Affiliation: University of Veterinary Medicine
- Brandt C, Hillmann P, Noack A, Römermann K, Öhler L, Rageot D, et al. The novel, catalytic mTORC1/2 inhibitor PQR620 and the PI3K/mTORC1/2 inhibitor PQR530 effectively cross the blood-brain barrier and increase seizure threshold in a mouse model of chronic epilepsy. Neuropharmacology. 2018;140:107-120 pubmed publisher..Overall, the novel compounds described here have the potential to overcome the disadvantages of rapalogs for treatment of epilepsy and mTORopathies directly connected to mutations in the mTOR signaling cascade. ..
- Hampel P, Römermann K, MacAulay N, Loscher W. Azosemide is more potent than bumetanide and various other loop diuretics to inhibit the sodium-potassium-chloride-cotransporter human variants hNKCC1A and hNKCC1B. Sci Rep. 2018;8:9877 pubmed publisher..Azosemide was found to exert an unexpectedly potent inhibitory effect and as a non-acidic compound, it is more likely to cross the blood-brain barrier than bumetanide. ..
- Loscher W, Langer O. Imaging of P-glycoprotein function and expression to elucidate mechanisms of pharmacoresistance in epilepsy. Curr Top Med Chem. 2010;10:1785-91 pubmed
- Loscher W. Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs. 2002;16:669-94 pubmed..In view of the advances in molecular neurobiology and neuroscience, future studies will undoubtedly further our understanding of the mechanisms of action of valproate. ..
- Loscher W. Drug transporters in the epileptic brain. Epilepsia. 2007;48 Suppl 1:8-13 pubmed..Cumulative clinical and experimental data support this hypothesis and offer novel therapeutic approaches for the treatment of drug-resistant epilepsy. ..
- Loscher W. Abnormal circling behavior in rat mutants and its relevance to model specific brain dysfunctions. Neurosci Biobehav Rev. 2010;34:31-49 pubmed publisher..The circling rat mutants described in this review illustrate how genetic animal models may serve to study multifaceted brain functions and dysfunctions, including disorders of the basal ganglia and vestibular system. ..
- Loscher W. Preclinical assessment of proconvulsant drug activity and its relevance for predicting adverse events in humans. Eur J Pharmacol. 2009;610:1-11 pubmed publisher..Furthermore, misconceptions regarding proconvulsant drug effects, which can result in the undertreatment of brain diseases, are discussed. ..
- Twele F, Bankstahl M, Klein S, RÃ¶mermann K, LÃ¶scher W. The AMPA receptor antagonist NBQX exerts anti-seizure but not antiepileptogenic effects in the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy. Neuropharmacology. 2015;95:234-42 pubmed publisher..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. ..
- Potschka H, Fischer A, LÃ¶scher W, Patterson N, Bhatti S, Berendt M, et al. International veterinary epilepsy task force consensus proposal: outcome of therapeutic interventions in canine and feline epilepsy. BMC Vet Res. 2015;11:177 pubmed publisher..In particular ethical aspects and the different options for study design and application of individual patient-centered outcome criteria are considered. ..
- Bhatti S, De Risio L, MuÃ±ana K, Penderis J, Stein V, Tipold A, et al. International Veterinary Epilepsy Task Force consensus proposal: medical treatment of canine epilepsy in Europe. BMC Vet Res. 2015;11:176 pubmed publisher..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. ..
- LÃ¶scher W, Hirsch L, Schmidt D. The enigma of the latent period in the development of symptomatic acquired epilepsy - Traditional view versus new concepts. Epilepsy Behav. 2015;52:78-92 pubmed publisher..The development of antiepileptogenic treatments to prevent epilepsy in patients at risk from a brain insult is a major unmet clinical need. ..
- Vezzani A, Fujinami R, White H, Preux P, BlÃ¼mcke I, Sander J, et al. Infections, inflammation and epilepsy. Acta Neuropathol. 2016;131:211-234 pubmed publisher..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. ..
- Loscher W, Schmidt D. Experimental and clinical evidence for loss of effect (tolerance) during prolonged treatment with antiepileptic drugs. Epilepsia. 2006;47:1253-84 pubmed..Knowledge of tolerance to AED effects as a mechanism of drug resistance in previous responders is important for patients, physicians, and scientists. ..
- TÃ¶llner K, Brandt C, Erker T, LÃ¶scher W. Bumetanide is not capable of terminating status epilepticus but enhances phenobarbital efficacy in different rat models. Eur J Pharmacol. 2015;746:78-88 pubmed publisher..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. ..
- Klein S, Bankstahl M, LÃ¶scher W. Inter-individual variation in the effect of antiepileptic drugs in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice. Neuropharmacology. 2015;90:53-62 pubmed publisher..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. ..
- Rundfeldt C, Tipold A, LÃ¶scher W. Efficacy, safety, and tolerability of imepitoin in dogs with newly diagnosed epilepsy in a randomized controlled clinical study with long-term follow up. BMC Vet Res. 2015;11:228 pubmed publisher..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. ..
- Klee R, TÃ¶llner K, Rankovic V, RÃ¶mermann K, Schidlitzki A, Bankstahl M, et al. Network pharmacology for antiepileptogenesis: Tolerability of multitargeted drug combinations in nonepileptic vs. post-status epilepticus mice. Epilepsy Res. 2015;118:34-48 pubmed publisher..As a next step, the rationally chosen drug combinations will be evaluated for antiepileptogenic activity in mouse and rat models of symptomatic epilepsy. ..
- Loscher W, Potschka H, Rieck S, Tipold A, Rundfeldt C. Anticonvulsant efficacy of the low-affinity partial benzodiazepine receptor agonist ELB 138 in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures. Epilepsia. 2004;45:1228-39 pubmed..These data thus substantiate that partial agonism at the BZD site of GABAA receptors offers advantages versus full agonism and constitutes a valuable approach for treatment of seizures. ..
- LÃ¶scher W. Single versus combinatorial therapies in status epilepticus: Novel data from preclinical models. Epilepsy Behav. 2015;49:20-5 pubmed publisher..This article is part of a Special Issue entitled "Status Epilepticus". ..
- BrÃ¶er S, LÃ¶scher W. Novel combinations of phenotypic biomarkers predict development of epilepsy in the lithium-pilocarpine model of temporal lobe epilepsy in rats. Epilepsy Behav. 2015;53:98-107 pubmed publisher..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. ..
- Brandt C, TÃ¶llner K, Klee R, BrÃ¶er S, LÃ¶scher W. Effective termination of status epilepticus by rational polypharmacy in the lithium-pilocarpine model in rats: Window of opportunity to prevent epilepsy and prediction of epilepsy by biomarkers. Neurobiol Dis. 2015;75:78-90 pubmed publisher..These data demonstrate that the duration of SE needed for induction of epileptogenesis in this model is longer than previously thought. ..
- Brandt C, Bankstahl M, TÃ¶llner K, Klee R, LÃ¶scher W. The pilocarpine model of temporal lobe epilepsy: Marked intrastrain differences in female Sprague-Dawley rats and the effect of estrous cycle. Epilepsy Behav. 2016;61:141-152 pubmed publisher..The marked intrastrain differences provide an interesting tool to study the impact of genetic and environmental factors on seizure susceptibility, epileptogenesis, and relationship between behavior and epilepsy and vice versa. ..
- BrÃ¶er S, KÃ¤ufer C, Haist V, Li L, Gerhauser I, Anjum M, et al. Brain inflammation, neurodegeneration and seizure development following picornavirus infection markedly differ among virus and mouse strains and substrains. Exp Neurol. 2016;279:57-74 pubmed publisher..However, intense microglia/macrophage activation and some hippocampal damage were also observed in SJL/J mice. Overall, the TMEV model provides a unique platform to study virus and host factors in ictogenesis and epileptogenesis. ..
- Klee R, Brandt C, TÃ¶llner K, LÃ¶scher W. Various modifications of the intrahippocampal kainate model of mesial temporal lobe epilepsy in rats fail to resolve the marked rat-to-mouse differences in type and frequency of spontaneous seizures in this model. Epilepsy Behav. 2017;68:129-140 pubmed publisher..These data indicate marked phenotypic differences between mice and rats in this model. Further studies should explore the mechanisms underlying this species difference. ..
- Loscher W, Gillard M, Sands Z, Kaminski R, Klitgaard H. Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond. CNS Drugs. 2016;30:1055-1077 pubmed
- Loscher W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure. 2011;20:359-68 pubmed publisher..To realize this goal, the molecular mechanisms of the next generation of therapies must necessarily evolve to include targets that contribute to epileptogenesis and pharmacoresistance in relevant epilepsy models. ..
- Loscher W, Puskarjov M, Kaila K. Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. Neuropharmacology. 2013;69:62-74 pubmed publisher..This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. ..
- Kasteleijn Nolst TrenitÃ© D, Groenwold R, Schmidt B, LÃ¶scher W. Single dose efficacy evaluation of two partial benzodiazepine receptor agonists in photosensitive epilepsy patients: A placebo-controlled pilot study. Epilepsy Res. 2016;122:30-6 pubmed publisher..Epilepsy is often associated with anxiety, so that the anxiolytic activity of abecarnil would be an added advantage when using this compound in epilepsy patients. ..
- LÃ¶scher W. Fit for purpose application of currently existing animal models in the discovery of novel epilepsy therapies. Epilepsy Res. 2016;126:157-84 pubmed publisher..Overall further development is needed to improve and validate animal models for the diverse areas in epilepsy research where suitable fit for purpose models are urgently needed in the search for more effective treatments. ..
- Gey L, Gernert M, LÃ¶scher W. Continuous bilateral infusion of vigabatrin into the subthalamic nucleus: Effects on seizure threshold and GABA metabolism in two rat models. Neurobiol Dis. 2016;91:194-208 pubmed publisher..The data demonstrate that chronic administration of very low, nontoxic doses of vigabatrin into STN is an effective means of increasing local GABA concentrations and seizure threshold. ..
- Loscher W, Rogawski M. How theories evolved concerning the mechanism of action of barbiturates. Epilepsia. 2012;53 Suppl 8:12-25 pubmed publisher..Despite the remarkable progress of the last century, there is still much to learn about the actions of barbiturates that can be applied to the discovery of new, more therapeutically useful agents. ..
- Lykke K, TÃ¶llner K, Feit P, Erker T, MacAulay N, LÃ¶scher W. The search for NKCC1-selective drugs for the treatment of epilepsy: Structure-function relationship of bumetanide and various bumetanide derivatives in inhibiting the human cation-chloride cotransporter NKCC1A. Epilepsy Behav. 2016;59:42-9 pubmed publisher..These data indicate that the structural requirements for inhibition of NKCC1 and NKCC2 are similar, which complicates development of bumetanide-related compounds with high selectivity for NKCC1. ..
- LÃ¶scher W. Animal Models of Seizures and Epilepsy: Past, Present, and Future Role for the Discovery of Antiseizure Drugs. Neurochem Res. 2017;42:1873-1888 pubmed publisher..The present review describes the previous and current approaches used in the search for new ASDs and offers some insight into future directions incorporating new and emerging animal models of therapy resistance. ..
- Bankstahl M, Klein S, RÃ¶mermann K, LÃ¶scher W. Knockout of P-glycoprotein does not alter antiepileptic drug efficacy in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice. Neuropharmacology. 2016;109:183-195 pubmed publisher..This was substantiated by the finding that epileptic wildtype mice do not exhibit increased Pgp expression in this model. ..
- Brandt C, Rankovic V, TÃ¶llner K, Klee R, BrÃ¶er S, LÃ¶scher W. Refinement of a model of acquired epilepsy for identification and validation of biomarkers of epileptogenesis in rats. Epilepsy Behav. 2016;61:120-131 pubmed publisher..The refined SE model may offer a platform to identify and validate biomarkers of epileptogenesis. ..
- Schidlitzki A, Twele F, Klee R, Waltl I, Römermann K, Bröer S, et al. A combination of NMDA and AMPA receptor antagonists retards granule cell dispersion and epileptogenesis in a model of acquired epilepsy. Sci Rep. 2017;7:12191 pubmed publisher..Longer treatment with NBQX and ifenprodil may shed further light on the apparent temporal relationship between dentate gyrus reorganization and development of spontaneous seizures. ..
- Loscher W, Luna Tortós C, Römermann K, Fedrowitz M. Do ATP-binding cassette transporters cause pharmacoresistance in epilepsy? Problems and approaches in determining which antiepileptic drugs are affected. Curr Pharm Des. 2011;17:2808-28 pubmed..For translating these findings to the clinical arena, in vivo imaging studies using positron emission tomography (PET) with (11)C-labelled AEDs in epileptic patients are under way. ..
- Loscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx. 2005;2:86-98 pubmed..Therefore, modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS diseases...
- Potschka H, Fedrowitz M, Loscher W. Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity. J Pharmacol Exp Ther. 2003;306:124-31 pubmed..In kindled MRP2-deficient rats, phenytoin exerted a markedly higher anticonvulsant activity than in normal rats. These data indicate that MRP2 substantially contributes to BBB function. ..