Journal article
Enhancement of Glutamate Uptake as Novel Antiseizure Approach: Preclinical Proof of Concept
Annals of neurology, v 97(2), pp 344-357
08 Nov 2024
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Objective Excitotoxicity is a common hallmark of epilepsy and other neurological diseases associated with elevated extracellular glutamate levels. Thus, here, we studied the protective effects of ( R )‐AS‐1 , a positive allosteric modulator (PAM) of glutamate uptake in epilepsy models. Methods ( R )‐AS‐1 was evaluated in a range of acute and chronic seizure models, while its adverse effect profile was assessed in a panel of standard tests in rodents. The effect of ( R )‐AS‐1 on glutamate uptake was assessed in COS‐7 cells expressing the transporter. WAY 213613, a selective competitive EAAT2 inhibitor, was used to probe the reversal of the enhanced glutamate uptake in the same transporter expression system. Confocal microscopy and Western blotting analyses were used to study a potential influence of ( R )‐AS‐1 on GLT‐1 expression in mice. Results ( R )‐AS‐1 showed robust protection in a panel of animal models of seizures and epilepsy, including the maximal electroshock‐ and 6 Hz‐induced seizures, corneal kindling, mesial temporal lobe epilepsy, lamotrigine‐resistant amygdala kindling, as well as seizures induced by pilocarpine or Theiler's murine encephalomyelitis virus. Importantly, ( R )‐AS‐1 displayed a favorable adverse effect profile in the rotarod, the minimal motor impairment, and the Irwin tests. ( R )‐AS‐1 enhanced glutamate uptake in vitro and this effect was abolished by WAY 213613, while no influence on GLT‐1 expression in vivo was observed after repeated treatment. Interpretation Collectively, our results show that ( R )‐AS‐1 has favorable tolerability and provides robust preclinical efficacy against seizures. Thus, allosteric enhancement of EAAT2 function could offer a novel therapeutic strategy for treatment of epilepsy and potentially other neurological disorders associated with glutamate excitotoxicity. ANN NEUROL 2024
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Details
- Title
- Enhancement of Glutamate Uptake as Novel Antiseizure Approach: Preclinical Proof of Concept
- Creators
- Krzysztof Kamiński - Jagiellonian UniversityKatarzyna Socała - Maria Curie-Skłodowska UniversityMichał Abram - Jagiellonian UniversityMarcin Jakubiec - Jagiellonian UniversityKatelyn L. Reeb - Drexel UniversityRhea Temmermand - Drexel UniversityMirosław Zagaja - Instytut Medycyny Wsi im. Witolda ChodźkiMaciej Maj - Medical University of LublinMagdalena Kolasa - Maj Institute of PharmacologyAgata Faron-Górecka - Maj Institute of PharmacologyMarta Andres-Mach - Instytut Medycyny Wsi im. Witolda ChodźkiAleksandra Szewczyk - Instytut Medycyny Wsi im. Witolda ChodźkiMustafa Q. Hameed - Harvard UniversityAndréia C. K. Fontana - Drexel UniversityAlexander Rotenberg - Boston Children's HospitalRafał M. Kamiński - Jagiellonian University
- Publication Details
- Annals of neurology, v 97(2), pp 344-357
- Publisher
- Wiley
- Number of pages
- 14
- Grant note
- National Science Centre, PolandEpilepsy Therapy Screening Program (ETSP) of the National Institute of Neurological Disorders and Stroke (NINDS)NIH/NINDS: NS111767
The authors are appreciative to Epilepsy Therapy Screening Program (ETSP) of the National Institute of Neurological Disorders and Stroke (NINDS, National Institutes of Health, Bethesda, USA), for testing and providing antiseizure data for compound (R)-AS-1. We are especially thankful to Dr. Brian Klein (ETSP Program Director) and Dr. Yogendra Raol (ETSP Scientific Project Manager) for scientific support and fruitful cooperation. A.C.K.F. and K.L.R. would like to acknowledge Juliette DiFlumeri (Drexel University) for her help with quantification of immunocytochemistry studies. The studies were supported by the National Science Centre, Poland grant UMO- 2022/45/B/NZ7/00598. A.C.K.F. also received NIH/NINDS support (grant NS111767).
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:001357721600001
- Scopus ID
- 2-s2.0-85208590543
- Other Identifier
- 991021960650204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Clinical Neurology
- Neurosciences