ABSTRACT NUMBER: ESOC2026A502 RE-EVALUATING MK-801 AS A NEUROPROTECTIVE STRATEGY: COMPARING INTRAVENOUS AND INTRA-ARTERIAL ADMINISTRATION IN A MOUSE MODEL OF CEREBRAL ISCHEMIA

Abstract Background and aims Ischemic stroke is currently treated using pharmacological or mechanical thrombolysis, and neuroprotective agents have so far failed clinical translation. This study investigates whether intra-arterial administration of MK-801, a non-competitive NMDAR antagonist, provides superior neuroprotection compared to intravenous delivery in a murine model of transient middle cerebral artery occlusion (tMCAO). Methods To evaluate systemic toxicity and neurological injury at 48h after intra-arterial or intravenous administration, MK-801 (2mg/kg) or vehicle was given to naïve C57 mice (n=8/group). Efficacy was examined in ischemic mice (n=7/group, tMCAO) receiving MK-801 (2 and 0.5mg/kg) or vehicle 30 minutes after reperfusion, with neurological function measured at 24h and 48h. Infarct size was quantified by TTC staining at 48h, and brain homogenates were analysed for pro-inflammatory cytokines via MILLIPLEX® assay. Results 2 mg/kg MK-801 caused no safety issues in naïve mice. High-dose of MK-801 (2mg/kg) reduced overall infarct size by 20.69% across routes compared to vehicle (p=0.050), whereas the low dose (0.5mg/kg) showed no neuroprotection (p=0.602). Functional outcome was not different between groups (p>0.05). Intravenous high-dose MK-801 achieved 25.31% total infarct reduction relative to vehicle (p=0.071), driven by 32.9% cortical decrease (p=0.005), while intra-arterial delivery produced a non-significant 16.6% reduction (p=0.293). Pro-inflammatory mediators (IL6, MCP1, MIP2) increased ipsilaterally but were not reduced by MK-801. Conclusions Our findings show that high-dose MK-801 provides partial acute neuroprotection in transient cerebral ischemia by reducing infarct size, with intravenous delivery achieving superior efficacy while maintaining safety across both routes. Conflict of interest M. Klimczak, K. Adrián-Campbell, A. Penalba, I. de la Torre-Sánchez, M.M. Garcias-Ramis, E. Allo-Urzainqui, C. Jacobs-Cachá, R. Ferrer, A. Rosell: nothing to disclose