Early Increased Bradykinin 1 Receptor Contributes to Hemorrhagic Transformation After Ischemic Stroke in Type 1 Diabetic Rats

Abstract

Hemorrhagic transformation (HT) is a major complication of ischemic stroke and further deteriorates neurological outcomes. Bradykinin 1 receptor (B1R) has been proven to mediate vasculo-toxicity in various experimental models. However, its role in the development of HT after stroke remains unclear. We detected the B1R expression in brain tissues with or without HT in a rat model of cerebral ischemia/reperfusion (I/R) with type 1 diabetes, showing higher B1R expression in the hemorrhagic areas than the ischemic tissues. Then, B1R agonist or antagonist was administrated intravenously just before reperfusion to investigate its effect on HT and the underlying molecular mechanism. Administration of low (300 nmol/kg) or high (1 μmol/kg) dose of B1R antagonist mitigated hemorrhage, improved neurobehavioral deficits, and preserved blood-brain-barrier (BBB) integrity after reperfusion for 8 h whereas the 300 nmol/kg of B1R agonist aggravated these outcomes, though only the high does of B1R antagonist affected the infarction volume. Extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation was increased by B1R activation but decreased by B1R inhibition, which mediated B1R toxicity on BBB disruption and ischemia-related HT. Furthermore, B1R activation facilitated the mRNA and protein expressions of MMP-9 in the hemorrhagic tissues, and these increases were blocked by both ERK inhibitor U0126 and NF-κB inhibitor PDTC. U0126 also remarkably decreased the B1R-induced NF-κB/p65 activation. We concluded that upregulated B1R may contribute to early HT after I/R in type 1 diabetic rats via ERK1/2/NF-κB/MMP-9 pathway. B1R inhibition could be an encouraging therapeutic strategy to withstand HT after ischemic stroke in diabetic patients.

Protective Effect of CXCR4 Antagonist CX807 in a Rat Model of Hemorrhagic Stroke

“…In a preliminary radioligand binding assay, we found that CX807, at a high dose, partially inhibited bradykinin B1 receptor (B1R) binding. It has been shown that B1R antagonist mitigated hemorrhage, improved neurobehavioral deficits, and preserved blood–brain barrier integrity after reperfusion [ 25 ]. CX807 may reduce ICH damage partially through the B1R, which warrants further investigation.…”

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

“…Despite that some astrocyte-derived factors maintain the BBB function, some astrocyte-derived factors damage the BBB by inducing endothelial cell apoptosis or decreasing the expression of endothelial tight junctionrelated proteins, which include vascular endothelial growth factor (VEGF) [204][205][206][207], glutamate [208][209][210], endothelins (ETs) [21,211,212], MMP [208,213,214], and nitric oxide (NO) [215,216] (Table 1). As zincendopeptidases, MMPs can directly degrade endothelial tight junction-related proteins and ECM molecules, which promotes angiogenesis whereas simultaneously increases BBB permeability [78,217,218]. And it is through the signaling pathway activating or suppressing MMPs that many other factors such as APOE, NO, and ETs get to affect the BBB integrity [201,212,215].…”

Impact of Bradykinin Generation During Thrombolysis in Ischemic Stroke

“…In addition, intravenous injection or overexpression of tissue kallikrein (able to generate kallidin, a bradykinin analog, after cleavage of low-molecular kininogen) has beneficial effects in stroke, which are dependent on B2R activation ( 54 , 55 ). Regarding B1R, the data are more homogenous since most studies described deleterious effects on ischemic lesion size, brain edema and post-stroke inflammation ( 48 , 56 – 58 ). It is however difficult to isolate the contribution of bradykinin on each of these pathophysiological processes, since reduction of lesion size itself is associated with reduced brain edema and inflammation.…”