Vignesh Subramanian ’24

Ischemic stroke, the subtype accounting for the vast majority of strokes, frequently occurs following obstruction of blood vessels by plaques or clots. This cerebrovascular accident is often characterized by the debilitating effects of postsynaptic density protein 95 (PSD-95), a scaffolding protein that typically mediates localization of neurotransmitter receptors such as NMDARs but does so excessively in the wake of strokes, triggering mass excitotoxic cell death. As such, numerous pharmacological therapeutic approaches have aimed to uncouple the protein-protein interactions of PSD-95 without inhibiting the ordinary signaling of neurotransmitters like glutamate. One such drug, known as nerinetide, was previously established as an effective PSD-95 inhibitor in non-human primates that underwent endovascular thrombectomies, successfully reperfusing (restoring blood flow to) impacted cerebral regions. To determine whether nerinetide could provide similar pharmacological neuroprotection in human subjects, a study at the University of Calgary explored the impact of the drug’s application on the prognosis of ischemic stroke patients.

Researchers first assigned 1,105 patients known to have previously suffered disabling ischemic strokes to nerinetide and placebo groups in a 1:1 ratio throughout a double-blind and randomized controlled trial. Following non-contrast CT and multiphase CT angiography imaging tests, patients with occlusions underwent rapid endovascular therapy (EVT) in a 12 hour treatment window and were then intravenously administered usual-care alteplase (a medication that breaks down clots by catalyzing formation of the responsible enzyme plasmin) and the trial drug nerinetide. Primary analyses of patient outcomes based on Alberta Stroke Program Early CT Scores, the National Institutes of Health Stroke Scale, and the Rankin scale were then performed to ascertain whether nerinetide application could reduce disability and establish reperfusion at specific time targets.

Researchers found that while nerinetide did not effectively mitigate the debilitating aftermath of stroke in patients who also received alteplase, patients that solely received nerinetide following EVT demonstrated a significant clinical benefit.  The latter group enjoyed both lower mortality rates and enhanced functional outcomes, though researchers concluded that two parallel trials – one directly comparing nerinetide with the placebo and the other comparing administration of alteplase versus a lack thereof – would have improved the trial design. The evidence suggested that alteplase exhibited a modifying effect on nerinetide’s amino acid sequences by forming the plasmin that cleaved and disabled them, nullifying nerinetide’s neuroprotective effect. Future research may thus ultimately determine that lone clinical application of the trial drug enables preservation of cerebral regions damaged by acute ischemic stroke.

Works Cited:

[1] M. Hill, et al., Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. The Lancet 395, 878-887 (2020). DOI: 10.1016/S0140-6736(20)30258-0

[2] Image retrieved from: http://www.strokecenter.org/patients/about-stroke/ischemic-stroke/