Human tissue kallikrein in the treatment of acute ischemic stroke

Figures

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  Figure 1.. BK receptors: second messengers and physiological effects. The main GPCR target of the KKS are bradykinin receptors, BK1 and BK2. Although, KLK1 is likely to have additional activities, the downstream activation of BK receptors by bradykinin triggers multiple second messenger pathways that may be beneficial in AIS. The physiological output of these systems directly maintains or improves blood flow and protects cells from damaging stressors often present during the hours and days following a stroke. AIS, acute ischemic stroke; BK, bradykinin; GPCR, G-protein-coupled receptor; KLK1, kallikrein; KKS, kallikrein–kinin system.

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  Figure 2.. Short- and long-term activity: hypotheses that may explain the efficacy of KLK1 treatment in AIS. Treatment with human, kallikrein or recombinant KLK1 is hypothesized to have both immediate and long-lasting actions that may improve outcomes following AIS. Immediate actions are largely mediated by activation of the KKS to release nitric oxide and improve microcirculation in ischemic tissue as well as normalizing neurovascular coupling. In the days following a stroke, additional mechanisms may become important including restoration of the blood–brain barrier through increases in Tregs, dampening of apoptotic cells death through increases in AKT and VEGF-mediated control of revascularization. AIS, acute ischemic stroke; AKT, protein kinase β, KLK1, kallikrein; KKS, kallikrein–kinin system; Tregs, regulatory T-cells; VEGF, vascular endothelial growth factor.