Abstract
Activation of the kallikrein-kinin system enhances cardiac and renal tolerance to ischemia. Here we investigated the effects of selective agonists of kinin B1 or B2 receptor (R) in brain ischemia-reperfusion in diabetic and non-diabetic mice. The role of endogenous kinins was assessed in tissue kallikrein deficient mice (TK−/−). Mice underwent 60min-middle cerebral artery occlusion (MCAO), eight weeks after type 1-diabetes induction. Treatment with B1R-, B2R-agonist or saline was started at reperfusion. Neurological deficit (ND), infarct size (IS), brain water content (BWC) were measured at day 0, 1 and 2 after injury. MCAO induced exaggerated ND, mortality and IS in diabetic mice. B2R-agonist increased ND and mortality to 60% and 80% in non-diabetic and diabetic mice respectively, by mechanisms involving hemodynamic failure and renal insufficiency. TK−/− mice displayed reduced ND and IS compared to wild-type littermate, consistent with suppression of B2R activity. B1R mRNA level increased in ischemic brain but B1R-agonist had no effect on ND, mortality or IS in non-diabetic mice. In contrast, in diabetic mice, B1R-agonist tested at two doses significantly reduced ND by 42–52% and IS by 66–71%, without effect on BWC or renal function. This suggests potential therapeutic interest of B1R agonism for cerebral protection in diabetes.
Highlights
Acute brain ischemia secondary to cerebral artery occlusion is a major cause of mortality or permanent disability
We evaluated effect of kinin signalling in mice submitted to transient focal cerebral ischemia
We addressed the role of endogenously produced kinins by studying mice deficient in tissue kallikrein (TK), the main kinin-forming enzyme
Summary
Acute brain ischemia secondary to cerebral artery occlusion is a major cause of mortality or permanent disability. Role of kinins in brain ischemia has been addressed so far by performing pharmacological blockade of B1R or B2R in rodents or studying mice genetically deficient in either B1 or B2 receptor. These studies have produced conflicting results[3]. Some studies have shown that B2R blockade reduced infarct size and neuronal damage after transient middle cerebral artery occlusion (MCAO)[19, 22,23,24] but other suggested that inactivation of this receptor has no effect or even aggravates ischemic brain damage[20, 25,26,27]. They show that in diabetic condition B1R signalling is neuroprotective
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