N-acetyl spermine (NASPM) is known from in vitro and in vivo animal models for its action as calcium permeable AMPA receptors (CP-AMPARs) antagonist. Our study aim to investigate the impact of NASPM on an ex vivo human brain slice neocortex model, focusing on its ability to suppress epileptic activity. While AMPA receptors play a central role in neocortical signaling and neuronal activity, the contribution of CP-AMPARs, particularly in the context of seizure-induced inhibition/excitation imbalance, remains unknown. By applying NASPM to ex vivo human cortex slices, we aimed to investigate its action on evoked seizure like events (SLEs). NASPM (100 µM) application on SLEs-induced models on ex vivo human brain slices leads to complete block of ictal activity in all epileptic models tested. Interestingly, by fine-tuning pharmacology induced-epileptic models, we observed that NASPM action is likely to not be restricted to CP-AMPARs but extends to NMDARs and KARs. NASPM is likely to deliver its antiepileptic action by in-concert antagonizing these three receptor classes. These results challenge the conventional understanding of NASPM mechanism of action and demonstrate that NASPM antiepileptic mechanism involves a more complex coordinated antagonism of various key CNS receptors. This study challenges the use of NASPM as a specific NMDAR antagonist and opens new possibilities to its potential clinical application as a novel anti-seizure medication compound.