Abstract
Delayed administration of kallikrein after cerebral infarction can improve neurological function. However, the appropriate kallkrein treatment time after ischemic stroke has not been illuminated. In this study, we compared the long-term outcome among three kallikrein therapeutic regimens starting at different time points following mouse cerebral ischemia. Furthermore, the protective mechanisms involving neurogenesis, angiogenesis, and AKT-GSK3β-VEGF signaling pathway were analyzed. Human tissue kallikrein was injected through the tail vein daily starting at 8 h, 24 h, or 36 h after right middle cerebral artery occlusion (MCAO) until the 28th day. Three therapeutic regimens all protected against neurological dysfunction, but kallikrein treatment starting at 8 h after MCAO had the best efficacy. Additionally, kallikrein treatment at 8 h after MCAO significantly enhanced cell proliferation including neural stem cell and induced differentiation of neural stem cell into mature neuron. Kallikrein treatment starting at 8 h also promoted more angiogenesis than other two treatment regimens, which was associated with AKT-GSK3β-VEGF signaling pathway. Thus, we confirm that three delayed kallikrein treatments provide protection against cerebral infarction and furthermore suggest that kallikrein treatment starting at 8 h had a better effect than that at 24 h and 36 h. These findings provide the experimental data contributing to better clinical application of exogenous kallikrein.
Highlights
Stroke is the leading cause of death and disability worldwide [1]
To compare the efficacy of kallikrein starting at different time points, the neurological function of mice was assessed at 14 d and 28 d after middle cerebral artery occlusion (MCAO)/reperfusion injury (Figure 1(a))
We found all exogenous tissue kallikrein treatments starting at 8 h, 24 h, and 36 h (i.e., KLK 8 h, KLK 24 h, and KLK 36 h) after ischemic stroke can ameliorate the neurological deficits, but the KLK 8 h group has lower scores than the KLK 24 h and KLK 36 h groups (Figures 1(b)–1(d))
Summary
Ischemic stroke is the most common type of stroke in China [2]. According to the guidelines from the American Stroke Association for the early management of patients with acute cerebral ischemia, intravenous administration of rtPA remains the only recommended pharmacological therapy within 4.5 hours after acute ischemic stroke [3]. More than 4.5 hours after acute ischemic stroke, therapies are being sought to improve functional neurological recovery and reduce disability. As an important element of the kallikrein/kinin system (KKS), tissue kallikrein can cleave low-molecule kininogen into kinins (e.g., bradykinin and kallidin). The biological function of tissue kallikrein is mainly produced by kinin binding to high-affinity kinin B1 or B2 receptors [4].
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