Nerinetide

Also known as: NA-1, Tat-NR2B9c

**Mechanism of Action** Nerinetide (NA-1, Tat-NR2B9c) is a 20-amino acid peptide that disrupts the interaction between postsynaptic density protein-95 (PSD-95) and N-methyl-D-aspartate (NMDA) receptors. By binding to the PDZ domain of PSD-95, it prevents the coupling of NMDA receptors to downstream neurotoxic signaling pathways, including neuronal nitric oxide synthase (nNOS) activation. This uncoupling reduces excitotoxic calcium influx and oxidative stress without blocking normal NMDA receptor-mediated synaptic transmission, thereby preserving neuronal viability during ischemic injury. **Key Research Findings** Preclinical studies demonstrated that Nerinetide reduces infarct volume and improves neurological outcomes in rodent and primate models of focal cerebral ischemia. The phase III ESCAPE-NA1 trial (NCT02930018) evaluated its efficacy in acute ischemic stroke patients undergoing endovascular thrombectomy. While the overall trial did not meet its primary endpoint (modified Rankin Scale at 90 days), a prespecified subgroup analysis showed significant benefit in patients not receiving concurrent intravenous alteplase. Secondary analyses suggested improved functional independence and reduced mortality in this subgroup, with no increased risk of intracranial hemorrhage. **Clinical Relevance** Nerinetide represents a novel neuroprotective strategy targeting excitotoxicity downstream of NMDA receptor activation, distinct from prior failed glutamate antagonists. Its potential benefit in patients treated without thrombolytics highlights the need for careful drug–drug interaction studies, as alteplase may cleave the peptide. Ongoing research aims to confirm these findings in dedicated trials and explore applications in other excitotoxic conditions (e.g., traumatic brain injury, subarachnoid hemorrhage). For research purposes only — not medical advice.

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