IM-12 activates the Wnt–β-catenin signaling pathway and attenuates rtPA-induced hemorrhagic transformation in rats after acute ischemic stroke

Abstract

Hemorrhagic transformation (HT) is a devastating complication for patients with acute ischemic stroke (AIS) who are treated with tissue plasminogen activator (tPA). HT is associated with high morbidity and mortality, but no effective treatments are currently available to reduce the risk of HT. Therefore, methods to prevent HT are urgently needed. In this study, we used IM-12, an inhibitor of glycogen synthase kinase 3β (GSK-3β), to evaluate the role of the Wnt–β-catenin signaling pathway in recombinant tPA (rtPA)-induced HT. Sprague–Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) model of ischemic stroke, and then were either administered rtPA, rtPA combined with IM-12, or the vehicle at 4 h after stroke was induced. Our results indicate that rats subjected to HT had more severe neurological deficits, brain edema, and blood–brain barrier (BBB) breakdown, and had a greater infarction volume than the control group. Rats treated with IM-12 had improved outcomes compared with those of rats treated with rtPA alone. Moreover, IM-12 increased the protein expression of β-catenin and downstream proteins while suppressing the expression of GSK-3β. These results suggest that IM-12 reduces rtPA-induced HT and attenuates BBB disruption, possibly through activation of the Wnt–β-catenin signaling pathway, and provides a potential therapeutic strategy for preventing tPA-induced HT after AIS.

Normalization of non‐canonical Wnt signalings does not compromise blood‐brain barrier protection conferred by upregulating endothelial Wnt/β‐catenin signaling following ischemic stroke

“…Given that upregulating endothelial Wnt/β‐cat has been demonstrated as a novel potential treatment for BBB protection following ischemic stroke, 10 , 11 , 12 , 13 we wondered if the treatment after ischemic stroke would induce any changes of non‐canonical Wnt signalings. The mice with endothelial β‐catenin constitutive activation were generated, shown in Figure 3A .…”

“…(2) Previous studies have shown that Wnt/β‐cat, Wnt/PCP, and Wnt/Ca 2+ signalings collectively contribute to the endothelial growth, angiogenesis, and BBB formation, 1 , 2 , 6 , 7 while the antagonisms between canonical (Wnt/β‐cat) and non‐canonical (Wnt/PCP and Wnt/Ca 2+ ) signalings in physiological status have been implicated. 8 , 9 Given that it has been reported that Wnt/β‐cat signaling augmentation could protect BBB after cerebral I/R, 10 , 11 , 12 if upregulating Wnt/β‐cat signaling could affect Wnt/PCP and Wnt/Ca 2+ signalings becomes a new question.…”

“…Besides, some other studies including ours showed that the treatment with glycogen synthase kinase 3β (GSK3β) inhibitors (IM‐12, TWS119, and lithium) significantly improved the outcomes of mice with ischemic stroke by upregulating Wnt/β‐cat signaling. 11 , 12 , 13 Since upregulating endothelial Wnt/β‐cat signaling has been considered as a novel therapeutic method for protecting BBB after ischemic stroke, and the antagonisms between canonical and non‐canonical Wnt signalings have been suggested to exist, 8 , 9 it is necessary to determine the changes of non‐canonical Wnt signalings and their consequences while manipulating endothelial Wnt/β‐cat signaling in the treatment of ischemic stroke.…”

LncRNA DANCR attenuates brain microvascular endothelial cell damage induced by oxygen-glucose deprivation through regulating of miR-33a-5p/XBP1s

“…Silencing of the Wnt/β-catenin pathway contributes to the development of ischemic stroke [28]. Activation of Wnt/β-catenin signaling contributes to the reduction of neuroinflammation, attenuation of BBB disruption, and facilitation of neurological recovery [29,30]. A previous study found that DANCR activated Wnt/βcatenin signaling to promote glioma proliferation [13].…”

Variants of WNT7A and GPR124 are associated with hemorrhagic transformation following intravenous thrombolysis in ischemic stroke

“…Recently, we demonstrated that following acute cerebral ischemia/reperfusion injury in mice, decreased canonical Wnt signaling activity in Gpr124 knockout brain endothelium led to exacerbation of BBB disruption and severe ICH, resembling severe PH in human strokes 21 . Furthermore, canonical Wnt signaling activity regulated rt‐PA‐induced HT in rodent ischemic stroke models 44‐46 . Nevertheless, the impact of canonical Wnt signaling pathway on human BBB integrity and HT after ischemic stroke remains completely unexplored.…”