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Thus, here, we studied the protective effects of <jats:bold>(<jats:italic>R<\/jats:italic>)\u2010AS\u20101<\/jats:bold>, a positive allosteric modulator (PAM) of glutamate uptake in epilepsy models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:bold>(<jats:italic>R<\/jats:italic>)\u2010AS\u20101<\/jats:bold> 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 <jats:bold>(<jats:italic>R<\/jats:italic>)\u2010AS\u20101<\/jats:bold> on glutamate uptake was assessed in COS\u20107 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 <jats:bold>(<jats:italic>R<\/jats:italic>)\u2010AS\u20101<\/jats:bold> on GLT\u20101 expression in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:bold>(<jats:italic>R<\/jats:italic>)\u2010AS\u20101<\/jats:bold> showed robust protection in a panel of animal models of seizures and epilepsy, including the maximal electroshock\u2010 and 6\u2009Hz\u2010induced seizures, corneal kindling, mesial temporal lobe epilepsy, lamotrigine\u2010resistant amygdala kindling, as well as seizures induced by pilocarpine or Theiler's murine encephalomyelitis virus. Importantly, <jats:bold>(<jats:italic>R<\/jats:italic>)\u2010AS\u20101<\/jats:bold> displayed a favorable adverse effect profile in the rotarod, the minimal motor impairment, and the Irwin tests. <jats:bold>(<jats:italic>R<\/jats:italic>)\u2010AS\u20101<\/jats:bold> enhanced glutamate uptake in vitro and this effect was abolished by WAY 213613, while no influence on GLT\u20101 expression in vivo was observed after repeated treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Collectively, our results show that <jats:bold>(<jats:italic>R<\/jats:italic>)\u2010AS\u20101<\/jats:bold> 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. 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