Aims We have shown that glycemic control with metformin or endothelin-1 (ET-1) inhibition with bosentan prevents and restores diabetes-mediated cerebral pathological remodeling and neovascularization. Our recent data suggest that linagliptin, a member of the dipeptidyl peptidase-4 inhibitor class of glucose-lowering agents, prevents cerebrovascular remodeling and dysfunction independent of its blood glucose lowering effects. We hypothesized that linagliptin prevents pathological neovascularization via the modulation of the ET-1 system. Materials and Methods 24-week old diabetic Goto-Kakizaki and nondiabetic Wistar rats were treated for 4 weeks with either vehicle chow or chow containing 166mg/kg linagliptin. At termination, FITC-dextran was injected to visualize the vasculature. Brain sections were imaged by confocal microscopy for vascular density, tortuosity, vascular volume, and surface in both the cortex and striatum. Retinal acellular capillary formation was measured. Brain microvascular endothelial cells (BMVEC) isolated from control or diabetic rats were treated with linagliptin with or without ET-1 dual receptor antagonist and tested for angiogenic properties with cell migration and tube formation assays. Key Finding Linagliptin reduced all indices of cerebral neovascularization compared with control rats. In vitro, linagliptin normalized the augmented angiogenic properties of BMVECs isolated from diabetic animals and bosentan reversed this response. Cells from diabetic animals had higher ET-1 and less ETB receptors than in control cells. Linagliptin significantly decreased ET-1 levels and increased ETB receptors. Significance ET system contributes to pathological neovascularization in diabetes as evidenced by restoration of functional angiogenesis by bosentan treatment and prevention of linagliptin-mediated improvement of angiogenesis in the in vitro model.

Patients with recurrent herpes simplex virus-2 (HSV-2) often are delivered by Caesarean section to minimize exposure of the neonate to the virus. A significant number of anaesthetists do not use regional anaesthesia in these patients for fear of introducing virus into the central nervous system. ~ We would like to report our experience with lumbar epidural anaesthesia in patients with recurrent HSV-2 infections.

Objective: Diabetes promotes dysfunctional neovascularization and cerebrovascular remodeling in diabetes. We showed that glycemic control with metformin prevents and restores diabetes-mediated pathological remodeling and neovascularization of the cerebrovasculature. Our recent data suggest that linagliptin, a dipeptidyl-peptidase-4 (DPP-4) inhibitor used for glycemic control, prevents vascular remodeling independent of glycemic control in diabetes. In this study, we test the hypothesis that linagliptin prevents dysfunctional neovascularization in a blood glucose independent manner in diabetes. Methods: 24 week old diabetic Goto-Kakizaki (GK) (Hemoglobin A1C >6.5%) and nondiabetic Wistar rats were treated for 4 weeks with either vehicle chow or chow containing 166mg/kg linagliptin. At termination, FITC-dextran was injected to full and visualize the vasculature and brain sections were imaged by confocal microscopy for vascular density, tortuosity, vascular volume, and surface area measurements in 3 dimensional reconstruction of the cortex and striatum regions. Retinal acellular capillary formation was measured as another surrogate marker for pathological neovascularization in diabetes (n=3-4). Brain microvascular endothelial cells (BMVEC) isolated from control or diabetic rats were also treated with (100 nM) linagliptin and tested for angiogenic properties with cell migration and tube formation assays. Results: Linagliptin reduced all indices of cerebral neovascularization compared with control rats (Table, n=3-5). In addition linagliptin significantly decreased retinal acellular capillaries and normalized the augmented angiogenic properties of diabetic BMVEC (p<0.05). Conclusions: These results suggest that linagliptin offers therapeutic potential and effective in reversing established pathological neovascularization. Mechanisms underlying glucose independent effects of linagliptin remain to be determined.