Abstract
Diabetes increases the risk of stroke, exacerbates neurological deficits, and increases mortality. Non-mitogenic fibroblast growth factor 1 (nmFGF1) is a powerful neuroprotective factor that is also regarded as a metabolic regulator. The present study aimed to investigate the effect of nmFGF1 on the improvement of functional recovery in a mouse model of type 2 diabetic (T2D) stroke. We established a mouse model of T2D stroke by photothrombosis in mice that were fed a high-fat diet and injected with streptozotocin (STZ). We found that nmFGF1 reduced the size of the infarct and attenuated neurobehavioral deficits in our mouse model of T2D stroke. Angiogenesis plays an important role in neuronal survival and functional recovery post-stroke. NmFGF1 promoted angiogenesis in the mouse model of T2D stroke. Furthermore, nmFGF1 reversed the reduction of tube formation and migration in human brain microvascular endothelial cells (HBMECs) cultured in high glucose conditions and treated with oxygen glucose deprivation/re-oxygenation (OGD). Amp-activated protein kinase (AMPK) plays a critical role in the regulation of angiogenesis. Interestingly, we found that nmFGF1 increased the protein expression of phosphorylated AMPK (p-AMPK) both in vivo and in vitro. We found that nmFGF1 promoted tube formation and migration and that this effect was further enhanced by an AMPK agonist (A-769662). In contrast, these processes were inhibited by the application of an AMPK inhibitor (compound C) or siRNA targeting AMPK. Furthermore, nmFGF1 ameliorated neuronal loss in diabetic stroke mice via AMPK-mediated angiogenesis. In addition, nmFGF1 ameliorated glucose and lipid metabolic disorders in our mouse model of T2D stroke without causing significant changes in body weight. These results revealed that nmFGF1-regulated glucolipid metabolism and angiogenesis play a key role in the improvement of functional recovery in a mouse model of T2D stroke and that these effects are mediated by the AMPK signaling pathway.
Highlights
Ischemic stroke, a common cerebrovascular disease, is the main cause of death around the world, but is the largest cause of long-term disability, representing a huge social burden
These results suggested that angiogenesis is involved in the neural functional recovery of Non-mitogenic fibroblast growth factor 1 (nmFGF1)-treated mice experiencing diabetic stroke and that this process was mediated by endothelial cell migration
We found that the administration of an AMPK inhibitor, compound C, and AMPK-target siRNA, resulted in the repression of tube formation and cell migration in HG + oxygen and glucose deprivation-reoxygenation (OGD)-cultured human brain microvascular endothelial cells (HBMECs) cells treated with nmFGF1; these findings concur with those of previous studies
Summary
A common cerebrovascular disease, is the main cause of death around the world, but is the largest cause of long-term disability, representing a huge social burden. There is a critical need for explorative research aimed at discovering effective drugs to improve glucose and lipid metabolism as well as ameliorate cerebral ischemic injury in diabetic stroke. One of the main characteristics of cerebral ischemia in diabetic patients is that the brain damage is aggravated by blood vessel injury. Angiogenesis in the ischemic border zone (IBZ) is a common endogenous repair response to cerebral ischemia and hypoxia, and has been shown to be positively correlated with the recovery of neurological function (Zhang et al, 2010; Banerjee et al, 2014; Rust et al, 2019). Endothelial cells play a primary role in angiogenesis but are functionally impaired in patients suffering from diabetic stroke (Yasmeen et al, 2019). The improvement of endothelial function will be an efficient method with which to encourage angiogenesis
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