MYDGF Attenuates Blood-Brain Barrier Breakdown and Improves Cognitive Impairment in Diabetic Encephalopathy

Blood-brain barrier (BBB) breakdown plays a key role in cognitive impairment in diabetic encephalopathy (DE). This study aimed to investigate whether myeloid-derived growth factor (MYDGF) can prevent BBB injury and cognitive impairment in DE. Circulating MYDGF levels were measured in patients with diabetes. In vivo experiments, both loss- and gain-of-function strategies, were used to evaluate the effect of MYDGF on BBB injury and cognitive impairment in diabetic mice. We used multiple low-dose streptozotocin-treated Mydgf knockout and wild-type (WT) mice on high-fat diets to induce diabetes. Then, cognitive function and BBB permeability were examined in diabetic mice that were subjected to adeno-associated virus-mediated Mydgf gene transfer. In vitro experiments, primary human brain microvascular endothelial cells (HBMECs) were treated with high glucose (HG) to mimic diabetic conditions. The effects of MYDGF on transendothelial permeability were investigated. The results indicated that circulating MYDGF levels were decreased in patients with DE and diabetic mice with cognitive impairment. Compared with WT mice, MYDGF deficiency presented more severe impaired cognitive performance, BBB leakage, and cerebrovascular inflammation in diabetic mice. Inversely, MYDGF restoration alleviated cognitive decline, BBB breakdown, and cerebrovascular inflammation in diabetic mice. In HG-treated HBMECs, MYDGF restoration attenuated the transendothelial permeability and junction protein downregulation and protected against endothelial inflammation and apoptosis. Mechanistically, the protective effect of MYDGF was attributed to mitogen-activated protein kinase kinase kinase kinase 4/nuclear factor-kappa B signaling pathway inhibition. This study demonstrated that MYDGF protects against BBB injury and prevents the progression of cognitive decline in DE, suggesting that MYDGF may be an effective therapeutic strategy for DE.