The effect of the DPP-4 inhibitor linagliptin to improve functional outcome after stroke is mediated by the CXCR4/SDF-1α pathway.

Abstract Background and Aim: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) decrease hyperglycemia by inhibiting glucagon-like peptide-1 (GLP-1)-cleavage. Gliptins can also improve stroke outcome in rodents independently from GLP-1 receptor [1,2]. However, the underlying mechanisms are unknown. We aimed to determine whether gliptins improve stroke outcome via the stromal cell-derived factor-1 α (SDF-1α)/ Chemokine Receptor Type 4 (CXCR4) pathway, and identify additional effectors behind the efficacy. Methods: Mice were subjected to stroke by transient middle cerebral artery occlusion (MCAO). Linagliptin was administered for 3 days or 3 weeks from stroke onset. The CXCR4-antagonist AMD3100 was administered one day before MCAO until three days thereafter. Stroke outcome was assessed by measuring upper-limb function, stroke volume and neuronal survival. Brain GLP-1, GIP and SDF-1α were quantified by ELISA. To identify additional gliptin-mediated molecular effectors, brain samples were analyzed by mass spectrometry. Results: Linagliptin specifically increased active SDF-1α (p<0,001) but not GIP or GLP-1 brain levels. Blocking of SDF-1α/CXCR4 pathway abolished the positive effects of Linagliptin on upper-limb function and histological outcome after stroke. Moreover, Linagliptin treatment after stroke decreased the presence of peptides derived from Neurogranin and from an isoform of the Myelin basic protein. Conclusion: We showed that Linagliptin improves functional stroke outcome in a CXCR4/SDF-1α-dependent manner. Considering that Calpain activity and intracellular Ca2+ regulate Neurogranin and Myelin basic protein detection, we propose a gliptin-mediated neuroprotective mechanism via the SDF-1α/CXCR4 pathway that involves the regulation of Ca2+ homeostasis and the reduction of Calpain activity. These results provide new insights into restorative gliptin-mediated effects against stroke. References: [1] Darsalia et al., Diabetes 2013, 62(4):1289-1296. [2] Darsalia et al., Diabetes Obes Metab 2016, 18(5):537-41.