DPP-4 Inhibitor and Sulfonylurea Differentially Reverse Type 2 Diabetes–Induced Blood–Brain Barrier Leakage and Normalize Capillary Pericyte Coverage

Microvascular pathology in the brain is one of the suggested mechanisms underlying the increased incidence and progression of neurodegenerative diseases in people with type 2 diabetes (T2D). Although accumulating data suggest a neuroprotective effect of antidiabetics, the underlying mechanisms are unclear. Here, we investigated whether two clinically used antidiabetics, the dipeptidyl peptidase-4 inhibitor linagliptin and the sulfonylurea glimepiride, which restore T2D-induced brain vascular pathology. Microvascular pathology was examined in the striatum of mice fed for 12 months with either normal chow diet or a high-fat diet (HFD) to induce T2D. A subgroup of HFD-fed mice was treated with either linagliptin or glimepiride for 3 months before sacrifice. We demonstrate that T2D caused leakage of the blood–brain barrier (BBB), induced angiogenesis, and reduced pericyte coverage of microvessels. However, linagliptin and glimepiride recovered the BBB integrity and restored the pericyte coverage differentially. Linagliptin normalized T2D-induced angiogenesis and restored pericyte coverage. In contrast, glimepiride enhanced T2D-induced angiogenesis and increased pericyte density, resulting in proper vascular coverage. Interestingly, glimepiride reduced microglial activation, increased microglial–vascular interaction, and increased collagen IV density. This study provides evidence that both DPP-4 inhibition and sulfonylurea reverse T2D-induced BBB leakage, which may contribute to antidiabetic neurorestorative effects.