KNG deficiency confers long-term neuroprotection and reduces mortality after acute ischemic stroke in young and aged mice of either sex. (A top) Representative TTC staining of 3 corresponding coronal brain sections of (left to right): 6-week-old male wild-type (WT) mouse, 6-week-old male Kng^−/− mouse, 6-week-old male Kng^−/− mouse reconstituted with human kininogen (KNG), 6-week-old male Kng^−/− mouse reconstituted with bradykinin (BK), 6-week-old female WT mouse, 6-week-old female Kng^−/− mouse, as well as 6-month-old male WT mouse and 6-month-old male Kng^−/− mouse on day 1 after tMCAO. The ischemic infarcts (white) appear smallest in the Kng^−/− mice (white arrows) of either age or sex, and this result was confirmed by infarct volumetry (bottom; N = 6-10 per group). Note that reconstitution of Kng^−/− mice with human KNG or BK fully restored infarct susceptibility underlining the specificity of the KNG effect. Infarctions in KNG-deficient mice remained small on day 3 after tMCAO, thereby excluding secondary infarct growth. In contrast, protection from stroke was lost in Kng^−/− mice after pMCAO. (B) Neurologic Bederson score (top) and grip test score (bottom) on day 1 or day 3 after tMCAO or day 1 after pMCAO in the 12 mouse groups indicated above. The reduction of infarct size in Kng^−/− mice after tMCAO also translated into better functional outcome (N = 6-10 per group). (C) Mortality in 6-week-old male Kng^−/− mice and WT controls between day 0 and day 8 after tMCAO (N = 10 per group). (A-B) ***P < .001, **P < .01, *P < .05, 1-way ANOVA followed by Bonferroni multiple comparison test (infarct volumes) or Kruskal-Wallis test followed by Dunn multiple comparison test (neurologic scores) compared with the respective WT groups. (C) Survival curve: **P = .008, log-rank test compared with WT mice.