Neuroprotective effect of kinin B1 receptor activation in acute cerebral ischemia in diabetic mice

Sci Rep. 2017 Aug 25;7(1):9410. doi: 10.1038/s41598-017-09721-0.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia / prevention & control*
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Type 1
  • Hemodynamics
  • Infarction, Middle Cerebral Artery
  • Male
  • Mice, Inbred C57BL
  • Neuroprotective Agents / pharmacology*
  • Receptor, Bradykinin B1 / agonists*
  • Receptor, Bradykinin B2 / agonists*
  • Renal Insufficiency

Substances

  • Neuroprotective Agents
  • Receptor, Bradykinin B1
  • Receptor, Bradykinin B2