{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:49:31Z","timestamp":1787014171815,"version":"build-2736575974"},"reference-count":56,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T00:00:00Z","timestamp":1726790400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003769","name":"Eisai","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>E2730, an uncompetitive \u03b3\u2010aminobutyric acid (GABA) transporter\u20101 (GAT\u20101) inhibitor, has potent anti\u2010seizure effects in a rodent model of chronic temporal lobe epilepsy, the kainic acid status epilepticus (KASE) rat model. In this study, we examined purported neuroimaging and physiological surrogate biomarkers of the effect of E2730 on brain GABAergic function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted a randomized cross\u2010over study, incorporating 1\u2010week treatments with E2730 (100\u2009mg\/kg\/day\u2009subcutaneous infusion) or vehicle in epileptic post\u2010KASE rats. KASE rats underwent serial 9.4\u2009T magnetic resonance spectroscopy (MRS) measuring GABA and other brain metabolites, [\n                      <jats:sup>18<\/jats:sup>\n                      F]Flumazenil positron emission tomography (PET) quantifying GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptor availability, quantitative electroencephalography (qEEG) and transcranial magnetic stimulation (TMS)\u2013mediated motor activity, as well as continuous video\u2010EEG recording to measure spontaneous seizures during each treatment. Age\u2010matched, healthy control animals treated with E2730 or vehicle were also studied.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      E2730 treatment significantly reduced spontaneous seizures, with 8 of 11 animals becoming seizure\u2010free. MRS revealed that E2730\u2010treated animals had significantly reduced taurine levels. [\n                      <jats:sup>18<\/jats:sup>\n                      F]Flumazenil PET imaging revealed no changes in GABA receptor affinity or density during E2730 treatment. The power of gamma frequency oscillations in the EEG was decreased significantly in the auditory cortex and hippocampus of KASE and control rats during E2730 treatment. Auditory evoked gamma frequency power was enhanced by E2730 treatment in the auditory cortex of KASE and healthy controls, but only in the hippocampus of KASE rats. E2730 did not influence motor evoked potentials triggered by TMS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>This study identified clinically relevant changes in multimodality imaging and functional purported biomarkers of GABAergic activity during E2730 treatment in epileptic and healthy control animals. These biomarkers could be utilized in clinical trials of E2730 and potentially other GABAergic drugs to provide surrogate endpoints, thereby reducing the cost of such trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.18119","type":"journal-article","created":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T11:25:34Z","timestamp":1726831534000},"page":"3376-3390","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["In vivo biomarkers of\n                    <scp>GABA<\/scp>\n                    ergic function in epileptic rats treated with the\n                    <scp>GAT<\/scp>\n                    \u20101 inhibitor\n                    <scp>E2730<\/scp>"],"prefix":"10.1111","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0971-4654","authenticated-orcid":false,"given":"Idrish","family":"Ali","sequence":"first","affiliation":[{"name":"The Department of Neuroscience Monash 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