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

Abstract

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). While 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 inhibitors (DPP-4i) linagliptin and the sulfonylurea glimepiride, 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 the 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 normalised 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 the antidiabetic neurorestorative effects.

Ropinirole Cotreatment Prevents Perivascular Glial Recruitment in a Rat Model of L-DOPA-Induced Dyskinesia

“…Pericytes are embedded in the basement membrane of small vessels and capillaries, where they play a key role in BBB maintenance, regulation of vessel diameter, as well as structural vessel remodelling under a number of pathophysiological conditions [41]. Recent studies in rodent models of brain disease have detected a positive correlation between the extent of microglial-blood vessel interactions and microvascular pericyte coverage [42,43]. This may depend on the pericytic capacity for cytokine and chemokine secretion, possibly affecting glial reactivity and migration [44].…”

The Role of Adipokines in the Pathologies of the Central Nervous System

“…DPP-4 inhibitors have been shown to reduce pericyte apoptosis, increase levels of tight junctions, and reduce vascular leakage in conditions like cerebral ischemia. Therefore, this suggests that DPP-4 inhibitors could improve BBB integrity by preserving pericytes and reducing pathological angiogenesis, as seen in T2DM [139].…”