Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial

An Atlas of Phosphorylation and Proteolytic Processing Events During Excitotoxic Neuronal Death Reveals New Therapeutic Opportunities

“…The complex formation facilitates over-activation of NOX2 and nNOS to form excess reactive oxygen species and nitric oxide, respectively. Nerinetide was modelled after the PSD95-binding motif in GluN2B C-terminal tail (Aarts et al, 2002;Hill et al, 2020). By blocking the interactions between the aberrantly stimulated extrasynaptic Glu2B-enriched NMDA receptors with PSD95, Nerinetide inhibits over-activation of nNOS (Aarts et al, 2002) and NOX2 (Chen et al, 2015) and in turn protects against excitotoxic neuronal death in vitro and in vivo in rodent and primate models of neurotoxicity (Cook et al, 2012;Sun et al, 2008).…”

“…By blocking the interactions between the aberrantly stimulated extrasynaptic Glu2B-enriched NMDA receptors with PSD95, Nerinetide inhibits over-activation of nNOS (Aarts et al, 2002) and NOX2 (Chen et al, 2015) and in turn protects against excitotoxic neuronal death in vitro and in vivo in rodent and primate models of neurotoxicity (Cook et al, 2012;Sun et al, 2008). More importantly, Nerinetide has been shown to reduce brain damage caused by micro-strokes as well as strokes caused by large vessel occlusion (Hill et al, 2020;Hill et al, 2012). Hence, Nerinetide is a useful tool to be used in conjunction with proteomic approaches to decipher the signalling events operating downstream of nNOS and NOX2 over-activated by the extrasynaptic NMDA receptors in excitotoxic neurons.…”

“…Unfortunately, there are no current FDA-approved pharmacological agents targeted to protect against excitotoxic neuronal loss in neurological disorders (O'Collins et al, 2006;Savitz and Fisher, 2007). This pessimistic scenario has been challenged by the promising results of two clinical trials of a cell membrane permeable peptide Nerinetide (also referred to as Tat-NR2B9c), which inhibits a key pathological cellular event directing excitotoxic neuronal death (Aarts et al, 2002;Hill et al, 2020;Hill et al, 2012).…”

“…In the first phase 2 clinical trial, Nerinetide effectively reduced the number and volume of new ischaemic strokes defined by MRI following procedurally induced ischaemic strokes in patients undergoing treatment to repair ruptured cerebral aneurysm (Hill et al, 2012). In a larger phase 3 clinical trial, favourable clinical outcomes of Nerinetide treatment were found in a group of patients who underwent endovascular thrombectomy for acute ischemic stroke with large vessel occlusion but not treated with the thrombolytic drug alteplase (Hill et al, 2020). Besides proving that neuroprotection to reduce brain damage in human acute ischaemic stroke is achievable, the positive clinical outcomes of Nerinetide treatment illustrate that other pathological cellular events occurring in neurons during excitotoxicity are potential therapeutic targets for the development of neuroprotective strategies to treat ischaemic stroke patients.…”

Therapie des akuten ischämischen Schlaganfalls

“…Thrombolysetherapie bis 12 Stunden nach Symptombeginn NA-1 bzw. Placebolösung verabreicht bekamen, keinen signifikanten Unterschied im Outcome nach 90 Tagen (mRS 0-2 in 61,4 % vs. 59,2 %, 95 % KI 0,96-1,14, p = 0,350) feststellen [38]. Auch im Schlaganfallvolumen zeigte sich kein signifikanter Unterschied (71,1 vs. 73,1 ml).…”