Linagliptin reduces ischemic brain damage following stroke in a high-fat diet mouse model: A comparison to Glimepiride

Aims: Type 2 Diabetes (T2D) is a major risk factor for premature and severe stroke. Linagliptin is a dipeptidyl peptidase (DPP)-4 inhibitor with unique pharmacological properties approved for the treatment of T2D. The aim of this study was to determine the efficacy of linagliptin in protecting against stroke-induced ischemic brain damage in a diabetic animal model.

Methods: C57BL/6J male mice fed a high-fat diet for 36 weeks were treated with oral linagliptin (10 mg/kg/d; n = 7), the sulfonylurea glimepiride (2.5 mg/kg/d; n = 7), or vehicle (n = 7) during Weeks 30 – 36. Blood glucose levels, body weight, and food intake were measured at regular intervals during the study. At Week 33, animals were subjected to 30 min of transient middle cerebral artery occlusion to induce a stroke. Drug treatment was continued until Week 36 when the animals were sacrificed. The severity of ischemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex.

Results: Glimepiride caused a marked reduction in non-fasted glucose (-48%; p < 0.001), but did not show any neuroprotective benefit compared with vehicle. In contrast, linagliptin, which demonstrated weaker effects on the glycemic status (-23%; p < 0.01), produced a pronounced and statistically significant reduction in ischemic stroke damage compared with vehicle, as measured by the quantification of surviving neurons in the stroke-damaged brain (p < 0.01).

Conclusions: These results indicate that the mechanism of linagliptin-induced neuroprotection is complex and cannot be explained solely by the reduction in hyperglycemia. In conclusion, this study is the first to show that DDP-4 inhibition in a diabetic animal model leads to neuroprotection following stroke, independent of glycemic changes. The results presented here demand further investigation of the neuroprotective actions of DPP-4 inhibitors in the treatment of diabetes as well as their possible use as anti-stroke medication in non-diabetic conditions.

This study was supported by Boehringer Ingelheim Pharma GmbH & Co. KG.