Systematic evaluation of rationally chosen multitargeted drug combinations: a combination of low doses of levetiracetam, atorvastatin and ceftriaxone exerts antiepileptogenic effects in a mouse model of acquired epilepsy

Epileptogenesis, the gradual process that leads to epilepsy after brain injury or genetic mutations, is a complex network phenomenon, involving a variety of morphological, biochemical and functional brain alterations. Although risk factors for developing epilepsy are known, there is currently no tre...

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Main Authors: Lisa Welzel, David H. Bergin, Alina Schidlitzki, Friederike Twele, Marie Johne, Pavel Klein, Wolfgang Löscher
Format: Article
Language:English
Published: Elsevier 2021-02-01
Series:Neurobiology of Disease
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S0969996120305027
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spelling doaj-ebf73ea039fa4ed9bcb04004def2080c2021-03-22T08:43:00ZengElsevierNeurobiology of Disease1095-953X2021-02-01149105227Systematic evaluation of rationally chosen multitargeted drug combinations: a combination of low doses of levetiracetam, atorvastatin and ceftriaxone exerts antiepileptogenic effects in a mouse model of acquired epilepsyLisa Welzel0David H. Bergin1Alina Schidlitzki2Friederike Twele3Marie Johne4Pavel Klein5Wolfgang Löscher6Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, GermanyMid-Atlantic Epilepsy and Sleep Center, Bethesda, MD, USADepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany; Corresponding author at: Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Bünteweg 17, D-30559 Hannover, Germany.Epileptogenesis, the gradual process that leads to epilepsy after brain injury or genetic mutations, is a complex network phenomenon, involving a variety of morphological, biochemical and functional brain alterations. Although risk factors for developing epilepsy are known, there is currently no treatment available to prevent epilepsy. We recently proposed a multitargeted, network-based approach to prevent epileptogenesis by rationally combining clinically available drugs and provided first proof-of-concept that this strategy is effective. Here we evaluated eight novel rationally chosen combinations of 14 drugs with mechanisms that target different epileptogenic processes. The combinations consisted of 2-4 different drugs per combination and were administered systemically over 5 days during the latent epileptogenic period in the intrahippocampal kainate mouse model of acquired temporal lobe epilepsy, starting 6 h after kainate. Doses and dosing intervals were based on previous pharmacokinetic and tolerability studies in mice. The incidence and frequency of spontaneous electrographic and electroclinical seizures were recorded by continuous (24/7) video linked EEG monitoring done for seven days at 4 and 12 weeks post-kainate, i.e., long after termination of drug treatment. Compared to vehicle controls, the most effective drug combination consisted of low doses of levetiracetam, atorvastatin and ceftriaxone, which markedly reduced the incidence of electrographic seizures (by 60%; p<0.05) and electroclinical seizures (by 100%; p<0.05) recorded at 12 weeks after kainate. This effect was lost when higher doses of the three drugs were administered, indicating a synergistic drug-drug interaction at the low doses. The potential mechanisms underlying this interaction are discussed. We have discovered a promising novel multitargeted combination treatment for modifying the development of acquired epilepsy.http://www.sciencedirect.com/science/article/pii/S0969996120305027Seizureskainatehippocampusneuroinflammationblood-brain barrier
collection DOAJ
language English
format Article
sources DOAJ
author Lisa Welzel
David H. Bergin
Alina Schidlitzki
Friederike Twele
Marie Johne
Pavel Klein
Wolfgang Löscher
spellingShingle Lisa Welzel
David H. Bergin
Alina Schidlitzki
Friederike Twele
Marie Johne
Pavel Klein
Wolfgang Löscher
Systematic evaluation of rationally chosen multitargeted drug combinations: a combination of low doses of levetiracetam, atorvastatin and ceftriaxone exerts antiepileptogenic effects in a mouse model of acquired epilepsy
Neurobiology of Disease
Seizures
kainate
hippocampus
neuroinflammation
blood-brain barrier
author_facet Lisa Welzel
David H. Bergin
Alina Schidlitzki
Friederike Twele
Marie Johne
Pavel Klein
Wolfgang Löscher
author_sort Lisa Welzel
title Systematic evaluation of rationally chosen multitargeted drug combinations: a combination of low doses of levetiracetam, atorvastatin and ceftriaxone exerts antiepileptogenic effects in a mouse model of acquired epilepsy
title_short Systematic evaluation of rationally chosen multitargeted drug combinations: a combination of low doses of levetiracetam, atorvastatin and ceftriaxone exerts antiepileptogenic effects in a mouse model of acquired epilepsy
title_full Systematic evaluation of rationally chosen multitargeted drug combinations: a combination of low doses of levetiracetam, atorvastatin and ceftriaxone exerts antiepileptogenic effects in a mouse model of acquired epilepsy
title_fullStr Systematic evaluation of rationally chosen multitargeted drug combinations: a combination of low doses of levetiracetam, atorvastatin and ceftriaxone exerts antiepileptogenic effects in a mouse model of acquired epilepsy
title_full_unstemmed Systematic evaluation of rationally chosen multitargeted drug combinations: a combination of low doses of levetiracetam, atorvastatin and ceftriaxone exerts antiepileptogenic effects in a mouse model of acquired epilepsy
title_sort systematic evaluation of rationally chosen multitargeted drug combinations: a combination of low doses of levetiracetam, atorvastatin and ceftriaxone exerts antiepileptogenic effects in a mouse model of acquired epilepsy
publisher Elsevier
series Neurobiology of Disease
issn 1095-953X
publishDate 2021-02-01
description Epileptogenesis, the gradual process that leads to epilepsy after brain injury or genetic mutations, is a complex network phenomenon, involving a variety of morphological, biochemical and functional brain alterations. Although risk factors for developing epilepsy are known, there is currently no treatment available to prevent epilepsy. We recently proposed a multitargeted, network-based approach to prevent epileptogenesis by rationally combining clinically available drugs and provided first proof-of-concept that this strategy is effective. Here we evaluated eight novel rationally chosen combinations of 14 drugs with mechanisms that target different epileptogenic processes. The combinations consisted of 2-4 different drugs per combination and were administered systemically over 5 days during the latent epileptogenic period in the intrahippocampal kainate mouse model of acquired temporal lobe epilepsy, starting 6 h after kainate. Doses and dosing intervals were based on previous pharmacokinetic and tolerability studies in mice. The incidence and frequency of spontaneous electrographic and electroclinical seizures were recorded by continuous (24/7) video linked EEG monitoring done for seven days at 4 and 12 weeks post-kainate, i.e., long after termination of drug treatment. Compared to vehicle controls, the most effective drug combination consisted of low doses of levetiracetam, atorvastatin and ceftriaxone, which markedly reduced the incidence of electrographic seizures (by 60%; p<0.05) and electroclinical seizures (by 100%; p<0.05) recorded at 12 weeks after kainate. This effect was lost when higher doses of the three drugs were administered, indicating a synergistic drug-drug interaction at the low doses. The potential mechanisms underlying this interaction are discussed. We have discovered a promising novel multitargeted combination treatment for modifying the development of acquired epilepsy.
topic Seizures
kainate
hippocampus
neuroinflammation
blood-brain barrier
url http://www.sciencedirect.com/science/article/pii/S0969996120305027
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