{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:04:32Z","timestamp":1789707872773,"version":"4.0.1"},"reference-count":48,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018818","name":"National Research, Development and Innovation Office","doi-asserted-by":"publisher","award":["K124558"],"award-info":[{"award-number":["K124558"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"award":["K124558"],"award-info":[{"award-number":["K124558"]}],"id":[{"id":"https:\/\/ror.org\/03g2am276","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Glial mechanisms regulate neuronal excitability through multiple mechanisms, including the control of extracellular inhibitory signaling. One such mechanism is the Glu\/GABA exchange process, in which glutamate uptake is coupled to GABA release, with GABA being synthesized from the polyamine putrescine, placing putrescine at a central position in metabolic pathways that may influence epileptiform activity. Here, we examined how pharmacological manipulation of key enzymes of putrescine metabolism affects seizure-like activity in the low-[Mg2+] in vitro model of frontotemporal epilepsy, complemented by in vivo recordings in the non-convulsive absence epilepsy model Wistar Albino Glaxo\/Rijswijk (WAG\/Rij) rats. Increasing putrescine availability by inhibiting spermidine synthase with trans-4-methylcyclohexylamine significantly reduced both the duration and appearance of seizure-like events. Strikingly, simultaneous inhibition of monoamine oxidase B (MAO-B) and diamine oxidase (DAO) with deprenyl and aminoguanidine almost completely abolished seizure-like events in vitro and markedly suppressed spike\u2013wave discharges in WAG\/Rij rats. This effect was largely reversed by blockade of GAT-2\/3 transporters with SNAP-5114, suggesting the presence and significant anti-epileptic potential of a MAO-B- and DAO-independent putrescine\u2013GABA synthesis pathway. Together, these findings indicate that the anticonvulsant effects of putrescine metabolism arise from the coordinated engagement of multiple parallel pathways rather than from a single dominant enzymatic route. Putrescine thus appears to function as a metabolic hub whose increased availability can be channeled into several anticonvulsant processes, suggesting that therapeutic strategies enhancing putrescine-dependent inhibitory pathways at the network level may offer promising avenues for the modulation of epileptiform activity.<\/jats:p>","DOI":"10.3390\/biom16091329","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T08:10:23Z","timestamp":1789373423000},"page":"1329","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Controlling Epileptic Activity by Modulating Putrescine Metabolism"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2679-0103","authenticated-orcid":false,"given":"Saif","family":"Qahtan","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry, HUN-REN Research Centre for Natural Sciences, Magyar Tud\u00f3sok K\u00f6r\u00fatja 2, 1117 Budapest, Hungary"},{"name":"Hevesy Gy\u00f6rgy PhD School of Chemistry, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, 1117 Budapest, Hungary"},{"name":"College of Science, University of Al-Qadisiyah, Al-Diwaniyah 58001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8571-5686","authenticated-orcid":false,"given":"Zsolt","family":"Kov\u00e1cs","sequence":"additional","affiliation":[{"name":"Department of Biology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, BDTTC, K\u00e1rolyi G\u00e1sp\u00e1r t\u00e9r 4, 9700 Szombathely, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enik\u0151","family":"Rauch","sequence":"additional","affiliation":[{"name":"Department of Biology, ELTE E\u00f6tv\u00f6s Lor\u00e1nd University, BDTTC, K\u00e1rolyi G\u00e1sp\u00e1r t\u00e9r 4, 9700 Szombathely, Hungary"},{"name":"Institute of Biology, University of P\u00e9cs, Ifj\u00fas\u00e1g 6, 7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2260-4641","authenticated-orcid":false,"given":"P\u00e1l","family":"Szab\u00f3","sequence":"additional","affiliation":[{"name":"Centre for Structural Science, HUN-REN Research Centre for Natural Sciences, Magyar Tud\u00f3sok K\u00f6r\u00fatja 2, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0035-7005","authenticated-orcid":false,"given":"L\u00e1szl\u00f3","family":"H\u00e9ja","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry, HUN-REN Research Centre for Natural Sciences, Magyar Tud\u00f3sok K\u00f6r\u00fatja 2, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107966","DOI":"10.1016\/j.neuropharm.2020.107966","article-title":"Mechanisms of Action of Currently Used Antiseizure Drugs","volume":"168","author":"Sills","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1111\/j.1528-1157.1993.tb05918.x","article-title":"Antiepileptic Drug Mechanisms of Action","volume":"34","author":"Macdonald","year":"1993","journal-title":"Epilepsia"},{"key":"ref_3","first-page":"a022780","article-title":"Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. 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