The novel PSD-95 inhibitor BXOS110 provides neuroprotection in acute ischemic stroke

Acute ischemic stroke remains a major public health challenge due to its high incidence and limited effective treatment options. Reperfusion therapies, including thrombolysis and endovascular intervention, help restore blood flow in some patients but often fall short due to ineffective recanalization or reperfusion injury, emphasizing the urgent need for adjunctive neuroprotective strategies. BXOS110, a novel neuroprotective agent, targets PSD-95, a postsynaptic density protein that mediates excitotoxic damage by interacting with N-methyl-D-aspartate (NMDA) receptors and neuronal nitric oxide synthase. In this study, BXOS110 demonstrated a higher binding affinity for PSD-95 than its predecessor, nerinetide (NA-1). Our data further confirmed that BXOS110 directly binds to PSD-95 and mitigates NMDA-induced neurotoxicity in vitro. In vivo, BXOS110 exhibited robust brain penetration and sustained localization in ischemic brain regions of rats, as well as significant neuroprotective effects in both rat and primate models of ischemic stroke when administered within 1 h of ischemia onset. Additionally, we determined that BXOS110 administration must be carefully timed with thrombolytic agents to prevent its degradation, identifying optimal dosing intervals to maximize therapeutic efficacy. These findings highlight the potential of BXOS110 as an integrated stroke therapeutic agent, which combines vascular recanalization with targeted neuroprotection to enhance patient outcomes.