy regimens. However, with the still limited knowledge, drug choices for polytherapy remain empirical. Here we report experimental data from a chronic epilepsy Model for the combination of perampanel and zonisamide, which can render guidance for clinical studies and individual drug choices. Methods: The anticonvulsant effects of the combination of perampanel and zonisamide were evaluated in a rat amygdala Kindling Model. Furthermore, the potential for motor impairment was evaluated. The type of interaction was quantitatively assessed based on isobolographic analysis. Results: When administered alone, zonisamide dose-dependently increased the afterdischarge threshold in fully kindled rats. Moreover, data confirmed efficacy of perampanel to inhibit seizure initiation and progression with an impact on propagation of activity from the focus. Pronounced threshold increases were observed following administration of a constant zonisamide dosage combined with different doses of perampanel. Isobolographic analysis of drug responses, which is based on individual drug dose-effect data, revealed a synergistic interaction substantiating the high efficacy of the combination. Furthermore, rotarod data indicated that the combination has a favorable tolerability profile when zonisamide is coadministered with low doses of perampanel. Plasma concentration analysis argued against a pharmacokinetic interaction as a basis for the synergism. Significance: The findings clearly indicate a pronounced synergistic anticonvulsant effect for the combination of the noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel with zonisamide, which modulates voltage-sensitive sodium channels and T-type calcium currents. Consequently, polytherapy using these two antiepileptic drugs might be efficacious for clinical management of partial-onset seizures. The findings indicate that the impact of dose ratios on tolerability needs be taken into account. With regard to conclusions about the extent of the synergism and its implications further antiepileptic drug combinations need to be evaluated allowing direct comparison.
-
Targeting the endocannabinoid system in the amygdala Kindling Model of temporal lobe epilepsy in mice.
Epilepsia, 2011Co-Authors: Hannes Wendt, Jonna Soerensen, Carsten T Wotjak, Heidrun PotschkaAbstract:The endocannabinoid system can be considered as a putative target to affect ictogenesis as well as the generation of a hyperexcitable epileptic network. Therefore, we evaluated the effect of a CB1 receptor agonist (WIN55.212-2) and of an inhibitor of the enzymatic degradation of the endocannabinoid anandamide (fatty acid hydrolase inhibitor URB597) in the amygdala Kindling Model of temporal lobe epilepsy. Only minor effects on seizure thresholds and seizure parameters without a clear dose-dependency were observed in fully kindled mice. When evaluating the impact on Kindling acquisition, WIN55.212-2 significantly delayed the progression of seizure severity. In contrast, URB597 did not affect the development of seizures in the Kindling paradigm. Analysis of cell proliferation and neurogenesis during the Kindling process revealed that URB597 significantly reduced the number of newborn neurons. These data give first evidence that CB1-receptor activation might render a disease-modifying approach. Future studies are necessary that further analyze the role of CB1 receptors and to confirm the efficacy of CB1-receptor agonists in other Models of chronic epilepsy.
-
Targeting the prostaglandin E2 EP1 receptor and cyclooxygenase-2 in the amygdala Kindling Model in mice.
Epilepsy research, 2010Co-Authors: Sarah Fischborn, Jonna Soerensen, Heidrun PotschkaAbstract:Summary The prostaglandin E2 EP1 receptor as well as the inflammatory enzyme cyclooxygenase-2 have been suggested as targets for disease modulation, improvement of therapeutic response, and restoration of pharmacosensitivity in epilepsies. Translational development of respective add-on approaches requires careful analysis of putative effects on ictogenesis. Therefore we evaluated the impact of the EP1 receptor antagonist SC-51089, the EP1 receptor agonist misoprostol and the COX-2 inhibitors celecoxib and NS-398 in the mouse amygdala Kindling Model of temporal lobe epilepsy. Neither celecoxib nor NS-398 affected the generation, spread and termination of seizure activity. Whereas SC-51089 did not affect the seizure threshold, the highest dose (30 mg/kg) significantly decreased the seizure severity when administered 60 min before stimulation. Moreover, SC-51089 significantly prolonged seizure duration at the highest dose. The EP1 receptor agonist misoprostol exerted contrasting effects on seizure duration with a significant decrease in the duration of motor seizure activity. The data suggest that doses of COX-2 inhibitors and EP1 receptor antagonists which exert disease modulating or antiepileptic drug potentiating effects do not negatively affect seizure control in temporal lobe epilepsy. The contrasting impact of the EP1 receptor antagonist and agonist suggests that EP1 receptors can influence endogenous mechanisms involved in termination of seizure activity.
-
Polymorphic variants of the multidrug resistance gene Mdr1a and response to antiepileptic drug treatment in the Kindling Model of epilepsy.
European journal of pharmacology, 2006Co-Authors: Cordula Baars, Wolfgang Löscher, Tosso Leeb, Albert Becker, Heidrun PotschkaAbstract:Allelic variants of the human P-glycoprotein encoding gene MDR1 (ABCB1) are discussed to be associated with different clinical conditions including pharmacoresistance of epilepsy. However, conflicting data have been reported with regard to the functional relevance of MDR1 allelic variants for the response to antiepileptic drugs. To our knowledge, it is not known whether functionally relevant genetic polymorphisms also occur in the two genes (Mdr1a/Abcb1a, Mdr1b/Abcb1b) coding for P-glycoprotein in the brain of rodents. Therefore, we have started to search for polymorphisms in the Mdr1a gene, which governs the expression of P-glycoprotein in brain capillary endothelial cells in rats. In the Kindling Model of temporal lobe epilepsy, subgroups of phenytoin-sensitive and phenytoin-resistant rats were selected in repeated drug trials. Sequencing of the Mdr1a gene coding sequence in the subgroups revealed no general differences between drug-resistant and drug-sensitive rats of the Wistar outbred strain. A comparison between different inbred and outbred rat strains also gave no evidence for polymorphisms in the Mdr1a coding sequence. However, in exon-flanking intron sequences, four genetic variants were identified by comparison between these rats strains. In conclusion, the finding that Wistar rats vary in their response to phenytoin, while having the same genetic background, argues against a major impact of Mdr1a genetics on pharmacosensitivity to antiepileptic drugs in the amygdala Kindling Model.
-
anticonvulsant and proconvulsant effects of tramadol its enantiomers and its m1 metabolite in the rat Kindling Model of epilepsy
British Journal of Pharmacology, 2000Co-Authors: Heidrun Potschka, Elmar Friderichs, Wolfgang LöscherAbstract:The centrally acting analgesic tramadol has recently been reported to cause seizures at re-commended dosages in patients, whereas animal experiments had indicated that seizures only occur in high, toxic doses. Tramadol has a dual mechanism of action that includes weak agonistic effects at the mu-opioid receptor as well as inhibition of monoamine (serotonin, norepinephrine) re-uptake. Its major (M1) metabolite mono-O-desmethyltramadol, which is rapidly formed in vivo, has a markedly higher affinity for mu receptors and may thus contribute to the effects of the parent compound. Furthermore, the pharmacological effects of tramadol appear to be related to the different, but complementary and interactive pharmacologies of its enantiomers. In the present study, we evaluated (±)-tramadol, its enantiomers, and its M1 metabolite ((+)-enantiomer) in the amygdala Kindling Model of epilepsy in rats. Adverse effects determined in kindled rats were compared to those in nonkindled rats. At doses within the analgesic range, (±)-tramadol and its enantiomers induced anticonvulsant effects in kindled rats. However, at only slightly higher doses seizures occurred. With (±)-tramadol, generalized seizures were observed at 30 mg kg−1 in most kindled but not in nonkindled rats. The (−)-enantiomer induced myoclonic seizures at 30 mg kg−1 in most kindled but not in nonkindled rats, although myoclonic seizure activity was observed in some nonkindled rats at 10 or 20 mg kg−1. Seizures were also observed after the (+)-enantiomer and the (+)-enantiomer of the M1 metabolite, but experiments with higher doses of these compounds were limited by marked respiratory depression. The data demonstrate that Kindling enhances the susceptibility of rats to convulsant adverse effects of tramadol and its enantiomers, indicating that a preexisting lowered seizure threshold increases the risk of tramadol-induced seizures. Keywords: Opioids, analgesics, seizures, noradrenaline, serotonin Introduction The centrally acting analgesic tramadol possesses weak opioid agonist properties and inhibits norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) uptake (Dayer et al., 1994; Raffa et al., 1995; Lewis & Han, 1997). Tramadol is an effective and relative safe analgesic that has been prescribed for almost two decades in Europe, and was approved for marketing in the United States in 1995 for the treatment of moderate to moderately severe pain (Lee et al., 1993; Gibson, 1996; Lewis & Han, 1997; Bamigbade & Langford, 1998). However, in the years after its release in the United States, an increased risk of seizures associated with tramadol was reported (Kahn et al., 1997). This adverse drug effect occurred at recommended dosages, although an overdose may increase the risk of tramadol-related seizures (Kahn et al., 1997). It is long known that opioid analgesics such as morphine and related drugs can produce convulsions, but with most opioids convulsions occur only in doses far in excess of those required to produce profound analgesia (c.f., Frenk, 1983). With respect to tramadol, animal experiments also indicated that convulsions only occur in high, toxic doses (Friderichs et al., 1978; Osterloh et al., 1978; Matthiesen et al., 1998). This apparent paradox between preclinical data and the risk of seizures associated with tramadol in patients may be related to the fact that most clinical reports were from patients receiving concomitant treatment with other drugs which may increase the risk of tramadol-related seizures (Khan et al., 1997; Jick et al., 1998). In the present study, we used the Kindling Model of temporal lobe epilepsy to evaluate the proconvulsant activity of tramadol in more detail. Because a recent study indicated that tramadol exerts anticonvulsant effects in the maximal electroshock seizure (MES) test in mice (Manocha et al., 1998), we also assessed whether tramadol possesses anticonvulsant activity in the Kindling Model. In view of our previous finding that Kindling-induced epileptogenesis may enhance the adverse effect potential of drugs (Loscher & Honack, 1991; Honack & Loscher, 1995; Loscher, 1998; Wlaz & Loscher, 1998), adverse effects of tramadol in kindled rats were compared to those in nonkindled rats. Tramadol is a racemic 1:1 mixture of two enantiomers, (+)-tramadol and (−)-tramadol which differ in their potencies at opioid receptors and monoamine uptake sites (Raffa et al., 1993). Furthermore, (±)-tramadol is rapidly metabolized to mono-O-desmethyltramadol (M1 metabolite; see Figure 1) which also binds to opioid receptors (Raffa et al., 1995; Gibson, 1996). In addition to testing tramadol, we therefore evaluated the extent to which the enantiomers and the M1 metabolite contribute to tramadol's anticonvulsant and proconvulsant effects in rats. Figure 1 Stereochemistry of tramadol and metabolic activation to the M1-metabolite O-desmethyltramadol. Methods Animals Female Wistar rats (Harlan-Winkelmann, Borchen, Germany), weighing 200–300 g, were used. The animals were purchased from the breeder at a body weight of 180–220 g. Following arrival in the animal colony, the rats were kept under controlled environmental conditions (ambient temperature 24–25°C, humidity 50–60%, 12/12 h light/dark cycle, light on at 0700) for at least 1 week before being used in the experiments. Standard laboratory chow (Altromin 1324 standard diet) and tap water were allowed ad libitum. All animal care and handling was conducted in compliance with the German Animal Welfare Act and was approved by the responsible governmental agency in Hannover. With respect to the use of females, it is important to note that we previously showed that neither seizure susceptibility nor anticonvulsant drug effects are affected by the estrous cycle in fully kindled female rats as used in the present study (Rundfeldt et al., 1990; Wahnschaffe & Loscher, 1992).
Keiko Sato - One of the best experts on this subject based on the ideXlab platform.
-
Increases in mRNA levels for Tα1-tubulin in the rat Kindling Model of epilepsy
Brain research, 2001Co-Authors: Keiko Sato, Koji AbeAbstract:Abstract The expression of mRNA for Tα1-tubulin, a cytoskeletal protein, was studied in the rat Kindling Model of epilepsy. The Tα1-tubulin mRNA level increased significantly in the dentate gyrus (DG) and CA3 of hippocampus ipsilateral to stimulation from 8 h to 4 weeks after amygdaloid kindled seizures. The peak increase was observed at 1 week after the last seizures both in the DG and CA3. These results suggest that the microtubule formation contributes to synaptic reModeling and reorganization of neural networks, which may be based on the Kindling-inducing epileptogenesity.
-
Effects of Antiepileptie Drugs on Seizure Thresholds in the Rat Kindling Model of Temporal Lobe Epilepsy
Epilepsia, 1998Co-Authors: Kiyoshi Morimoto, Keiko Sato, Hitoshi Sato, Takemi Watanabe, Toru Hirao, Soichiro Sato, Norihito YamadaAbstract:Purpose: To determine the antiepileptic profiles of antiepileptic drugs (AEDs), we compared the effects of various AEDs, including phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), and diazepam (DZP), on seizure thresholds in the rat Kindling Model of temporal lobe epilepsy. Methods: Male Sprague-Dawley rats were used. A tripolar electrode was implanted into the amygdala under pentobarbital anesthesia. All rats underwent daily Kindling stimulation (100 Hz, 2 s) until stable generalized seizures were induced. The generalized seizure-triggering threshold (GST) was then determined for each rat by the application of stimulation, which increased in intensity by 50 μA steps at intervals of 15 min. After intraperitoneal administration of PHT (180 mg/kg), CBZ (40 mg/kg), VPA (200 mg/kg), or DZP (2 mg/kg), electrical stimulation at the intensity of the GST, or 2 or 3 times the GST, was delivered to the amygdala, and reversal of the anticonvulsant effects was measured. Results: All AEDs had potent anticonvulsant effects on amygdala-kindled seizures induced by stimulation at the GST. After treatment with PHT and CBZ, when the stimulus intensity was increased to 2 or 3 times the GST, the anticonvulsant effects were completely eliminated. In contrast, the effects of VPA were partially reversed and those of DZP were only slightly reversed by increases in the stimulus intensity. Conclusions: These findings suggest that the prinicipal mechanism for the anticonvulsant effects of PHT and CBZ, which act primarily on voltage-sensitive Na+ channels, is the significant increase of seizure thresholds in epileptogenic foci. In our previous study, lamotrigine had the same effects as PHT and CBZ on seizure thresholds. In contrast, the fundamental profile of VPA and DZP, which enhance a-aminobutyric acid (GABA)/benzodiazepine (BZD) systems, differs from that of PHT/CBZ-type AEDs, and the main mechanism for the anticonvulsant effects of these two drugs is blockade of seizure propagation and generalization. This conclusion is consistent with our recent findings for tiagabine (a selective GABA uptake inhibitor) in the Kindling Model (Morimoto et al. Epilepsia 1997;38:966).
-
BW1003C87, phenytoin and carbamazepine elevate seizure threshold in the rat amygdala-Kindling Model of epilepsy
European journal of pharmacology, 1997Co-Authors: Kiyoshi Morimoto, Keiko Sato, Hitoshi Sato, Soichiro Sato, Norihito YamadaAbstract:Abstract We examined the anticonvulsant effects of BW1003C87 (5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine ethane sulphonic acid), which is structurally related to the new antiepileptic drug, lamotrigine, and compared its effects to those of the conventional antiepileptic drugs, phenytoin and carbamazopine, using the rat amygdala-Kindling Model of epilepsy. BW1003C87 (2.5–10 mg/kg, i.p.) had potent and long-lasting (48 h after single administration) effects on amygdala-kindled seizures. The effects of BW1003C87 were completely reversed when the stimulus intensity was increased to 2 or 3 times the threshold determined. Since the same effects on seizure threshold were obtained for phenytoin and carbamazepine in the present study and for lamotrigine in our previous study, we propose that the principal mechanism of these antiepileptic drugs, which act primarily on voltage-sensitive Na+ channels, is significant elevation of the seizure threshold in epileptogenic foci and that BW1003C87 has a profile similar to that of these drugs.
-
Antiepileptogenic and anticonvulsant effects of NBQX, a selective AMPA receptor antagonist, in the rat Kindling Model of epilepsy.
Brain Research, 1994Co-Authors: T Namba, Kiyoshi Morimoto, Keiko Sato, Norihito Yamada, S KurodaAbstract:Abstract To investigate the role of non-NMDA receptors in epileptic seizures, we examined the antiepileptogenic and anticonvulsant effects of NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline), a potent and selective AMPA receptor antagonist, in the rat Kindling Model. Systemic administration of 10–40 mg/kg NBQX significantly and dose dependently suppressed previously kindled seizures from the amygdala (AM), assessed in terms of the motor seizure stage and afterdischarge (AD) duration. The maximal effects were observed at 0.5–1 h after drug injection. When the intensity of electrical stimulation was increased to twice the generalized seizure-triggering threshold (GST), the anticonvulsant effects of NBQX on AM-kindled seizures were not reversed, suggesting that the effects were not due to non-specific elevation of the GST. In contrast to AM-kindled seizures, 20–40 mg/kg NBQX significantly suppressed only the motor seizure stage without reducing the AD duration of previously hippocampal-kindled seizures. Daily administration of 15 or 30 mg/kg NBQX prior to each electrical stimulation of the AM markedly and significantly suppressed the development of Kindling. During drug sessions, the growth of the AD duration was blocked almost completely, while the waveform of ADs became more complex. These results indicate that NBQX has potent antiepileptogenic and anticonvulsant actions on Kindling, at least more from the AM and that non-NMDA receptors have an important role in seizure propagation.
Kiyoshi Morimoto - One of the best experts on this subject based on the ideXlab platform.
-
Effects of Antiepileptie Drugs on Seizure Thresholds in the Rat Kindling Model of Temporal Lobe Epilepsy
Epilepsia, 1998Co-Authors: Kiyoshi Morimoto, Keiko Sato, Hitoshi Sato, Takemi Watanabe, Toru Hirao, Soichiro Sato, Norihito YamadaAbstract:Purpose: To determine the antiepileptic profiles of antiepileptic drugs (AEDs), we compared the effects of various AEDs, including phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), and diazepam (DZP), on seizure thresholds in the rat Kindling Model of temporal lobe epilepsy. Methods: Male Sprague-Dawley rats were used. A tripolar electrode was implanted into the amygdala under pentobarbital anesthesia. All rats underwent daily Kindling stimulation (100 Hz, 2 s) until stable generalized seizures were induced. The generalized seizure-triggering threshold (GST) was then determined for each rat by the application of stimulation, which increased in intensity by 50 μA steps at intervals of 15 min. After intraperitoneal administration of PHT (180 mg/kg), CBZ (40 mg/kg), VPA (200 mg/kg), or DZP (2 mg/kg), electrical stimulation at the intensity of the GST, or 2 or 3 times the GST, was delivered to the amygdala, and reversal of the anticonvulsant effects was measured. Results: All AEDs had potent anticonvulsant effects on amygdala-kindled seizures induced by stimulation at the GST. After treatment with PHT and CBZ, when the stimulus intensity was increased to 2 or 3 times the GST, the anticonvulsant effects were completely eliminated. In contrast, the effects of VPA were partially reversed and those of DZP were only slightly reversed by increases in the stimulus intensity. Conclusions: These findings suggest that the prinicipal mechanism for the anticonvulsant effects of PHT and CBZ, which act primarily on voltage-sensitive Na+ channels, is the significant increase of seizure thresholds in epileptogenic foci. In our previous study, lamotrigine had the same effects as PHT and CBZ on seizure thresholds. In contrast, the fundamental profile of VPA and DZP, which enhance a-aminobutyric acid (GABA)/benzodiazepine (BZD) systems, differs from that of PHT/CBZ-type AEDs, and the main mechanism for the anticonvulsant effects of these two drugs is blockade of seizure propagation and generalization. This conclusion is consistent with our recent findings for tiagabine (a selective GABA uptake inhibitor) in the Kindling Model (Morimoto et al. Epilepsia 1997;38:966).
-
BW1003C87, phenytoin and carbamazepine elevate seizure threshold in the rat amygdala-Kindling Model of epilepsy
European journal of pharmacology, 1997Co-Authors: Kiyoshi Morimoto, Keiko Sato, Hitoshi Sato, Soichiro Sato, Norihito YamadaAbstract:Abstract We examined the anticonvulsant effects of BW1003C87 (5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine ethane sulphonic acid), which is structurally related to the new antiepileptic drug, lamotrigine, and compared its effects to those of the conventional antiepileptic drugs, phenytoin and carbamazopine, using the rat amygdala-Kindling Model of epilepsy. BW1003C87 (2.5–10 mg/kg, i.p.) had potent and long-lasting (48 h after single administration) effects on amygdala-kindled seizures. The effects of BW1003C87 were completely reversed when the stimulus intensity was increased to 2 or 3 times the threshold determined. Since the same effects on seizure threshold were obtained for phenytoin and carbamazepine in the present study and for lamotrigine in our previous study, we propose that the principal mechanism of these antiepileptic drugs, which act primarily on voltage-sensitive Na+ channels, is significant elevation of the seizure threshold in epileptogenic foci and that BW1003C87 has a profile similar to that of these drugs.
-
antiepileptic effects of tiagabine a selective gaba uptake inhibitor in the rat Kindling Model of temporal lobe epilepsy
Epilepsia, 1997Co-Authors: Kiyoshi Morimoto, Hitoshi Sato, Takemi Watanabe, Yoshitaka Yamamoto, Hiroshi SuwakiAbstract:Summary: Purpose: We determined the antiepileptic profile of tiagabine (TGB), a selective γ-aminobutyric acid (GABA) uptake inhibitor, in the rat Kindling Model of temporal lobe epilepsy (TLE). Methods: The anticonvulsant and adverse effects of TGB were examined in amygdala- or hippocampal-kindled rats and compared with those of other GABA uptake inhibitors (SKF89976A and NNC-7 1 1) and conventional antiepileptic drugs [AEDs: valproate (VPA) and carbamazepine (CBZ)]. In addition, the antiepileptogenic effects of TGB on amygdala Kindling development were examined. Results: TGB (2.5–40 mgkg intraperitoneally, i.p.) had potent and dose-dependent anticonvulsant effects on both amygdala-and hippocampal-kindled seizures. The order of anticonvulsant potency of the three GABA uptake inhibitors tested was: NNC-711 > TGB > SKF-89976A and paralleled the in vitro GABA uptake efficacy. In addition, daily treatment with TGB 10 mgkg for 10 days significantly retarded Kindling development. Although adverse effects of TGB on motor systems were significantly less than those of VPA and CBZ, high toxic doses of TGB often caused EEG paroxysm and myoclonus. Conclusions: Our results indicate the clinical usefulness of TGB for treatment of drug-resistant TLE.
-
Antiepileptogenic and anticonvulsant effects of NBQX, a selective AMPA receptor antagonist, in the rat Kindling Model of epilepsy.
Brain Research, 1994Co-Authors: T Namba, Kiyoshi Morimoto, Keiko Sato, Norihito Yamada, S KurodaAbstract:Abstract To investigate the role of non-NMDA receptors in epileptic seizures, we examined the antiepileptogenic and anticonvulsant effects of NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline), a potent and selective AMPA receptor antagonist, in the rat Kindling Model. Systemic administration of 10–40 mg/kg NBQX significantly and dose dependently suppressed previously kindled seizures from the amygdala (AM), assessed in terms of the motor seizure stage and afterdischarge (AD) duration. The maximal effects were observed at 0.5–1 h after drug injection. When the intensity of electrical stimulation was increased to twice the generalized seizure-triggering threshold (GST), the anticonvulsant effects of NBQX on AM-kindled seizures were not reversed, suggesting that the effects were not due to non-specific elevation of the GST. In contrast to AM-kindled seizures, 20–40 mg/kg NBQX significantly suppressed only the motor seizure stage without reducing the AD duration of previously hippocampal-kindled seizures. Daily administration of 15 or 30 mg/kg NBQX prior to each electrical stimulation of the AM markedly and significantly suppressed the development of Kindling. During drug sessions, the growth of the AD duration was blocked almost completely, while the waveform of ADs became more complex. These results indicate that NBQX has potent antiepileptogenic and anticonvulsant actions on Kindling, at least more from the AM and that non-NMDA receptors have an important role in seizure propagation.
