Linagliptin reduces effects of ET-1 and TLR2-mediated cerebrovascular hyperreactivity in diabetes

Abstract

Aims The anti-hyperglycemic agent linagliptin, a dipeptidyl peptidase-4 inhibitor, has been shown to reduce inflammation and improve endothelial cell function. In this study, we hypothesized that DPP-IV inhibition with linagliptin would improve impaired cerebral blood flow in diabetic rats through improved insulin-induced cerebrovascular relaxation and reversal of pathological cerebrovascular remodeling that subsequently leads to improvement of cognitive function. Main Methods Male type-2 diabetic Goto-Kakizaki (GK) and nondiabetic Wistar rats were treated with linagliptin, and ET-1 plasma levels and dose response curves to ET-1 (0.1–100 nM) in basilar arteries were assessed. The impact of TLR2 antagonism on ET-1 mediated basilar contraction and endothelium-dependent relaxation to acetylcholine (ACh, 1 nM–1 M) in diabetic GK rats was examined with antibody directed against the TLR2 receptor (Santa Cruz, 5 μg/mL). The expression of TLR2 in middle cerebral arteries (MCAs) from treated rats and in brain microvascular endothelial cells (BMVEC) treated with 100nM linagliptin was assessed. Key Findings Linagliptin lowered plasma ET-1 levels in diabetes, and reduced ET-1-induced vascular contraction. TLR2 antagonism in diabetic basilar arteries reduced ET-1-mediated cerebrovascular dysfunction and improved endothelium-dependent vasorelaxation. Linagliptin treatment in the BMVEC was able to reduce TLR2 expression in cells from both diabetic and nondiabetic rats. Conclusions These results suggest that inhibition of DPPIV using linagliptin improves the ET-1-mediated cerebrovascular dysfunction observed in diabetes through a reduction in ET-1 plasma levels and reduced cerebrovascular hyperreactivity. This effect is potentially a result of linagliptin causing a decrease in endothelial TLR2 expression and a subsequent increase in NO bioavailability.

The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates High-fat Induced Cognitive Decline in Tauopathy Model Mice

“…Linagliptin has been shown to improve cerebrovascular dysfunction observed in diabetes through anti-inflammatory and vasodilatory effects in a glucose-independent manner [32]. Alternatively, linagliptin may restore cerebrovascular function via the regulation of hyper-reactivity to endothelin 1 and Toll-like receptors 2 expression [33]. Treatment with sitagliptin was reported to reverse memory impairment in HFD-fed mice through reduced oxidative stress and enhanced neurogenesis [34].…”

Neuroprotective Properties of Linagliptin: Focus on Biochemical Mechanisms in Cerebral Ischemia, Vascular Dysfunction and Certain Neurodegenerative Diseases

“…Linagliptin seems to exhibit antagonistic properties towards TLR-2s (Toll-like receptors 2) [23]. TLR-2s serve an essential role in modulating the immune response of the brain [66].…”

Endothelin and Diabetic Complications: a Brain-Centric View

“…Intriguingly, dual blockade of both ET A and ET B receptors with bosentan improves the maximum relaxation response (Li et al 2011). A recent study demonstrated that oral hypoglycemic linagliptin improves the ET-1-mediated cerebrovascular dysfunction observed in the GK model through a reduction in ET-1 plasma levels and reduced cerebrovascular hyperreactivity (Hardigan et al 2016a, Hardigan et al 2016c. This effect is potentially a result of linagliptin causing a decrease in endothelial toll like receptor 2 (TLR2) expression and a subsequent increase in NO bioavailability (Hardigan et al 2016a, Hardigan et al 2016c.…”