{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T23:21:07Z","timestamp":1787181667991,"version":"build-2736575974"},"reference-count":111,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T00:00:00Z","timestamp":1621814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010621","name":"Uniwersytet Medyczny w Lublinie","doi-asserted-by":"publisher","award":["DS 474\/2018"],"award-info":[{"award-number":["DS 474\/2018"]}],"id":[{"id":"10.13039\/501100010621","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Combination therapy with two or three antiseizure medications (ASMs) is sometimes a preferred method of treatment in epilepsy patients. (1) Background: To detect the most beneficial combination among three ASMs, a screen test evaluating in vivo interactions with respect to their anticonvulsant properties, was conducted on albino Swiss mice; (2) Methods: Classification of interactions among lacosamide (LCM) and selected second-generation ASMs (lamotrigine (LTG), pregabalin (PGB), oxcarbazepine (OXC), and topiramate (TPM)) was based on the isobolographic analysis in the mouse maximal electroshock-induced seizure (MES) model. Interactions among LCM and second-generation ASMs were visualized using a polygonogram; (3) Results: In the mouse MES model, synergy was observed for the combinations of LCM + TPM + PGB and LCM + OXC + PGB. Additivity was reported for the other combinations tested i.e., LCM + LTG + TPM, LCM + LTG + PGB, LCM + LTG + OXC, and LCM + OXC + TPM in this seizure model. No adverse effects associated with triple ASM combinations, containing LCM and second-generation ASMs were observed in mice; (4) Conclusions: The combination of LCM + TPM + PGB was the most beneficial combination among the tested in this study, offering synergistic suppression of tonic-clonic seizures in mice subjected to the MES model. Both the isobolographic analysis and polygonogram method can be recommended for experimental epileptology when classifying interactions among the ASMs.<\/jats:p>","DOI":"10.3390\/ijms22115537","type":"journal-article","created":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T12:38:01Z","timestamp":1621859881000},"page":"5537","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Interactions among Lacosamide and Second-Generation Antiepileptic Drugs in the Tonic-Clonic Seizure Model in Mice"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5358-8889","authenticated-orcid":false,"given":"Katarzyna","family":"Za\u0142uska-Ogryzek","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, Medical University of Lublin, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawe\u0142","family":"Marz\u0119da","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Medical University of Lublin, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7099-1968","authenticated-orcid":false,"given":"Paula","family":"Wr\u00f3blewska-\u0141uczka","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Medical University of Lublin, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Florek-\u0141uszczki","sequence":"additional","affiliation":[{"name":"Department of Medical Anthropology, Institute of Rural Health, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zbigniew","family":"Plewa","sequence":"additional","affiliation":[{"name":"Department of General, Oncological and Minimally Invasive Surgery, 1st Military Clinical Hospital, 20-048 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert","family":"Bojar","sequence":"additional","affiliation":[{"name":"Department of Toxicology and Food Safety, Institute of Rural Health, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Zolkowska","sequence":"additional","affiliation":[{"name":"Department of Neurology, UC Davis School of Medicine, Sacramento, CA 95816, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3059-0393","authenticated-orcid":false,"given":"Jarogniew J.","family":"\u0141uszczki","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Medical University of Lublin, 20-090 Lublin, Poland"},{"name":"Isobolographic Analysis Laboratory, Institute of Rural Health, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1056\/NEJMra1004418","article-title":"Drug-resistant epilepsy","volume":"365","author":"Kwan","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1007\/s11910-016-0678-x","article-title":"Pharmacological treatment of drug-resistant epilepsy in adults: A practical guide","volume":"16","author":"Brodie","year":"2016","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1002\/epi4.12445","article-title":"Perampanel in real-world clinical care of patients with epilepsy: Interim analysis of a phase IV study","volume":"6","author":"Wheless","year":"2021","journal-title":"Epilepsia Open"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1002\/epi4.12448","article-title":"Efficacy and safety of adjunctive perampanel in patients with focal seizures or generalized tonic-clonic seizures: Post hoc analysis of Phase II and Phase III double-blind and open-label extension studies in India","volume":"6","author":"Mehndiratta","year":"2021","journal-title":"Epilepsia Open"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lattanzi, S., Riva, A., and Striano, P. (2021). Ganaxolone treatment for epilepsy patients: From pharmacology to place in therapy. Expert Rev. Neurother.","DOI":"10.1080\/14737175.2021.1904895"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"106592","DOI":"10.1016\/j.eplepsyres.2021.106592","article-title":"Efficacy of adjunctive cenobamate based on number of concomitant antiseizure medications, seizure frequency, and epilepsy duration at baseline: A post-hoc analysis of a randomized clinical study","volume":"172","author":"Rosenfeld","year":"2021","journal-title":"Epilepsy Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"107790","DOI":"10.1016\/j.neuropharm.2019.107790","article-title":"Pharmacoresistance\u2014Epidemiology, mechanisms, and impact on epilepsy treatment","volume":"168","author":"Janmohamed","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1111\/j.1528-1167.2009.02397.x","article-title":"Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies","volume":"51","author":"Kwan","year":"2010","journal-title":"Epilepsia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S1474-4422(03)00409-5","article-title":"Clinically important drug interactions in epilepsy: General features and interactions between antiepileptic drugs","volume":"2","author":"Patsalos","year":"2003","journal-title":"Lancet Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.phrs.2016.03.016","article-title":"The challenges of treating epilepsy with 25 antiepileptic drugs","volume":"107","author":"Santulli","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1053\/seiz.2002.0711","article-title":"Seizure freedom with more than one antiepileptic drug","volume":"11","author":"Stephen","year":"2002","journal-title":"Seizure"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1097\/WCO.0b013e328350ba68","article-title":"Antiepileptic drug monotherapy versus polytherapy: Pursuing seizure freedom and tolerability in adults","volume":"25","author":"Stephen","year":"2012","journal-title":"Curr. Opin. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.eplepsyres.2011.09.008","article-title":"Antiepileptic drug combinations-have newer agents altered clinical outcomes?","volume":"98","author":"Stephen","year":"2012","journal-title":"Epilepsy Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1111\/j.1528-1157.2000.tb00111.x","article-title":"Selection of antiepileptic drug polytherapy based on mechanisms of action: The evidence reviewed","volume":"41","author":"Deckers","year":"2000","journal-title":"Epilepsia"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1111\/j.1528-1167.2010.02520.x","article-title":"Relationship between adverse effects of antiepileptic drugs, number of coprescribed drugs, and drug load in a large cohort of consecutive patients with drug-refractory epilepsy","volume":"51","author":"Canevini","year":"2010","journal-title":"Epilepsia"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"(2017). Rationalizing combination therapies. Nature Med., 23, 1113.","DOI":"10.1038\/nm.4426"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s43440-020-00164-5","article-title":"Polygonogram with isobolographic synergy for three-drug combinations of phenobarbital with second-generation antiepileptic drugs in the tonic-clonic seizure model in mice","volume":"73","author":"Jankiewicz","year":"2021","journal-title":"Pharmacol. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1111\/j.0013-9580.2004.05104.x","article-title":"Preclinical profile of combinations of some second-generation antiepileptic drugs: An isobolographic analysis","volume":"45","author":"Luszczki","year":"2004","journal-title":"Epilepsia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1111\/j.0013-9580.2005.34704.x","article-title":"Pharmacodynamic and pharmacokinetic interaction studies of loreclezole with felbamate, lamotrigine, topiramate, and oxcarbazepine in the mouse maximal electroshock seizure model","volume":"46","author":"Luszczki","year":"2005","journal-title":"Epilepsia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.yebeh.2015.02.027","article-title":"Single versus combinatorial therapies in status epilepticus: Novel data from preclinical models","volume":"49","author":"Loscher","year":"2015","journal-title":"Epilepsy Behav."},{"key":"ref_21","unstructured":"National Clinical Guideline Centre (2012). National Clinical Guideline Centre. National Institute for Health and Clinical Excellence: Guidance. The Epilepsies: The Diagnosis and Management of the Epilepsies in Adults and Children in Primary and Secondary Care: Pharmacological Update of Clinical Guideline 20, Royal College of Physicians (UK) National Clinical Guideline Centre."},{"key":"ref_22","first-page":"92","article-title":"Antagonistic interaction of lacosamide with carbamazepine and valproate in the mouse tonic-clonic seizure model","volume":"13","author":"Walczak","year":"2019","journal-title":"Health Prob. Civil."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1007\/s43440-020-00117-y","article-title":"Sub-additive (antagonistic) interaction of lacosamide with lamotrigine and valproate in the maximal electroshock-induced seizure model in mice: An isobolographic analysis","volume":"72","author":"Luszczki","year":"2020","journal-title":"Pharmacol. Rep."},{"key":"ref_24","first-page":"55","article-title":"Interaction of three-drug combination of lacosamide, carbamazepine and phenobarbital in the mouse maximal electroshock-induced seizure model\u2014An isobolographic analysis","volume":"10","author":"Luszczki","year":"2016","journal-title":"Health Probl. Civil."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"881","DOI":"10.17219\/acem\/69132","article-title":"Isobolographic additivity among lacosamide, lamotrigine and phenobarbital in the mouse tonic-clonic seizure model","volume":"27","author":"Luszczki","year":"2018","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_26","first-page":"303","article-title":"Additive interaction for three-drug combination of carbamazepine, lacosamide and lamotrigine against maximal electroshock-induced seizures\u2014A type I isobolographic analysis","volume":"15","author":"Luszczki","year":"2017","journal-title":"Eur. J. Clin. Exp. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"72","DOI":"10.26444\/jpccr\/109381","article-title":"Additive suppression of tonic-clonic seizures in mice receiving the combination of carbamazepine, phenobarbital and valproate","volume":"13","author":"Bojar","year":"2019","journal-title":"J. Pre-Clin. Clin. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.eplepsyres.2018.06.003","article-title":"Combination of phenobarbital with phenytoin and pregabalin produces synergy in the mouse tonic-clonic seizure model: An isobolographic analysis","volume":"145","author":"Luszczki","year":"2018","journal-title":"Epilepsy Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"111","DOI":"10.26444\/jpccr\/101578","article-title":"Synergy among oxcarbazepine, pregabalin and topiramate in the mouse maximal electroshockinduced seizure test\u2014An isobolographic analysis","volume":"12","author":"Walczak","year":"2018","journal-title":"J. Pre-Clin. Clin. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1159\/000444452","article-title":"Isobolographic analysis of interaction for three-drug combination of carbamazepine, phenobarbital and topiramate in the mouse maximal electroshock-induced seizure model","volume":"97","author":"Luszczki","year":"2016","journal-title":"Pharmacology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14","DOI":"10.14581\/jer.19002","article-title":"Antiepileptic drug therapy in patients with drug-resistant epilepsy","volume":"9","author":"Park","year":"2019","journal-title":"J. Epilepsy Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies","volume":"58","author":"Chou","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","article-title":"Drug combination studies and their synergy quantification using the Chou-Talalay method","volume":"70","author":"Chou","year":"2010","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0920-1211(02)00182-1","article-title":"Overtreatment in epilepsy: Adverse consequences and mechanisms","volume":"52","author":"Perucca","year":"2002","journal-title":"Epilepsy Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"897","DOI":"10.2165\/00023210-200519110-00001","article-title":"Overtreatment in epilepsy: How it occurs and how it can be avoided","volume":"19","author":"Perucca","year":"2005","journal-title":"CNS Drugs"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and human","volume":"7","author":"Nair","year":"2016","journal-title":"J. Basic Clin. Pharm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1046\/j.1528-1157.2003.10003.x","article-title":"Interactions of lamotrigine with topiramate and first-generation antiepileptic drugs in the maximal electroshock test in mice: An isobolographic analysis","volume":"44","author":"Luszczki","year":"2003","journal-title":"Epilepsia"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/j.1528-1157.1998.tb01356.x","article-title":"Carbamazepine toxicity with lamotrigine: Pharmacokinetic or pharmacodynamic interaction?","volume":"39","author":"Besag","year":"1998","journal-title":"Epilepsia"},{"key":"ref_39","first-page":"279","article-title":"[Lamotrigine in the therapy of resistant epilepsy]","volume":"150","author":"Sopranzi","year":"1999","journal-title":"Clin. Ter."},{"key":"ref_40","first-page":"203","article-title":"[Lamotrigine: First experience in Italy]","volume":"146","author":"Sopranzi","year":"1995","journal-title":"Clin. Ter."},{"key":"ref_41","first-page":"294","article-title":"Rational approach to the clinical protocol design for drug combinations: A review","volume":"41","author":"Chang","year":"2000","journal-title":"Acta Paediatr. Taiwan"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Luszczki, J.J., Panasiuk, A., Zagaja, M., Karwan, S., Bojar, H., Plewa, Z., and Florek-\u0141uszczki, M. (2020). Polygonogram and isobolographic analysis of interactions between various novel antiepileptic drugs in the 6-Hz corneal stimulation-induced seizure model in mice. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0234070"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1111\/j.1476-5381.2010.00872.x","article-title":"Animal research: Reporting in vivo experiments: The ARRIVE guidelines","volume":"160","author":"Kilkenny","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/nn.3934","article-title":"Animal models in epilepsy research: Legacies and new directions","volume":"18","author":"Grone","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.seizure.2011.01.003","article-title":"Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs","volume":"20","author":"Loscher","year":"2011","journal-title":"Seizure"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/0920-1211(91)90075-Q","article-title":"The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models","volume":"8","author":"Loscher","year":"1991","journal-title":"Epilepsy Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.2147\/NDT.S50371","article-title":"Animal models of epilepsy: Use and limitations","volume":"10","author":"Kandratavicius","year":"2014","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.eplepsyres.2018.07.008","article-title":"In vitro and in vivo experimental models employed in the discovery and development of antiepileptic drugs for pharmacoresistant epilepsy","volume":"146","author":"Campos","year":"2018","journal-title":"Epilepsy Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/j.1528-1167.2001.00002.x","article-title":"Animal models used in the screening of antiepileptic drugs","volume":"4","author":"Kupferberg","year":"2001","journal-title":"Epilepsia"},{"key":"ref_50","unstructured":"Stables, J.P., and Kupferberg, H.J. (1997). The NIH Anticonvulsant Drug Development (ADD) Program: Preclinical Anticonvulsant Screening Project, John Libbey."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/0920-1211(91)90062-K","article-title":"The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III. Pentylenetetrazole seizure models","volume":"8","author":"Loscher","year":"1991","journal-title":"Epilepsy Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1007\/s00702-014-1173-7","article-title":"Effects of WIN 55,212-2 (a non-selective cannabinoid CB1 and CB 2 receptor agonist) on the protective action of various classical antiepileptic drugs in the mouse 6 Hz psychomotor seizure model","volume":"121","author":"Wlaz","year":"2014","journal-title":"J. Neural Transm."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1016\/j.pnpbp.2011.07.001","article-title":"Effects of WIN 55,212-2 mesylate (a synthetic cannabinoid) on the protective action of clonazepam, ethosuximide, phenobarbital and valproate against pentylenetetrazole-induced clonic seizures in mice","volume":"35","author":"Luszczki","year":"2011","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.pbb.2011.01.002","article-title":"Synthetic cannabinoid WIN 55,212-2 mesylate enhances the protective action of four classical antiepileptic drugs against maximal electroshock-induced seizures in mice","volume":"98","author":"Luszczki","year":"2011","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0920-1211(91)90041-D","article-title":"The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. IV. Protective indices","volume":"9","author":"Loscher","year":"1991","journal-title":"Epilepsy Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/0300-483X(95)03210-7","article-title":"Isobolographic analysis of interactions: An update on applications and utility","volume":"105","author":"Gessner","year":"1995","journal-title":"Toxicology"},{"key":"ref_57","first-page":"93","article-title":"What is synergy?","volume":"41","author":"Berenbaum","year":"1989","journal-title":"Pharmacol. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/S1734-1140(09)70128-8","article-title":"Characterization of acute adverse-effect profiles of selected antiepileptic drugs in the grip-strength test in mice","volume":"61","author":"Zadrozniak","year":"2009","journal-title":"Pharmacol. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1007\/s11064-017-2215-y","article-title":"The Anticonvulsant Screening Program of the National Institute of Neurological Disorders and Stroke, NIH: History and contributions to clinical care in the twentieth century and beyond","volume":"42","author":"Porter","year":"2017","journal-title":"Neurochem Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s13300-018-0550-x","article-title":"Pregabalin in the management of painful diabetic neuropathy: A narrative review","volume":"10","author":"Azmi","year":"2019","journal-title":"Diabetes Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1016\/j.bja.2018.02.066","article-title":"Analgesic mechanisms of gabapentinoids and effects in experimental pain models: A narrative review","volume":"120","author":"Chincholkar","year":"2018","journal-title":"Br. J. Anaesth."},{"key":"ref_62","first-page":"Cd007076","article-title":"Pregabalin for neuropathic pain in adults","volume":"1","author":"Derry","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1212\/WNL.59.5_suppl_2.S14","article-title":"Use of anticonvulsants for treatment of neuropathic pain","volume":"59","author":"Backonja","year":"2002","journal-title":"Neurology"},{"key":"ref_64","first-page":"Cd007963","article-title":"Oxcarbazepine for neuropathic pain","volume":"12","author":"Zhou","year":"2017","journal-title":"Cochrane Database Syst Rev."},{"key":"ref_65","first-page":"Cd009318","article-title":"Lacosamide for neuropathic pain and fibromyalgia in adults","volume":"2","author":"Hearn","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_66","first-page":"Cd006044","article-title":"Lamotrigine for acute and chronic pain","volume":"2","author":"Wiffen","year":"2011","journal-title":"Cochrane Database Syst Rev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1038\/sj.npp.1300243","article-title":"Tiagabine synergistically interacts with gabapentin in the electroconvulsive threshold test in mice","volume":"28","author":"Luszczki","year":"2003","journal-title":"Neuropsychopharmacology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/sj.npp.1300602","article-title":"Pharmacological and behavioral characteristics of interactions between vigabatrin and conventional antiepileptic drugs in pentylenetetrazole-induced seizures in mice: An isobolographic analysis","volume":"30","author":"Luszczki","year":"2005","journal-title":"Neuropsychopharmacology"},{"key":"ref_69","first-page":"660","article-title":"7-Nitroindazole enhances dose-dependently the anticonvulsant activities of conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model","volume":"58","author":"Luszczki","year":"2006","journal-title":"Pharmacol. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"107849","DOI":"10.1016\/j.neuropharm.2019.107849","article-title":"Evaluation of the impact of compound C11 a new anticonvulsant candidate on cognitive functions and hippocampal neurogenesis in mouse brain","volume":"163","author":"Szewczyk","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1111\/j.1528-1167.2009.02485.x","article-title":"Effect of sildenafil on the anticonvulsant action of classical and second-generation antiepileptic drugs in maximal electroshock-induced seizures in mice","volume":"51","author":"Nieoczym","year":"2010","journal-title":"Epilepsia"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.euroneuro.2005.03.005","article-title":"Levetiracetam selectively potentiates the acute neurotoxic effects of topiramate and carbamazepine in the rotarod test in mice","volume":"15","author":"Luszczki","year":"2005","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s43440-019-00044-7","article-title":"Anticonvulsant and neurotoxic effects of a novel 1,2,4-triazole-3-thione derivative (TPF-34) and its isobolographic interaction profile with classical antiepileptic drugs in mice","volume":"72","author":"Luszczki","year":"2020","journal-title":"Pharmacol. Rep."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S1474-4422(03)00483-6","article-title":"Clinically important drug interactions in epilepsy: Interactions between antiepileptic drugs and other drugs","volume":"2","author":"Patsalos","year":"2003","journal-title":"Lancet Neurol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.eplepsyres.2010.07.009","article-title":"Additive interactions of pregabalin with lamotrigine, oxcarbazepine and topiramate in the mouse maximal electroshock-induced seizure model: A type I isobolographic analysis for non-parallel dose-response relationship curves","volume":"91","author":"Luszczki","year":"2010","journal-title":"Epilepsy Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1124\/mol.107.039867","article-title":"The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels","volume":"73","author":"Errington","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.neuropharm.2006.02.002","article-title":"Seeking a mechanism of action for the novel anticonvulsant lacosamide","volume":"50","author":"Errington","year":"2006","journal-title":"Neuropharmacology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1080\/14737175.2016.1202764","article-title":"Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: A review of their clinical pharmacology and therapeutic use","volume":"16","author":"Calandre","year":"2016","journal-title":"Expert Rev. Neurother."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s11910-008-0053-7","article-title":"New molecular targets for antiepileptic drugs: Alpha(2)delta, SV2A, and K(v)7\/KCNQ\/M potassium channels","volume":"8","author":"Rogawski","year":"2008","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s40263-017-0441-0","article-title":"Sodium channel blockers in the treatment of epilepsy","volume":"31","author":"Brodie","year":"2017","journal-title":"CNS Drugs"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1046\/j.1471-4159.2003.02186.x","article-title":"Topiramate modulation of kainate-induced calcium currents is inversely related to channel phosphorylation level","volume":"88","author":"Angehagen","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1124\/jpet.109.153908","article-title":"Topiramate reduces excitability in the basolateral amygdala by selectively inhibiting GluK1 (GluR5) kainate receptors on interneurons and positively modulating GABAA receptors on principal neurons","volume":"330","author":"Braga","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1111\/j.1528-1157.2000.tb02164.x","article-title":"Cellular actions of topiramate: Blockade of kainate-evoked inward currents in cultured hippocampal neurons","volume":"41","author":"Gibbs","year":"2000","journal-title":"Epilepsia"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/S0028-3908(01)00171-X","article-title":"Two new actions of topiramate: Inhibition of depolarizing GABA(A)-mediated responses and activation of a potassium conductance","volume":"42","author":"Herrero","year":"2002","journal-title":"Neuropharmacology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1007\/s00702-017-1771-2","article-title":"Topiramate via NMDA, AMPA\/kainate, GABAA and Alpha2 receptors and by modulation of CREB\/BDNF and Akt\/GSK3 signaling pathway exerts neuroprotective effects against methylphenidate-induced neurotoxicity in rats","volume":"124","author":"Motaghinejad","year":"2017","journal-title":"J. Neural Transm."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.ejphar.2013.10.020","article-title":"Effects of WIN 55,212-2 mesylate on the anticonvulsant action of lamotrigine, oxcarbazepine, pregabalin and topiramate against maximal electroshock-induced seizures in mice","volume":"720","author":"Luszczki","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.pbb.2015.01.003","article-title":"Effects of WIN 55,212-2 (a synthetic cannabinoid CB1 and CB2 receptor agonist) on the anticonvulsant activity of various novel antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice","volume":"130","author":"Wlaz","year":"2015","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_88","first-page":"99","article-title":"A simplified method of evaluating dose-effect experiments","volume":"96","author":"Litchfield","year":"1949","journal-title":"J. Pharmacol. Exp. Ther"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s00210-006-0055-4","article-title":"Isobolographic analysis of interactions between loreclezole and conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model","volume":"373","author":"Luszczki","year":"2006","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/0024-3205(89)90148-3","article-title":"Statistical analysis of drug-drug and site-site interactions with isobolograms","volume":"45","author":"Tallarida","year":"1989","journal-title":"Life Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"9.19.1","DOI":"10.1002\/0471141755.ph0919s72","article-title":"Drug combinations: Tests and analysis with isoboles","volume":"72","author":"Tallarida","year":"2016","journal-title":"Curr. Protoc. Pharmacol."},{"key":"ref_92","first-page":"285","article-title":"The problem of synergism and antagonism of combined drugs","volume":"3","author":"Loewe","year":"1953","journal-title":"Arzneimittelforschung"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.ejphar.2005.03.046","article-title":"Synergistic interaction of gabapentin and oxcarbazepine in the mouse maximal electroshock seizure model\u2014An isobolographic analysis","volume":"515","author":"Luszczki","year":"2005","journal-title":"Eur. J. Pharmacol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.eplepsyres.2010.01.001","article-title":"Interactions of 1-methyl-1,2,3,4-tetrahydroisoquinoline with lamotrigine, oxcarbazepine, pregabalin, and topiramate in the mouse maximal electroshock-induced seizure model: A type I isobolographic analysis","volume":"89","author":"Luszczki","year":"2010","journal-title":"Epilepsy Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.pnpbp.2006.11.020","article-title":"Isobolographic characterization of interactions between vigabatrin and tiagabine in two experimental models of epilepsy","volume":"31","author":"Luszczki","year":"2007","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s00210-006-0100-3","article-title":"Biphasic characteristic of interactions between stiripentol and carbamazepine in the mouse maximal electroshock-induced seizure model: A three-dimensional isobolographic analysis","volume":"374","author":"Luszczki","year":"2006","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.euroneuro.2004.06.002","article-title":"Interaction between lamotrigine and felbamate in the maximal electroshock-induced seizures in mice: An isobolographic analysis","volume":"15","author":"Luszczki","year":"2005","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s00210-004-0983-9","article-title":"Three-dimensional isobolographic analysis of interactions between lamotrigine and clonazepam in maximal electroshock-induced seizures in mice","volume":"370","author":"Luszczki","year":"2004","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/S1734-1140(12)70867-8","article-title":"Synergistic interaction of pregabalin with the synthetic cannabinoid WIN 55,212-2 mesylate in the hot-plate test in mice: An isobolographic analysis","volume":"64","author":"Luszczki","year":"2012","journal-title":"Pharmacol. Rep."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ejphar.2008.07.051","article-title":"Isobolographic and behavioral characterizations of interactions between vigabatrin and gabapentin in two experimental models of epilepsy","volume":"595","author":"Luszczki","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1046\/j.1528-1157.2003.32702.x","article-title":"Interactions between oxcarbazepine and conventional antiepileptic drugs in the maximal electroshock test in mice: An isobolographic analysis","volume":"44","author":"Luszczki","year":"2003","journal-title":"Epilepsia"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1080\/10428190802353591","article-title":"Preclinical versus clinical drug combination studies","volume":"49","author":"Chou","year":"2008","journal-title":"Leuk. Lymphoma"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","article-title":"Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors","volume":"22","author":"Chou","year":"1984","journal-title":"Adv. Enzyme Regul."},{"key":"ref_104","first-page":"233","article-title":"A method for the routine assessment of fore- and hindlimb grip strength of rats and mice","volume":"1","author":"Meyer","year":"1979","journal-title":"Neurobehav. Toxicol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ejphar.2006.07.037","article-title":"Arachidonyl-2\u2019-chloroethylamide, a highly selective cannabinoid CB1 receptor agonist, enhances the anticonvulsant action of valproate in the mouse maximal electroshock-induced seizure model","volume":"547","author":"Luszczki","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.pnpbp.2009.09.005","article-title":"Effect of arachidonyl-2\u2019-chloroethylamide, a selective cannabinoid CB1 receptor agonist, on the protective action of the various antiepileptic drugs in the mouse maximal electroshock-induced seizure model","volume":"34","author":"Luszczki","year":"2010","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.pnpbp.2012.07.001","article-title":"Effect of ACEA\u2014A selective cannabinoid CB1 receptor agonist on the protective action of different antiepileptic drugs in the mouse pentylenetetrazole-induced seizure model","volume":"39","author":"Zolkowska","year":"2012","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Carter, R.J., Morton, J., and Dunnett, S.B. (2001). Motor coordination and balance in rodents. Curr. Protoc. Neurosci.","DOI":"10.1002\/0471142301.ns0812s15"},{"key":"ref_109","first-page":"e2609","article-title":"Measuring motor coordination in mice","volume":"75","author":"Deacon","year":"2013","journal-title":"J. Vis. Exp."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1177\/1947601912440575","article-title":"Quantitative methods for assessing drug synergism","volume":"2","author":"Tallarida","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1186\/s12967-018-1709-y","article-title":"Immunological effects of the intraparenchymal administration of allogeneic and autologous adipose-derived mesenchymal stem cells after the acute phase of middle cerebral artery occlusion in rats","volume":"16","author":"Yu","year":"2018","journal-title":"J. Transl. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5537\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:06:57Z","timestamp":1760162817000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5537"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,24]]},"references-count":111,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22115537"],"URL":"https:\/\/doi.org\/10.3390\/ijms22115537","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,24]]}}}