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SignificanceWhy the brain is uniquely sensitive to hypoxia and which cells are involved is incompletely understood. Here we identify that, upon ischemic stroke, in endothelial cells and neurons the reactive oxygen-forming NADPH oxidase 4 (NOX4) causes breakdown of the BBB and neuronal cell death. This mechanism is unique to the brain and not found in other forms of ischemia in the body. Genetic deletion of either cell type (endothelial or neuronal) or pharmacological inhibition of NOX4 leads to a significant reduction of infarct volume and direct neuroprotection. This mechanism explains the unique vulnerability of the hypoxic brain compared with other organs and provides a clear rationale for first-in-class neuroprotective therapies in stroke.

Background and Purpose— The selection of appropriate neurological scores and tests is crucial for the evaluation of stroke consequences. The validity and reliability of neurological deficit scores and tests has repeatedly been questioned in ischemic stroke models in the past. Methods— In 198 male mice exposed to transient intraluminal middle cerebral artery occlusion, we examined the validity and reliability of 11 neurological scores (Bederson score 0–3, Bederson score 0–4, Bederson score 0–5, modified neurological severity [0–14], subjective overall impression [0–10], or simple neurological tests: grip test, latency to move body length test, pole test, wire hanging test, negative geotaxis test, and elevated body swing test) in the acute stroke phase, that is, after 24 hours. Combinations of neurological scores or tests for predicting infarct volume were statistically analyzed. Results— Infarct volume was left skewed (median [Q1–Q3], 78.4 [54.8–101.3] mm 3 ). Among all tests, the Bederson (0–5; r=0.63, P <0.001), modified neurological severity (r=0.80, P <0.001), and subjective overall impression (r=−0.63, P <0.001) scores had the highest test validities, using infarct volume as external reference. Subjective overall impression had the best agreement between 5 raters (Kendall W=0.11, P <0.001). The Bederson (0–5) score discriminated infarct volume in mice with small (≤50 mm 3 ; r=0.33, P =0.027) and large (>50 mm 3 ; r=0.48, P <0.001) brain infarcts, all other tests only in mice with large infarcts. Combining subjective overall impression with Bederson (0–5) score explained 47.6% of the variance of infarct volume. Conclusions— Despite their simplicity, the Bederson (0–5) score, modified neurological severity score, and subjective overall impression have reasonable validity and reliability in the acute stroke phase. The Bederson (0–5) score equally distinguishes infarct volume in small and large infarcts. Visual Overview— An online visual overview is available for this article.

Commissie Dierproeven). Experiments were approved by the responsible authority of the Regierung von Oberbayern (Germany) and the Institutional Ethics Committee of the Universidad Autónoma de Madrid. Author contributions AIC, PWMK, and EG performed in vivo and in vitro experiments and data analysis and contributed to writing the manuscript. TA performed immunological phenotyping, which DHB, VGD, and MHDA supervised. JE helped with data acquisition, and FL helped with sample collection. HHHWS designed experiments, contributed to writing the manuscript, and acquired funding. MGL, CK, and JE acquired funding and methods. JE helped with some in vitro experiments and animal breeding.