Wolfgang Löscher

University of Veterinary Medicine Hannover, Hanover, Lower Saxony, Germany

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Publications (603)2291.42 Total impact

  • Friederike Twele · Kathrin Töllner · Claudia Brandt · Wolfgang Löscher
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    ABSTRACT: The intrahippocampal kainate mouse model of mesial temporal lobe epilepsy is increasingly being used for studies on epileptogenesis and antiepileptogenesis. Almost all previous studies used male mice for this purpose, and no study is available in this or other models of acquired epilepsy that directly compared epileptogenesis in female and male rodents. Epidemiological studies suggest that gender may affect susceptibility to epilepsy and its prognosis; therefore, one goal of this study was to investigate whether sex has an influence on latent period and epileptogenesis in the intrahippocampal kainate model in mice. Another aspect that was examined in the present study was whether mouse strain differences in epileptogenesis exist. Finally, we examined the effects of different types of anesthesia (chloral hydrate, isoflurane) on kainate-induced status epilepticus (SE) and epileptogenesis. Continuous (24/7) video-EEG monitoring was used during SE and the 2weeks following SE as well as 4-6weeks after SE. In male NMRI mice with chloral hydrate anesthesia during kainate injection, SE was followed by a seizure-free latent period of 10-14days if hippocampal paroxysmal discharges (HPDs) recorded from the kainate focus were considered the onset of epilepsy. Anesthesia with isoflurane led to a more rapid onset and higher severity of SE, and not all male NMRI mice exhibited a seizure-free latent period. Female NMRI mice differed from male animals in the lack of any clear latent period, independently of anesthesia type. Furthermore, HPDs were only rarely observed. These problems were not resolved by decreasing the dose of kainate or using other strains (C57BL/6, FVB/N) of female mice. The present data are the first to demonstrate marked sex-related differences in the latent period following brain injury in a rodent model of acquired epilepsy. Furthermore, our data demonstrate that the choice of anesthestic agent during kainate administration affects SE severity and as a consequence, the latent period, which may explain some of the differences reported for this model in the literature.
    No preview · Article · Feb 2016 · Epilepsy & Behavior
  • Michael A. Rogawski · Wolfgang Löscher · Jong M. Rho
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    ABSTRACT: Antiseizure drugs (ASDs), also termed antiepileptic drugs, are the main form of symptomatic treatment for people with epilepsy, but not all patients become free of seizures. The ketogenic diet is one treatment option for drug-resistant patients. Both types of therapy exert their clinical effects through interactions with one or more of a diverse set of molecular targets in the brain. ASDs act by modulation of voltage-gated ion channels, including sodium, calcium, and potassium channels; by enhancement of γ-aminobutyric acid (GABA)-mediated inhibition through effects on GABAA receptors, the GABA transporter 1 (GAT1) GABA uptake transporter, or GABA transaminase; through interactions with elements of the synaptic release machinery, including synaptic vesicle 2A (SV2A) and α2δ; or by blockade of ionotropic glutamate receptors, including α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. The ketogenic diet leads to increases in circulating ketones, which may contribute to the efficacy in treating pharmacoresistant seizures. Production in the brain of inhibitory mediators, such as adenosine, or ion channel modulators, such as polyunsaturated fatty acids, may also play a role. Metabolic effects, including diversion from glycolysis, are a further postulated mechanism. For some ASDs and the ketogenic diet, effects on multiple targets may contribute to activity. Better understanding of the ketogenic diet will inform the development of improved drug therapies to treat refractory seizures.
    No preview · Article · Jan 2016 · Cold Spring Harbor Perspectives in Medicine
  • P. Wlaz · U. Ebert · W. Löscher

    No preview · Conference Paper · Nov 2015
  • H. Potschka · P. Wlaz · W. Löscher

    No preview · Conference Paper · Nov 2015
  • Sonja Bröer · Wolfgang Löscher
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    ABSTRACT: The discovery and validation of biomarkers in neurological and neurodegenerative diseases is an important challenge for early diagnosis of disease and for the development of therapeutics. Epilepsy is often a consequence of brain insults such as traumatic brain injury or stroke, but as yet no biomarker exists to predict the development of epilepsy in patients at risk. Given the complexity of epilepsy, it is unlikely that a single biomarker is sufficient for this purpose, but a combinatorial approach may be needed to overcome the challenge of individual variability and disease heterogeneity. The goal of the present prospective study in the lithium-pilocarpine model of epilepsy in rats was to determine the discriminative utility of combinations of phenotypic biomarkers by examining their ability to predict epilepsy. For this purpose, we used a recent model refinement that allows comparing rats that will or will not develop spontaneous recurrent seizures (SRS) after pilocarpine-induced status epilepticus (SE). Potential biomarkers included in our study were seizure threshold and seizure severity in response to timed i.v. infusion of pentylenetetrazole (PTZ) and behavioral alterations determined by a battery of tests during the three weeks following SE. Three months after SE, video/EEG monitoring was used to determine which rats had developed SRS. To determine whether a biomarker or combination of biomarkers performed better than chance at predicting epilepsy after SE, derived data underwent receiver operating characteristic (ROC) curve analyses. When comparing rats with and without SRS and sham controls, the best intergroup discrimination was obtained by combining all measurements, resulting in a ROC area under curve (AUC) of 0.9592 (P<0.01), indicating an almost perfect discrimination or accuracy to predict development of SRS. These data indicate that a combinatorial biomarker approach may overcome the challenge of individual variability in the prediction of epilepsy.
    No preview · Article · Nov 2015 · Epilepsy & Behavior
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    ABSTRACT: Prevention of symptomatic epilepsy ("antiepileptogenesis") in patients at risk is a major unmet clinical need. Several drugs underwent clinical trials for epilepsy prevention, but none of the drugs tested was effective. Similarly, most previous preclinical attempts to develop antiepileptogenic strategies failed. In the majority of studies, drugs were given as monotherapy. However, epilepsy is a complex network phenomenon, so that it is unlikely that a single drug can halt epileptogenesis. We recently proposed multitargeted approaches ("network pharmacology") to interfere with epileptogenesis. One strategy, which, if effective, would allow a relatively rapid translation into the clinic, is developing novel combinations of clinically used drugs with diverse mechanisms that are potentially relevant for antiepileptogenesis. In order to test this strategy preclinically, we developed an algorithm for testing such drug combinations, which was inspired by the established drug development phases in humans. As a first step of this algorithm, tolerability of four rationally chosen, repeatedly administered drug combinations was evaluated by a large test battery in mice: A, levetiracetam and phenobarbital; B, valproate, losartan, and memantine; C, levetiracetam and topiramate; and D, levetiracetam, parecoxib, and anakinra. As in clinical trials, tolerability was separately evaluated before starting efficacy experiments to identify any adverse effects of the combinations that may critically limit the successful translation of preclinical findings to the clinic. Except combination B, all drug cocktails were relatively well tolerated. Based on previous studies, we expected that tolerability would be lower in the latent and chronic phases following status epilepticus in mice, but, except combinations C and D, no significant differences were determined between nonepileptic and post-status epilepticus animals. As a next step, the rationally chosen drug combinations will be evaluated for antiepileptogenic activity in mouse and rat models of symptomatic epilepsy.
    No preview · Article · Nov 2015 · Epilepsy research
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    ABSTRACT: Epilepsy is the tendency to have unprovoked epileptic seizures. Anything causing structural or functional derangement of brain physiology may lead to seizures, and different conditions may express themselves solely by recurrent seizures and thus be labelled "epilepsy." Worldwide, epilepsy is the most common serious neurological condition. The range of risk factors for the development of epilepsy varies with age and geographic location. Congenital, developmental and genetic conditions are mostly associated with the development of epilepsy in childhood, adolescence and early adulthood. Head trauma, infections of the central nervous system (CNS) and tumours may occur at any age and may lead to the development of epilepsy. Infections of the CNS are a major risk factor for epilepsy. The reported risk of unprovoked seizures in population-based cohorts of survivors of CNS infections from developed countries is between 6.8 and 8.3 %, and is much higher in resource-poor countries. In this review, the various viral, bacterial, fungal and parasitic infectious diseases of the CNS which result in seizures and epilepsy are discussed. The pathogenesis of epilepsy due to brain infections, as well as the role of experimental models to study mechanisms of epileptogenesis induced by infectious agents, is reviewed. The sterile (non-infectious) inflammatory response that occurs following brain insults is also discussed, as well as its overlap with inflammation due to infections, and the potential role in epileptogenesis. Furthermore, autoimmune encephalitis as a cause of seizures is reviewed. Potential strategies to prevent epilepsy resulting from brain infections and non-infectious inflammation are also considered.
    No preview · Article · Oct 2015 · Acta Neuropathologica
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    Wolfgang Löscher · Lawrence J Hirsch · Dieter Schmidt
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    ABSTRACT: A widely accepted hypothesis holds that there is a seizure-free, pre-epileptic state, termed the "latent period", between a brain insult, such as traumatic brain injury or stroke, and the onset of symptomatic epilepsy, during which a cascade of structural, molecular, and functional alterations gradually mediates the process of epileptogenesis. This review, based on recent data from both animal models and patients with different types of brain injury, proposes that epileptogenesis and often subclinical epilepsy can start immediately after brain injury without any appreciable latent period. Even though the latent period has traditionally been the cornerstone concept representing epileptogenesis, we suggest that the evidence for the existence of a latent period is spotty both for animal models and human epilepsy. Knowing whether a latent period exists or not is important for our understanding of epileptogenesis and for the discovery and the trial design of antiepileptogenic agents. The development of antiepileptogenic treatments to prevent epilepsy in patients at risk from a brain insult is a major unmet clinical need.
    Full-text · Article · Sep 2015 · Epilepsy & Behavior
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    ABSTRACT: Inactivating mutations of the NF-κB essential modulator (NEMO), a key component of NF-κB signaling, cause the genetic disease incontinentia pigmenti (IP). This leads to severe neurological symptoms, but the mechanisms underlying brain involvement were unclear. Here, we show that selectively deleting Nemo or the upstream kinase Tak1 in brain endothelial cells resulted in death of endothelial cells, a rarefaction of brain microvessels, cerebral hypoperfusion, a disrupted blood-brain barrier (BBB), and epileptic seizures. TAK1 and NEMO protected the BBB by activating the transcription factor NF-κB and stabilizing the tight junction protein occludin. They also prevented brain endothelial cell death in a NF-κB-independent manner by reducing oxidative damage. Our data identify crucial functions of inflammatory TAK1-NEMO signaling in protecting the brain endothelium and maintaining normal brain function, thus explaining the neurological symptoms associated with IP.
    Full-text · Article · Sep 2015 · Journal of Experimental Medicine
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    Chris Rundfeldt · Andrea Tipold · Wolfgang Löscher
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    ABSTRACT: Imepitoin is a novel antiepileptic drug for the treatment of canine idiopathic epilepsy. The present study was conducted to demonstrate superior antiepileptic activity of a high dose of 30 mg/kg BID over a low dose of 1 mg/kg BID of imepitoin during 12 weeks of treatment under double blind conditions in a field population of dogs with previously untreated epilepsy. In a consecutive 12 weeks open label follow up (phase 2), all animals received 30 mg/kg BID, to evaluate the persistence of the antiepileptic activity, and to evaluate the effect of a dose step up to 30 mg/kg in the former low-dose animals. A treatment with 30 mg/kg BID resulted in a significantly greater reduction in monthly seizure frequency relative to baseline data as compared to the 1 mg/kg dose. Both generalized and partial seizures but not cluster seizures were significantly less frequent in the high dose group. The antiepileptic activity was maintained during study phase 2 in the high dose group. An increase to 30 mg/kg BID in the low- dose animals resulted in a significant reduction in generalized and partial seizures, but not cluster seizures. At the end of study phase 2, 32.1 and 46.8 % of dogs of the former high and former low-dose groups respectively, remained free of generalized tonic-clonic seizures. Imepitoin was well tolerated. The frequency of dogs with any adverse drug reactions was higher in the 30 mg/kg BID dose (59 % vs. 41 %, p = 0.041), and the main target organ was the central nervous system (CNS). The occurrence of CNS related adverse reactions was transient and findings were mostly restricted to the first weeks of treatment. No hepatic enzyme increase and no other organ toxicity were observed. The administration of imepitoin twice daily at a dose of 30 mg/kg results in significant and persistent antiepileptic effects in patients with newly diagnosed epilepsy and generalized tonic-clonic seizures, as observed over a study period of up to 6 months. Imepitoin was well tolerated. Most CNS related adverse drug reactions were transient. Both the antiepileptic activity and the safety profile make the drug suitable for long-term clinical use.
    Full-text · Article · Sep 2015 · BMC Veterinary Research
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    ABSTRACT: Common criteria for the diagnosis of drug resistance and the assessment of outcome are needed urgently as a prerequisite for standardized evaluation and reporting of individual therapeutic responses in canine epilepsy. Thus, we provide a proposal for the definition of drug resistance and partial therapeutic success in canine patients with epilepsy. This consensus statement also suggests a list of factors and aspects of outcome, which should be considered in addition to the impact on seizures. Moreover, these expert recommendations discuss criteria which determine the validity and informative value of a therapeutic trial in an individual patient and also suggest the application of individual outcome criteria. Agreement on common guidelines does not only render a basis for future optimization of individual patient management, but is also a presupposition for the design and implementation of clinical studies with highly standardized inclusion and exclusion criteria. Respective standardization will improve the comparability of findings from different studies and renders an improved basis for multicenter studies. Therefore, this proposal provides an in-depth discussion of the implications of outcome criteria for clinical studies. In particular ethical aspects and the different options for study design and application of individual patient-centered outcome criteria are considered.
    Full-text · Article · Aug 2015 · BMC Veterinary Research
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    ABSTRACT: In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors' experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible.
    Full-text · Article · Aug 2015 · BMC Veterinary Research
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    Felix Kaspar Gesell · Sonja Hoppe · Wolfgang Löscher · Andrea Tipold
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    ABSTRACT: Epilepsy is one of the most common neurological disorders in dogs and is treated by chronic administration of antiepileptic drugs (AEDs). In human beings with epilepsy, it is common clinical practice to consider drug withdrawal after a patient has been in remission (seizure free) for three or more years, but withdrawal is associated with the risk of relapse. In the present study, the consequences of AED withdrawal were studied in dogs with epilepsy. Therefore, 200 owners of dogs with idiopathic or presumed idiopathic epilepsy were contacted by telephone interview, 138 cases could be enrolled. In 11 cases, the therapy had been stopped after the dogs had become seizure free for a median time of 1 year. Reasons for AED withdrawal were appearance or fear of adverse side effects, financial aspects, and the idea that the medication could be unnecessary. Following AED withdrawal, four of these dogs remained seizure free, seven dogs suffered from seizure recurrence, of which only three dogs could regain seizure freedom after resuming AED therapy. Due to the restricted case number, an exact percentage of dogs with seizure recurrence after AED withdrawal cannot be given. However, the present study gives a hint that similar numbers as in human patients are found, and the data can help owners of epileptic dogs and the responsible clinician to decide when and why to stop antiepileptic medication.
    Full-text · Article · Aug 2015
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    ABSTRACT: The adenosine triphosphate-binding cassette transporter P-glycoprotein (ABCB1/Abcb1a) restricts at the blood-brain barrier (BBB) brain distribution of many drugs. ABCB1 may be involved in drug-drug interactions (DDIs) at the BBB, which may lead to changes in brain distribution and central nervous system side effects of drugs. Positron emission tomography (PET) with the ABCB1 substrates (R)-[(11)C]verapamil and [(11)C]-N-desmethyl-loperamide and the ABCB1 inhibitor tariquidar has allowed direct comparison of ABCB1-mediated DDIs at the rodent and human BBB. In this work we evaluated different factors which could influence the magnitude of the interaction between tariquidar and (R)-[(11)C]verapamil or [(11)C]-N-desmethyl-loperamide at the BBB and thereby contribute to previously observed species differences between rodents and humans. We performed in vitro transport experiments with [(3)H]verapamil and [(3)H]-N-desmethyl-loperamide in ABCB1 and Abcb1a overexpressing cell lines. Moreover we conducted in vivo PET experiments and biodistribution studies with (R)-[(11)C]verapamil and [(11)C]-N-desmethyl-loperamide in wild-type mice without and with tariquidar pretreatment and in homozygous Abcb1a/1b((-/-)) and heterozygous Abcb1a/1b((+/-)) mice. We found no differences for in vitro transport of [(3)H]verapamil and [(3)H]-N-desmethyl-loperamide by ABCB1 and Abcb1a and its inhibition by tariquidar. [(3)H]-N-Desmethyl-loperamide was transported with a 5 to 9 times higher transport ratio than [(3)H]verapamil in ABCB1- and Abcb1a-transfected cells. In vivo, brain radioactivity concentrations were lower for [(11)C]-N-desmethyl-loperamide than for (R)-[(11)C]verapamil. Both radiotracers showed tariquidar dose dependent increases in brain distribution with tariquidar half-maximum inhibitory concentrations (IC50) of 1052 nM (95% confidence interval CI: 930-1189) for (R)-[(11)C]verapamil and 1329 nM (95% CI: 980-1801) for [(11)C]-N-desmethyl-loperamide. In homozygous Abcb1a/1b((-/-)) mice brain radioactivity distribution was increased by 3.9- and 2.8-fold and in heterozygous Abcb1a/1b((+/-)) mice by 1.5- and 1.1-fold, for (R)-[(11)C]verapamil and [(11)C]-N-desmethyl-loperamide, respectively, as compared with wild-type mice. For both radiotracers radiolabeled metabolites were detected in plasma and brain. When brain and plasma radioactivity concentrations were corrected for radiolabeled metabolites, brain distribution of (R)-[(11)C]verapamil and [(11)C]-N-desmethyl-loperamide was increased in tariquidar (15 mg/kg) treated animals by 14.1- and 18.3-fold, respectively, as compared with vehicle group. Isoflurane anesthesia altered [(11)C]-N-desmethyl-loperamide but not (R)-[(11)C]verapamil metabolism, and this had a direct effect on the magnitude of the increase in brain distribution following ABCB1 inhibition. Our data furthermore suggest that in the absence of ABCB1 function brain distribution of [(11)C]-N-desmethyl-loperamide but not (R)-[(11)C]verapamil may depend on cerebral blood flow. In conclusion, we have identified a number of important factors, i.e., substrate affinity to ABCB1, brain uptake of radiolabeled metabolites, anesthesia, and cerebral blood flow, which can directly influence the magnitude of ABCB1-mediated DDIs at the BBB and should therefore be taken into consideration when interpreting PET results.
    Full-text · Article · Jul 2015 · Molecular Pharmaceutics
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    ABSTRACT: The N-K-Cl cotransporters (NKCCs) mediate the coupled, electroneutral movement of Na(+) , K(+) and Cl(-) ions across cell membranes. There are two isoforms of this cation cotransporter, NKCC1 and NKCC2. NKCC2 is expressed primarily in the kidney and is the target of diuretics such as bumetanide. Bumetanide was discovered as a result of screening of ∼5000 3-amino-5-sulfamoylbenzoic acid derivatives long before NKCC2 was identified in the kidney. Therefore structure-activity studies on effects of bumetanide derivatives on NKCC2 are not available. In this study, the effect of a series of diuretically active bumetanide derivatives was investigated on human NKCC2 variant A (hNKCC2A) expressed in Xenopus laevis oocytes. hNKCC2A displayed an IC50 towards bumetanide of 4 μM. A good correlation between the diuretic potency of bumetanide and its derivatives in dogs and their inhibition of hNKCC2A was found (r(2) = 0.817; P<0.01). Replacement of the carboxylic group of bumetanide by a nonionic residue, e.g., an anilinomethyl group, resulted in a loss of inhibition of hNKCC2A, indicating that an acidic group is required for transporter inhibition. Exchange of the phenoxy group of bumetanide by a 4-chloroanilino group or the sulfamoyl group by a methylsulfonyl group resulted in compounds with higher potency to inhibit hNKCC2A than bumetanide. The Xenopus laevis oocyte expression system as used in these experiments allows studying the structural requirements that determine relative potency of loop diuretics on human NKCC2 splice variants, and may lead to the discovery of novel high-ceiling diuretics. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2015 · British Journal of Pharmacology
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    ABSTRACT: The AMPA receptor subtype of glutamate receptors, which mediates fast synaptic excitation, is of primary importance in initiating epileptiform discharges, so that AMPA receptor antagonists exert anti-seizure activity in diverse animal models of partial and generalized seizures. Recently, the first AMPA receptor antagonist, perampanel, was approved for use as adjunctive therapy for the treatment of resistant partial seizures in patients. Interestingly, the competitive AMPA receptor antagonist NBQX has recently been reported to prevent development of spontaneous recurrent seizures (SRS) in a neonatal seizure model in rats, indicating the AMPA antagonists may exert also antiepileptogenic effects. This prompted us to evaluate competitive (NBQX) and noncompetitive (perampanel) AMPA receptor antagonists in an adult mouse model of mesial temporal lobe epilepsy. In this model, SRS develop after status epilepticus (SE) induced by intrahippocampal injection of kainate. Focal electrographic seizures in this model are resistant to several major antiepileptic drugs. In line with previous studies, phenytoin was not capable of blocking such seizures in the present experiments, while they were markedly suppressed by NBQX and perampanel. However, perampanel was less tolerable than NBQX in epileptic mice, so that only NBQX was subsequently tested for antiepileptogenic potential. When mice were treated over three days after kainate-induced SE with NBQX (20 mg/kg t.i.d.), no effect on development or frequency of seizures was found in comparison to vehicle controls. These results suggest that AMPA receptor antagonists, while being effective in suppressing resistant focal seizures, are not exerting antiepileptogenic effects in an adult mouse model of partial epilepsy. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Mar 2015 · Neuropharmacology
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    Wolfgang Löscher
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    ABSTRACT: Drug-refractory status epilepticus (RSE) is a major medical emergency with a mortality of up to 40% and the risk of severe long-term consequences. The mechanisms involved in RSE are incompletely understood. Animal models are important in developing treatment strategies for more effective termination of SE and prevention of its long-term outcomes. The pilocarpine and lithium-pilocarpine rat models are widely used in this respect. In these models, resistance to diazepam and other antiseizure drugs (ASDs) develops during SE so that an SE that is longer than 30min is difficult to suppress. Furthermore, because all ASDs used in SE treatment are much more rapidly eliminated by rodents than by humans, SE recurs several hours after ASD treatment. Long-term consequences include hippocampal damage, behavioral alterations, and epilepsy with spontaneous recurrent seizures. In this review, different rational polytherapies for SE, which are more effective than monotherapies, are discussed, including a novel polytherapy recently developed by our group. Based on data from diverse seizure models, we hypothesized that cholinergic mechanisms are involved in the mechanisms underlying ASD resistance of SE. We, therefore, developed an intravenous drug cocktail, consisting of diazepam, phenobarbital, and the anticholinergic scopolamine. This drug combination irreversibly terminated SE when administered 60, 90, or 120min after SE onset. The efficacy of this cocktail in terminating SE was comparable with the previously reported efficacy of polytherapies with the glutamate receptor antagonist ketamine. Furthermore, when injected 60min after SE onset, the scopolamine-containing cocktail prevented development of epilepsy and hippocampal neurodegeneration, which was not observed with high doses of diazepam or a combination of phenobarbital and diazepam. Our data add to the existing preclinical evidence that rational polytherapy can be more effective than monotherapy in the treatment of SE and that combinatorial therapy may offer a clinically useful option for the treatment of RSE. This article is part of a Special Issue entitled "Status Epilepticus". Copyright © 2015 Elsevier Inc. All rights reserved.
    Preview · Article · Mar 2015 · Epilepsy & Behavior

  • No preview · Conference Paper · Feb 2015
  • Kerstin Römermann · Renate Helmer · Wolfgang Löscher
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    ABSTRACT: Resistance to antiepileptic drugs (AEDs) is the major problem in the treatment of epilepsy. One hypothesis to explain AED resistance suggests that seizure-induced overexpression of efflux transporters at the blood-brain barrier (BBB) restricts AEDs to reach their brain targets. Various studies examined whether AEDs are substrates of P-glycoprotein (Pgp; MDR1; ABCB1), whereas information about the potential role of breast cancer resistance protein (BCRP; ABCG2) is scanty. We used a highly sensitive in vitro assay (concentration equilibrium transport assay; CETA) with MDCKII cells transduced with murine Bcrp1 or human BCRP to evaluate whether AEDs are substrates of this major efflux transporter. Six of 7 AEDs examined, namely phenytoin, phenobarbital, carbamazepine, levetiracetam, topiramate, and valproate, were not transported by Bcrp at therapeutic concentrations, whereas lamotrigine exhibited a marked asymmetric, Bcrp-mediated transport in the CETA, which could be almost completely inhibited with the Bcrp inhibitor Ko143. Significant but less marked transport of lamotrigine was detetermined in MDCK cells transfected with human BCRP. Lamotrigine is also a substrate of human Pgp, so that this drug is the first AED that has been identified as a dual substrate of the two major human efflux transporters at the BBB. Previous in vivo studies have demonstrated a synergistic or cooperative role of Pgp and Bcrp in the efflux of dual substrates at the BBB, so that transport of lamotrigine by Pgp and BCRP may be an important mechanism of pharmacoresistance in epilepsy patients in whom both transporters are overexpressed. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Jan 2015 · Neuropharmacology
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    ABSTRACT: The pilocarpine rat model, in which status epilepticus (SE) leads to epilepsy with spontaneous recurrent seizures (SRS), is widely used to study the mechanisms of epileptogenesis and develop strategies for epilepsy prevention. SE is commonly interrupted after 30-90min by high-dose diazepam or other anticonvulsants to reduce mortality. It is widely believed that SE duration of 30-60min is sufficient to induce hippocampal damage and epilepsy. However, resistance to diazepam develops during SE, so that a SE that is longer than 30min is difficult to terminate, and SE typically recurs several hours after diazepam, thus forming a bias for studies on epileptogenesis or antiepileptogenesis. We developed a drug cocktail, consisting of diazepam, phenobarbital, and scopolamine that allows complete and persistent SE termination in the lithium-pilocarpine model. A number of novel findings were obtained with this cocktail. (a) In contrast to previous reports with incomplete SE suppression, a SE of 60min duration did not induce epilepsy, whereas epilepsy with SRS developed after 90 or 120min SE; (b) by comparing groups of rats with 60 and 90min of SE, development of epilepsy could be predicted by behavioral hyperexcitability and decrease in seizure threshold, indicating that these read-outs are suited as biomarkers of epileptogenesis; (c) CA1 damage was prevented by the cocktail, but rats exhibited cell loss in the dentate hilus, which was related to development of epilepsy. These data demonstrate that the duration of SE needed for induction of epileptogenesis in this model is longer than previously thought. Copyright © 2014. Published by Elsevier Inc.
    No preview · Article · Dec 2014 · Neurobiology of Disease

Publication Stats

26k Citations
2,291.42 Total Impact Points

Institutions

  • 1995-2015
    • University of Veterinary Medicine Hannover
      • Institute of Pathology
      Hanover, Lower Saxony, Germany
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
  • 2008
    • University Medical Center Hamburg - Eppendorf
      Hamburg, Hamburg, Germany
  • 2002
    • University of Münster
      • Institute of Physiology
      Muenster, North Rhine-Westphalia, Germany
  • 1998
    • University of Bonn
      • Epileptologische Klinik
      Bonn, North Rhine-Westphalia, Germany
  • 1977-1995
    • Freie Universität Berlin
      • • Pharmacology
      • • Department of Veterinary Medicine
      Berlín, Berlin, Germany