Abstract
Recombinant fibroblast growth factor 21 (rFGF21) has been shown to be potently beneficial for improving long-term neurological outcomes in type 2 diabetes mellitus (T2DM) stroke mice. Here, we tested the hypothesis that rFGF21 protects against poststroke blood–brain barrier (BBB) damage in T2DM mice via peroxisome proliferator-activated receptor gamma (PPARγ) activation in cerebral microvascular endothelium. We used the distal middle cerebral occlusion (dMCAO) model in T2DM mice as well as cultured human brain microvascular endothelial cells (HBMECs) subjected to hyperglycemic and inflammatory injury in the current study. We detected a significant reduction in PPARγ DNA-binding activity in the brain tissue and mRNA levels of BBB junctional proteins and PPARγ-targeting gene CD36 and FABP4 in cerebral microvasculature at 24 h after stroke. Ischemic stroke induced a massive BBB leakage two days after stroke in T2DM mice compared to in their lean controls. Importantly, all abnormal changes were significantly prevented by rFGF21 administration initiated at 6 h after stroke. Our in vitro experimental results also demonstrated that rFGF21 protects against hyperglycemia plus interleukin (IL)-1β-induced transendothelial permeability through upregulation of junction protein expression in an FGFR1 activation and PPARγ activity elevation-dependent manner. Our data suggested that rFGF21 has strong protective effects on acute BBB leakage after diabetic stroke, which is partially mediated by increasing PPARγ DNA-binding activity and mRNA expression of BBB junctional complex proteins. Together with our previous investigations, rFGF21 might be a promising candidate for treating diabetic stroke.
Highlights
About 30% of stroke patients are diabetic, and more than 90% of them have type 2 diabetes mellitus (T2DM) [1]
The treatment at 30 min prior to recombinant fibroblast growth factor 21 (rFGF21) administration with GW9662 eliminated the inhibitory effect of rFGF21 on blood–brain barrier (BBB) extravasation (Figure 2B,C). These results suggested that the potentiated BBB leakage after ischemic focal stroke in T2DM can be largely protected by rFGF21 and this beneficial effect might be contributed by PPARγ activation
The major findings of the present study can be summarized as follows: (1) T2DM db/db mice exhibited much worse BBB permeability in acute phase after focal ischemic stroke compared to their lean db/+ counterparts; (2) delayed rFGF21 administration given 6 h after stroke onset largely mitigated the ischemia-induced BBB permeability in db/db mice; (3) the BBB-protective effect of rFGF21 was at least partially contributed by FGFR1-mediated promotion of PPARγ activity in cerebral microvascular endothelium (Figure 6)
Summary
About 30% of stroke patients are diabetic, and more than 90% of them have type 2 diabetes mellitus (T2DM) [1]. Emerging evidence obtained from clinical and experimental studies suggests that T2DM impairs blood–brain barrier (BBB) integrity and aggravates BBB permeability in baseline state or after ischemic stroke [5,6,7,8], which has been considered an important pathological feature of T2DM stroke responsible, at least in part, for the worsening of neurological deficits [9]. We have previously proposed a disease-modifying approach using recombinant fibroblast growth factor 21 (rFGF21) to treat ischemic stroke mice with T2DM and observed the beneficial effects of rFGF21 on long-term neurological outcomes in T2DM stroke mice [10]. Our previous study showed that rFGF21 administration increases PPARγ DNA-binding activity three days after stroke in the perilesion cortex of T2DM mice, which might be partially responsible for the reduction of brain tissue damage and detrimental proinflammatory cytokine expressions [10]. Pharmacological effects of rFGF21 on aggravated early BBB disruption after ischemic stroke with T2DM and its potential underlying molecular mechanisms have not been investigated
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