Wolfgang Löscher

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

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Publications (382)1546.74 Total impact

  • 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.
    Neuropharmacology 01/2015; 93. DOI:10.1016/j.neuropharm.2015.01.015 · 4.82 Impact Factor
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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.
    Neurobiology of Disease 12/2014; DOI:10.1016/j.nbd.2014.12.015 · 5.62 Impact Factor
  • Sabine Klein, Marion Bankstahl, Wolfgang Löscher
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    ABSTRACT: Despite more than 20 clinically approved antiepileptic drugs (AEDs), there remains a substantial unmet clinical need for patients with refractory (AED-resistant) epilepsy. Animal models of refractory epilepsy are needed for at least two goals; (1) better understanding of the mechanisms underlying resistance to AEDs, and (2) development of more efficacious AEDs for patients with refractory seizures. It is only incompletely understood why two patients with seemingly identical types of epilepsy and seizures may respond differently to the same AED. Prompted by this well-known clinical phenomenon, we previously evaluated whether epileptic rats respond differently to AEDs and discovered AED responsive and resistant animals in the same models. In the present study, we used the same approach for the widely used intrahippocampal kainate mouse model of mesial temporal lobe epilepsy. In a first step, we examined anti-seizure effects of 6 AEDs on spontaneous recurrent focal electrographic seizures and secondarily generalized convulsive seizures in epileptic mice, showing that the focal nonconvulsive seizures were resistant to carbamazepine and phenytoin, whereas valproate and levetiracetam exerted moderate and phenobarbital and diazepam marked anti-seizure effects. All AEDs seemed to suppress generalized convulsive seizures. Next we investigated the inter-individual variation in the anti-seizure effects of these AEDs and, in case of focal seizures, found responders and nonresponders to all AEDs except carbamazepine. Most nonresponders were resistant to more than one AED. Our data further validate the intrahippocampal kainate mouse model as a model of difficult-to-treat focal seizures that can be used to investigate the determinants of AED efficacy. Copyright © 2014. Published by Elsevier Ltd.
    Neuropharmacology 11/2014; 90. DOI:10.1016/j.neuropharm.2014.11.008 · 4.82 Impact Factor
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    ABSTRACT: Bumetanide is increasingly being used for experimental treatment of brain disorders, including neonatal seizures, epilepsy, and autism, because the neuronal Na-K-Cl cotransporter NKCC1, which is inhibited by bumetanide, is implicated in the pathophysiology of such disorders. However, use of bumetanide for treatment of brain disorders is associated with problems, including poor brain penetration and systemic adverse effects such as diuresis, hypokalemic alkalosis, and hearing loss. The poor brain penetration is thought to be related to its high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, but more recently brain efflux transporters have been involved, too. Multidrug resistance protein 4 (MRP4), organic anion transporter 3 (OAT3) and organic anion transporting polypeptide 2 (OATP2) were suggested to mediate bumetanide brain efflux, but direct proof is lacking. Because MRP4, OAT3, and OATP2 can be inhibited by probenecid, we studied whether this drug alters brain levels of bumetanide in mice. Probenecid (50mg/kg) significantly increased brain levels of bumetanide up to 3-fold; however, it also increased its plasma levels, so that the brain:plasma ratio (~0.015-0.02) was not altered. Probenecid markedly increased the plasma half-life of bumetanide, indicating reduced elimination of bumetanide most likely by inhibition of OAT-mediated transport of bumetanide in the kidney. However, the diuretic activity of bumetanide was not reduced by probenecid. In conclusion, our study demonstrates that the clinically available drug probenecid can be used to increase brain levels of bumetanide and decrease its elimination, which could have therapeutic potential in the treatment of brain disorders. Copyright © 2014 Elsevier B.V. All rights reserved.
    European Journal of Pharmacology 11/2014; 746C:167-173. DOI:10.1016/j.ejphar.2014.11.019 · 2.68 Impact Factor
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    ABSTRACT: In about 20-40% of patients, status epilepticus (SE) is refractory to standard treatment with benzodiazepines, necessitating second- and third-line treatments that are not always successful, resulting in increased mortality. Rat models of refractory SE are instrumental in studying the changes underlying refractoriness and to develop more effective treatments for this severe medical emergency. Failure of GABAergic inhibition is a likely cause of the development of benzodiazepine resistance during SE. In addition to changes in GABAA receptor expression, trafficking, and function, alterations in Cl(-) homeostasis with increased intraneuronal Cl(-) levels may be involved. Bumetanide, which reduces intraneuronal Cl(-) by inhibiting the Cl(-) intruding Na(+), K(+), Cl(-) cotransporter NKCC1, has been reported to interrupt SE induced by kainate in urethane-anesthetized rats, indicating that this diuretic drug may be an interesting candidate for treatment of refractory SE. In this study, we evaluated the effects of bumetanide in the kainate and lithium-pilocarpine models of SE as well as a model in which SE is induced by sustained electrical stimulation of the basolateral amygdala. Unexpectedly, bumetanide alone was ineffective to terminate SE in both conscious and anesthetized adult rats. However, it potentiated the anticonvulsant effect of low doses of phenobarbital, although this was only seen in part of the animals; higher doses of phenobarbital, particularly in combination with diazepam, were more effective to terminate SE than bumetanide/phenobarbital combinations. These data do not suggest that bumetanide, alone or in combination with phenobarbital, is a valuable option in the treatment of refractory SE in adult patients. Copyright © 2014 Elsevier B.V. All rights reserved.
    European Journal of Pharmacology 11/2014; 746C:78-88. DOI:10.1016/j.ejphar.2014.10.056 · 2.68 Impact Factor
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    ABSTRACT: Ethanol is commonly used as a solvent in injectable formulations of poorly watersoluble drugs. The concentrations of ethanol in such formulations are generally considered reasonably safe. It is long known that ethanol can potentiate central effects of sedatives and tranquillizers, particularly the benzodiazepines, most likely as a result of a synergistic interaction at the GABA(A) receptor. However, whether this occurs at the low systemic doses of ethanol resulting from its use as solvent in parenteral formulations of benzodiazepines is not known. In the present study we evaluated whether a commercial ethanol-containing aqueous solution of diazepam exerts more potent anti-seizure effects than an aqueous solution of diazepam hydrochloride or an aqueous emulsion of this drug in the intrahippocampal kainate model of temporal lobe epilepsy in mice. Spontaneous epileptic seizures in this model are known to be resistant to major antiepileptic drugs. Administration of the ethanol-containing formulation of diazepam caused an almost complete suppression of seizures. This was not seen when the same dose (5 mg/kg) of diazepam was administered as aqueous solution or emulsion, although all three diazepam formulations resulted in similar drug and metabolite concentrations in plasma. Our data demonstrate that ethanol-containing solutions of diazepam are superior to block difficult-to-treat seizures to other formulations of diazepam. To our knowledge, this has not been demonstrated before and, if this finding can be translated to humans, may have important consequences for emergency treatment of acute seizures, series of seizures, and initial treatment of status epilepticus in patients.
    Epilepsy Research 10/2014; 108(10). DOI:10.1016/j.eplepsyres.2014.10.002 · 2.19 Impact Factor
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    ABSTRACT: Among the co-morbidities observed in epilepsy patients depression is the most frequent one. Likewise, depression by itself is accompanied by an increased risk to develop epilepsy. Both epilepsy and depression are characterized by a high incidence of pharmacoresistance, which might be based on overactivity of multidrug transporters like P-glycoprotein at the blood-brain barrier. Using genetically modified mice in preclinical epilepsy research is pivotal for investigating this bidirectional relationship. In the present study, we used the sucrose consumption test (SCT) in the pilocarpine and the intrahippocampal kainate mouse post-status epilepticus model to reveal anhedonic behavior, i.e. hyposensitivity to pleasure, as a key symptom of depression. Mice were repetitively investigated by SCT during early epilepsy and the chronic phase of the disease, during which response to antidepressant drug treatment was assessed. SCT revealed long-lasting anhedonia in both models. Anhedonia appeared to be pharmacoresistant, as neither chronic treatment with imipramine in the pilocarpine model nor chronic treatment with fluoxetine in the kainate model could annihilate the differences in sucrose consumption between control and epileptic mice. Moreover, knock-out of P-glycoprotein did not improve the treatment effect of fluoxetine. In conclusion, our findings show for the first time that the SCT is suited for detection of depression-like behavior in mouse models of temporal-lobe epilepsy. Both models might serve as tools to further investigate the neurobiology and pharmacology of epilepsy-associated pharmacoresistant depression.
    Experimental Neurology 09/2014; 263. DOI:10.1016/j.expneurol.2014.09.004 · 4.62 Impact Factor
  • Claudia Brandt, Wolfgang Löscher
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    ABSTRACT: About 25% of patients with epilepsy are refractory to treatment, so that new, more effective antiepileptic drugs (AEDs) are urgently needed. Animal models that simulate the clinical situation with individuals responding and not responding to treatment are important to determine mechanisms of AED resistance and develop novel more effective treatments. We have previously developed and characterized such a model in which spontaneous recurrent seizures (SRS) develop after a status epilepticus induced by sustained electrical stimulation of the basolateral amygdala. In this model, prolonged treatment of epileptic rats with phenobarbital (PB) results in two subgroups, PB responders and PB nonresponders. When PB nonresponders were treated in previous experiments with phenytoin (PHT), 83% of the PB-resistant rats were also resistant to PHT. In the present study we examined if rats with PB resistant seizures are also resistant to lamotrigine (LTG), using continuous EEG/video recording of spontaneous seizures over 10 consecutive weeks. For this purpose, a new group of epileptic rats was produced and selected by treatment with PB into responders and nonresponders. As in previous studies, PB nonresponders had a significantly higher seizure frequency before onset of treatment. During subsequent treatment with LTG, all PB nonresponders and 60% of the PB responders exhibited >75% reduction of seizure frequency and were therefore considered LTG responders. Plasma levels of LTG did not differ significantly between responders and nonresponders. The data of this pilot study indicate that LTG is more effective than PHT to suppress seizures in PB nonresponders in this model, but that not all PB responders also respond to LTG. Overall, our data provide further evidence that AED studies in post-SE TLE models are useful in determining and comparing AED efficacy and investigating predictors and mechanisms of pharmacoresistance.
    Epilepsy Research 09/2014; 108(7). DOI:10.1016/j.eplepsyres.2014.05.008 · 2.19 Impact Factor
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    ABSTRACT: The anticonvulsant activity and safety of imepitoin, a novel antiepileptic drug licensed in the European Union, were evaluated in a multicentre field efficacy study as well as in a safety study under laboratory conditions. Efficacy of imepitoin was compared with phenobarbital in 226 client-owned dogs in a blinded parallel group design. The administration of imepitoin twice daily in incremental doses of 10, 20 or 30 mg/kg demonstrated comparable efficacy to phenobarbital in controlling seizures in dogs. The frequency of adverse events including somnolence/sedation, polydipsia and increased appetite was significantly higher in the phenobarbital group. In phenobarbital-treated dogs, significantly increased levels of alkaline phosphatase, gamma-glutamyl-transferase and other liver enzymes occurred, while no such effect was observed in the imepitoin group. In a safety study under laboratory conditions, healthy beagle dogs were administered 0, 30, 90 or 150 mg/kg imepitoin twice daily for 26 weeks. A complete safety evaluation including histopathology was included in the study. A no-observed-adverse-event level of 90 mg/kg twice daily was determined. These results indicate that imepitoin is a potent and safe antiepileptic drug for dogs.
    Journal of Veterinary Pharmacology and Therapeutics 07/2014; DOI:10.1111/jvp.12151 · 1.32 Impact Factor
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    ABSTRACT: Electroconvulsive therapy is the most effective therapy for major depressive disorder (MDD). The remission rate is above 50% in previously pharmacoresistant patients but the mechanisms of action are not fully understood. Electroconvulsive stimulation (ECS) in rodents mimics antidepressant electroconvulsive therapy (ECT) in humans and is widely used to investigate the underlying mechanisms of ECT. For the translational value of findings in animal models it is essential to establish models with the highest construct, face and predictive validity possible. The commonly used model for ECT in rodents does not meet the demand for high construct validity. For ECT, cortical surface electrodes are used to induce therapeutic seizures whereas ECS in rodents is exclusively performed by auricular or corneal electrodes. However, the stimulation site has a major impact on the type and spread of the induced seizure activity and its antidepressant effect. We propose a method in which ECS is performed by screw electrodes placed above the motor cortex of rats to closely simulate the clinical situation and thereby increase the construct validity of the model. Cortical ECS in rats induced reliably seizures comparable to human ECT. Cortical ECS was more effective than auricular ECS to reduce immobility in the forced swim test. Importantly, auricular stimulation had a negative influence on the general health condition of the rats with signs of fear during the stimulation sessions. These results suggest that auricular ECS in rats is not a suitable ECT model. Cortical ECS in rats promises to be a valid method to mimic ECT.
    Journal of Psychiatric Research 06/2014; DOI:10.1016/j.jpsychires.2014.02.007 · 4.09 Impact Factor
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    Jens P. Bankstahl, Claudia Brandt, Wolfgang Löscher
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    ABSTRACT: Chronically implanted intracranial depth electrodes are widely used for studying electroencephalographic activities in deep cerebral locations and for electrical stimulation of such locations. We have previously reported that prolonged implantation of an electrode in the basolateral amygdala (BLA) of rats facilitates subsequent kindling from this site, indicating a pro-kindling or pro-epileptogenic effect. To further characterize this phenomenon, we analyzed data from experiments in which we induced a self-sustaining status epilepticus (SSSE) by BLA stimulation following different periods of post-surgical delay. In a total of 183 Sprague-Dawley rats, three groups with different periods of postsurgical delay to onset of electrical stimulation were compared: group 1 (16 days on average), group 2 (28 days) and group 3 (48 days). Three types of SSSE were observed after BLA stimulation: type 1 (nonconvulsive), type 2 (nonconvulsive occasionally interrupted by generalized convulsive activity), and type 3 (generalized convulsive). While groups 1 and 2 did not differ in the frequency of these SSSE types, the group with the longest interval between electrode implantation and stimulation (group 3) showed significantly more severe SSSE than the two other groups. The data indicate that intracranial electrode implantation may increase the sensitivity of the implanted area to seizure induction, extending previous findings in the kindling model. Potential mechanisms of these findings include the functional consequences of local microhemorrhages and blood-brain barrier destruction.
    Epilepsy research 05/2014; DOI:10.1016/j.eplepsyres.2014.01.025 · 2.48 Impact Factor
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    ABSTRACT: Objective. There is considerable interest in using bumetanide, a chloride importer NKCC antagonist, for treatment of neurological diseases, such as epilepsy or ischemic and traumatic brain injury, which may involve deranged cellular chloride homeostasis. However, bumetanide is heavily bound to plasma proteins (~98%) and highly ionized at physiological pH, so that it only poorly penetrates into the brain, and chronic treatment with bumetanide is compromised by its potent diuretic effect. Methods: To overcome these problems, we designed lipophilic and uncharged prodrugs of bumetanide that should penetrate the blood-brain barrier more easily than the parent drug and are converted into bumetanide in the brain. The feasibility of this strategy was evaluated in mice and rats. Results: Analysis of bumetanide levels in plasma and brain showed that administration of two ester prodrugs of bumetanide, the pivaloyloxymethyl (BUM1) and N,N-dimethylaminoethylester (BUM5), resulted in significantly higher brain levels of bumetanide than administration of the parent drug. BUM5, but not BUM1, was less diuretic than bumetanide, so that BUM5 was further evaluated in chronic models of epilepsy in mice and rats. In the pilocarpine model in mice, BUM5, but not bumetanide, counteracted the alteration in seizure threshold during the latent period. In the kindling model in rats, BUM5 was more efficacious than bumetanide in potentiating the anticonvulsant effect of phenobarbital. Interpretation: Our data demonstrate that the goal to design bumetanide prodrugs that specifically target the brain is feasible and that such drugs may resolve the problems associated with using bumetanide for treatment of neurological disorders. ANN NEUROL 2014. © 2014 American Neurological Association.
    Annals of Neurology 04/2014; 75(4). DOI:10.1002/ana.24124 · 11.91 Impact Factor
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    ABSTRACT: P-glycoprotein (Pgp; ABCB1/MDR1) is a major efflux transporter at the blood-brain barrier (BBB), restricting the penetration of various compounds. In other tissues, trafficking of Pgp from subcellular stores to the cell surface has been demonstrated and may constitute a rapid way of the cell to respond to toxic compounds by functional membrane insertion of the transporter. It is not known whether drug-induced Pgp trafficking also occurs in brain capillary endothelial cells that form the BBB. In this study, trafficking of Pgp was investigated in human brain capillary endothelial cells (hCMEC/D3) that were stably transfected with a doxycycline-inducible MDR1-EGFP fusion plasmid. In the presence of doxycycline, these cells exhibited a 15-fold increase in Pgp-EGFP fusion protein expression, which was associated with an increased efflux of the Pgp substrate rhodamine 123 (Rho123). The chemotherapeutic agent mitomycin C (MMC) was used to study drug-induced trafficking of Pgp. Confocal fluorescence microscopy of single hCMEC/D3-MDR1-EGFP cells revealed that Pgp redistribution from intracellular pools to the cell surface occurred within 2 h of MMC exposure. Pgp-EGFP exhibited a punctuate pattern at the cell surface compatible with concentrated regions of the fusion protein in membrane microdomains, i.e., lipid rafts, which was confirmed by Western blot analysis of biotinylated cell surface proteins in Lubrol-resistant membranes. MMC exposure also increased the functionality of Pgp as assessed in three functional assays with Pgp substrates (Rho123, eFluxx-ID Gold, calcein-AM). However, this increase occurred with some delay after the increased Pgp expression and coincided with the release of Pgp from the Lubrol-resistant membrane complexes. Disrupting rafts by depleting the membrane of cholesterol increased the functionality of Pgp. Our data present the first direct evidence of drug-induced Pgp trafficking at the human BBB and indicate that Pgp has to be released from lipid rafts to gain its full functionality.
    PLoS ONE 02/2014; 9(2):e88154. DOI:10.1371/journal.pone.0088154 · 3.53 Impact Factor
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    ABSTRACT: The expression of P-glycoprotein (Pgp) is increased in brain capillary endothelial cells (BCECs) of patients with pharmacoresistant epilepsy. This may restrict the penetration of antiepileptic drugs (AEDs) into the brain. However, the mechanisms underlying increased Pgp expression in epilepsy patients are not known. One possibility is that AEDs induce the expression and functionality of Pgp in BCECs. Several older AEDs that induce human cytochrome P450 enzymes also induce Pgp in hepatocytes and enterocytes, but whether this extends to Pgp at the human BBB and to newer AEDs is not known. This prompted us to study the effects of various old and new AEDs on Pgp functionality in the human BCEC line, hCMEC/D3, using the rhodamine 123 (Rho123) efflux assay. For comparison, experiments were performed in two rat BCEC lines, RBE4 and GPNT, and primary cultures of rat and pig BCECs. Furthermore, known Pgp inducers, such as dexamethasone and several cytostatic drugs, were included in our experiments. Under control conditions, GPNT cells exhibited the highest and RBE4 the lowest Pgp expression and Rho123 efflux, while intermediate values were determined in hCMEC/D3. Known Pgp inducers increased Rho123 efflux in all cell lines, but marked inter-cell line differences in effect size were observed. Of the various AEDs examined, only carbamazepine (100 μM) moderately increased Pgp functionality in hCMEC/D3, while valproate (300 μM) inhibited Pgp. These data do not indicate that treatment with AEDs causes a clinically relevant induction in Pgp functionality in BCECs that form the BBB.
    Pharmaceutical Research 01/2014; DOI:10.1007/s11095-013-1264-4 · 4.74 Impact Factor
  • H Steve White, Wolfgang Löscher
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    ABSTRACT: A major unmet medical need is the lack of treatments to prevent (or modify) epilepsy in patients at risk, for example, after epileptogenic brain insults such as traumatic brain injury, stroke, or prolonged acute symptomatic seizures like complex febrile seizures or status epilepticus. Typically, following such brain insults there is a seizure-free interval ("latent period"), lasting months to years before the onset of spontaneous recurrent epileptic seizures. The latent period after a brain insult offers a window of opportunity in which an appropriate treatment may prevent or modify the epileptogenic process induced by a brain insult. A similar latent period occurs in patients with epileptogenic gene mutations. Studies using animal models of epilepsy have led to a greater understanding of the factors underlying epileptogenesis and have provided significant insight into potential targets by which the development of epilepsy may be prevented or modified. This review focuses largely on some of the most common animal models of epileptogenesis and their potential utility for evaluating proposed antiepileptogenic therapies and identifying useful biomarkers. The authors also describe some of the limitations of using animal models in the search for therapies that move beyond the symptomatic treatment of epilepsy. Promising results of previous studies designed to evaluate antiepileptogenesis and the role of monotherapy versus polytherapy approaches are also discussed. Recent data from both models of genetic and acquired epilepsies strongly indicate that it is possible to prevent or modify epileptogenesis, and, hopefully, such promising results can ultimately be translated into the clinic.
    Journal of the American Society for Experimental NeuroTherapeutics 01/2014; 11(2). DOI:10.1007/s13311-013-0250-1 · 3.88 Impact Factor
  • Scott C Baraban, Wolfgang Löscher
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    ABSTRACT: Despite the development of numerous novel antiepileptic drugs (AEDs) in recent years, several unmet clinical needs remain, including resistance to AEDs in about 30 % of patients with epilepsy, adverse effects of AEDs that can reduce quality of life, and the lack of treatments that can prevent development of epilepsy in patients at risk. Animal models of seizures and epilepsy have been instrumental in the discovery and preclinical development of novel AEDs, but obviously the previously used models have failed to identify drugs that address unmet medical needs. Thus, we urgently need fresh ideas for improving preclinical AED development. In this review, a number of promising models will be described, including the use of simple vertebrates such as zebrafish (Danio rerio), large animal models such as the dog and newly characterized rodent models of pharmacoresistant epilepsy. While these strategies, like any animal model approach also have their limitations, they offer hope that new more effective AEDs will be identified in the coming years.
    Advances in Experimental Medicine and Biology 01/2014; 813:283-94. DOI:10.1007/978-94-017-8914-1_23 · 2.01 Impact Factor
  • Chris Rundfeldt, Wolfgang Löscher
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    ABSTRACT: Although benzodiazepines (BZDs) offer a wide spectrum of antiepileptic activity against diverse types of epileptic seizures, their use in the treatment of epilepsy is limited because of adverse effects, loss of efficacy (tolerance), and development of physical and psychological dependence. BZDs act as positive allosteric modulators of the inhibitory neurotransmitter GABA by binding to the BZD recognition site ("BZD receptor") of the GABAA receptor. Traditional BZDs such as diazepam or clonazepam act as full agonists at this site, so that one strategy to resolve the disadvantages of these compounds would be the development of partial agonists with lower intrinsic efficacy at the BZD site of the GABAA receptor. Several BZD site partial or subtype selective compounds, including bretazenil, abecarnil, or alpidem, have been developed as anxioselective anxiolytic drugs, but epilepsy was not a target indication for such compounds. More recently, the imidazolone derivatives imepitoin (ELB138) and ELB139 were shown to act as low-affinity partial agonists at the BZD site of the GABAA receptor, and imepitoin was developed for the treatment of epilepsy. Imepitoin displayed a broad spectrum of anticonvulsant activity in diverse seizure and epilepsy models at tolerable doses, and, as expected from its mechanism of action, lacked tolerance and abuse liability in rodent and primate models. The more favorable pharmacokinetic profile of imepitoin in dogs versus humans led to the decision to develop imepitoin for the treatment of canine epilepsy. Based on randomized controlled trials that demonstrated antiepileptic efficacy and high tolerability and safety in epileptic dogs, the drug was recently approved for this indication in Europe. Hopefully, the favorable profile of imepitoin for the treatment of epilepsy in dogs will reactivate the interest in partial BZD site agonists as new treatments for human epilepsy.
    CNS Drugs 12/2013; 28(1). DOI:10.1007/s40263-013-0129-z · 4.38 Impact Factor
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    ABSTRACT: The diuretic bumetanide, which acts by blocking the Na-K-Cl cotransporter (NKCC), is widely used to inhibit neuronal NKCC1, particularly when NKCC1 expression is abnormally increased in brain diseases such as epilepsy. However, bumetanide poorly penetrates into the brain and, in rodents, is rapidly eliminated because of extensive oxidation of its N-butyl sidechain, reducing the translational value of rodent experiments. Inhibition of oxidation by piperonyl butoxide (PBO) has previously been reported to increase the half-life and diuretic activity of bumetanide in rats. Here we studied whether inhibition of bumetanide metabolism by PBO also increases brain levels of bumetanide in rats, and whether this alters pharmacodynamic effects in the kindling model of epilepsy. Furthermore, we studied the effects of PBO in mice. Mice eliminated bumetanide less rapidly than rats (elimination half-life 47 min vs. 13 min). Pretreatment with PBO increased the half-life in mice to average values (70 min) previously determined in humans, and markedly elevated brain levels of bumetanide. In rats, the increase in plasma and brain levels of bumetanide by PBO was less marked than in mice. PBO significantly increased the diuretic activity of bumetanide in rats and, less effectively, in mice. In epileptic mice, bumetanide (with PBO) did not suppress spontaneous seizures. In the rat kindling model, bumetanide (with or without PBO) did not exert anticonvulsant effects on fully kindled seizures, but dose-dependently altered kindling development. These data indicate that PBO offers a simple means to enhance the translational properties of rodent experiments with bumetanide, particularly when using mice.
    European Journal of Neuroscience 11/2013; DOI:10.1111/ejn.12424 · 3.67 Impact Factor
  • Marion Bankstahl, Jens P Bankstahl, Wolfgang Löscher
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    ABSTRACT: In human medicine, adverse outcomes associated with switching between bioequivalent brand name and generic antiepileptic drug products is a subject of concern among clinicians. In veterinary medicine, epilepsy in dogs is usually treated with phenobarbital, either with the standard brand name formulation Luminal(R) or the veterinary products Luminal(R) vet and the generic formulation Phenoleptil(R). Luminal(R) and Luminal(R) vet are identical 100 mg tablet formulations, while Phenoleptil(R) is available in the form of 12.5 and 50 mg tablets. Following approval of Phenoleptil(R) for treatment of canine epilepsy, it was repeatedly reported by clinicians and dog owners that switching from Luminal(R) (human tablets) to Phenoleptil(R) in epileptic dogs, which were controlled by treatment with Luminal(R), induced recurrence of seizures. In the present study, we compared bioavailability of phenobarbital after single dose administration of Luminal(R) vet vs. Phenoleptil(R) with a crossover design in 8 healthy Beagle dogs. Both drugs were administered at a dose of 100 mg/dog, resulting in 8 mg/kg phenobarbital on average. Peak plasma concentrations (Cmax) following Luminal(R) vet vs. Phenoleptil(R) were about the same in most dogs (10.9 +/- 0.92 vs. 10.5 +/- 0.77 mug/ml), and only one dog showed noticeable lower concentrations after Phenoleptil(R) vs. Luminal(R) vet. Elimination half-life was about 50 h (50.3 +/- 3.1 vs. 52.9 +/- 2.8 h) without differences between the formulations. The relative bioavailability of the two products (Phenoleptil(R) vs. Luminal(R) vet.) was 0.98 +/- 0.031, indicating that both formulations resulted in about the same bioavailability. Overall, the two formulations did not differ significantly with respect to pharmacokinetic parameters when mean group parameters were compared. Thus, the reasons for the anecdotal reports, if true, that switching from the brand to the generic formulation of phenobarbital may lead to recurrence of seizures are obviously not related to a generally lower bioavailability of the generic formulation, although single dogs may exhibit lower plasma levels after the generic formulation that could be clinically meaningful.
    BMC Veterinary Research 10/2013; 9(1):202. DOI:10.1186/1746-6148-9-202 · 1.74 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    Marion Bankstahl, Jens P Bankstahl, Wolfgang Löscher
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    ABSTRACT: The 6-Hz psychomotor seizure model in mice is increasingly been used as a model for differentiation of anticonvulsant activity during development of new antiepileptic drugs (AEDs). It was previously proposed as a useful model of AED-resistant seizures, but more recent data have cast doubt on this proposal. The aim of the present study was to determine whether performing the 6-Hz test not in normal but epileptic mice renders the 6-Hz test more resistant to AEDs. Furthermore, thresholds for induction of 6-Hz seizures, maximal electroshock seizures (MES) and pentylenetetrazole (PTZ) seizures were compared in normal and epileptic mice, using the pilocarpine model. Epileptic mice had a significantly lower threshold for induction of 6-Hz seizures and were more susceptible to PTZ, whereas the MES threshold was not altered. Unexpectedly, 6-Hz seizures were not more resistant to AEDs in epileptic vs. nonepileptic mice, but instead showed an increased sensitivity to the anticonvulsant effects of some AEDs, particularly levetiracetam. The anticonvulsant ED50 of levetiracetam in the 6-Hz test (using a 32mA stimulus) was 17.6mg/kg in nonepileptic mice, but only 1.5mg/kg in epileptic mice. The data indicate that the complex pathophysiological and functional alterations associated with epilepsy in mice may strikingly alter the sensitivity of acutely induced seizures to an AED.
    Epilepsy research 10/2013; DOI:10.1016/j.eplepsyres.2013.09.014 · 2.48 Impact Factor

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  • 1995–2015
    • University of Veterinary Medicine Hannover
      • Institute of Pathology
      Hanover, Lower Saxony, Germany
    • University of Zurich
      Zürich, Zurich, Switzerland
    • University of Hamburg
      • Department of Anaesthesiology
      Hamburg, Hamburg, Germany
  • 2013
    • University of Eastern Finland
      • A.I. Virtanen Institute for Molecular Sciences
      Kuopio, Eastern Finland Province, Finland
  • 2012
    • The Scripps Research Institute
      • Department of Cell and Molecular Biology
      La Jolla, CA, United States
  • 2009–2012
    • AIT Austrian Institute of Technology
      • Department of Health & Environment
      Wien, Vienna, Austria
    • Medical University of Vienna
      • Universitätsklinik für Klinische Pharmakologie
      Vienna, Vienna, Austria
  • 2011
    • University of Vienna
      • Department of Medicinal Chemistry
      Vienna, Vienna, Austria
    • Ludwig-Maximilians-University of Munich
      München, Bavaria, Germany
  • 2008–2010
    • Forschungszentrum Jülich
      • Institut für Neurowissenschaften und Medizin (INM)
      Düren, North Rhine-Westphalia, Germany
  • 2007
    • Georgetown University
      • Lombardi Cancer Center
      Washington, D. C., DC, United States
  • 2004
    • National Institutes of Health
      • Division of Epilepsy Research
      Bethesda, MD, United States
  • 1995–2004
    • Hannover Medical School
      • Institute for Cellular and Molecular Pathology
      Hannover, Lower Saxony, Germany
  • 2002
    • The Children's Hospital of Philadelphia
      Philadelphia, Pennsylvania, United States
  • 2000
    • Historisches Museum Hannover
      Hanover, Lower Saxony, Germany
  • 1998–1999
    • Agricultural University in Lublin
      Lyublin, Lublin Voivodeship, Poland
  • 1982–1987
    • Freie Universität Berlin
      • Department of Veterinary Medicine
      Berlín, Berlin, Germany