Nerinetide

Protection against ischemic stroke may be most effective when multiple components of the neurovascular unit are protected, yet current treatments target mainly neurons. Here we explored whether the PSD-95 inhibitor Tat-NR2B9c (NA-1) can protect not only neurons but also the blood-brain barrier.

Adult male Sprague-Dawley rats were randomly divided into three groups, which were subjected to either sham surgery or transient cerebral ischemia-reperfusion, after which some animals were treated with Tat-NR2B9c. The therapeutic efficacy of Tat-NR2B9c was assessed in terms of the degree of neurological deficit and cerebral infarction, integrity of the blood-brain barrier, cerebral water content, as well as expression of PSD-95, nitric oxide synthase, and matrix metalloprotease-9.

Tat-NR2B9c (NA-1) ameliorated neurofunctional deficit, reduced cerebral infarction, mitigated blood-brain barrier injury and improved its integrity following ischemia-reperfusion, leading to less cerebral edema. These improvements were associated with upregulation of tight junction proteins in the blood-brain barrier. At the same time, Tat-NR2B9c (NA-1) downregulated neuronal nitric oxide synthase and matrix metalloprotease-9, while reversing the ischemia-induced downregulation of endothelial nitric oxide synthase in brain. We report here the first evidence that PSD-95 is expressed in vascular endothelial cells in the brain.

Our experiments in a rat model of transient occlusion of the middle cerebral artery suggest that Tat-NR2B9c (NA-1) can mitigate ischemic injury to the blood-brain barrier, and that it may do so by downregulating matrix metalloprotease-9 and upregulating endothelial nitric oxide synthase.

Brain frailty may impair the ability of acute stroke patients to cope with the injury, irrespective of their chronologic age, resulting in impaired recovery. We aim to investigate the impact of brain atrophy on functional outcome assessed at different time points after endovascular thrombectomy (EVT).

In this retrospective post hoc analysis of the ESCAPE-NA1 trial, we analyzed CT imaging data for cortical atrophy by using the GCA scale, including region-specific scales, and subcortical atrophy by using the intercaudate distance to inner table width (CC/IT) ratio. The primary outcome was 90-day mRS (ordinal shift analysis), and the secondary outcome was the mRS score over time. Adjustments were made for age, sex, baseline NIHSS, final infarct volume, stroke laterality, total Fazekas score, and nerinetide-alteplase interaction. Sensitivity analyses were additionally performed in only those patients for whom MRI data were available.

Of 1,102 participants (mean age of 69.5 ± 13.7 years; 554 men), 818 (74%) had GCA = 0, 220 (20%) had GCA = 1, and 64 (6%) had GCA = 2/3. The median CC/IT ratio was 0.12 (IQR0.10-0.15). Cortical atrophy (GCA ≥ 1 vs GCA 0) was associated with worse 90-day mRS (acOR = 1.62 [95% CI 1.22-2.16]; p = 0.001), lower rates of 90-day mRS0-2 (aOR = 0.65 [95% CI 0.45-0.94]; p = 0.022), and higher mortality (aOR = 2.12 [95% CI 1.28-3.5]; p = 0.003), regardless of the region assessed. Subcortical atrophy was associated with worse 90-day mRS (acOR [per 0.01 increase in CC/IT ratio] = 1.07 [95% CI 1.04-1.11]; p < 0.001) and lower rates of 90-day mRS0-2 (aOR = 0.92 [95% CI 0.88-0.97]; p = 0.001). Furthermore, with various degrees of atrophy, we observed heterogeneity in mRS measurements during follow-up: worse mRS scores for higher atrophy grades (p < 0.001). Compared with participants with GCA = 0, the mRS for participants with GCA = 1 was higher at 30 days (adjusted difference = 0.41 [95% CI 0.18-0.65]) and remained worse at 90 days (adjusted difference = 0.72 [95% CI 0.49-0.95]). Similar effects were seen for participants with worse cortical atrophy, regardless of the region assessed, and worse subcortical atrophy. Furthermore, 26/63(41%) and 124/274(45%) patients with severe cortical/subcortical atrophy (GCA 2/3 and highest CC/IT ratio quartile, respectively) achieved good functional outcome (mRS0-2), compared with 539/812(66.4%) with no cortical atrophy and 209/274(76%) in the lowest CC/IT ratio quartile.

In this large RCT-derived population, participants with brain atrophy, as visually assessed on acute noncontrast computed tomography imaging, showed less favorable stroke recovery after EVT and worse 90-day functional outcomes compared with participants without brain atrophy. This may support physicians with recovery expectations when planning post-EVT care with patients and their families.