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. Evidence from most clinical and experimental studies indicated that DPP-4 inhibitors have favorable effects on cardiovascular diseases, despite they failed to show superiority vs. placebo in the prevention of cardiovascular events in patients with T2DM and high CV risk [1]. We have recently demonstrated that DPP-4 inhibitors improve stroke outcome in rodents independently from GLP-1 receptor [2,3]. However, the underlying mechanisms are unknown. The present study aims 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 the beneficial effects of gliptins in stroke, thus suggesting further innovative pharmacological target for preventing cerebrovascular injury. References: [1] Scheen, Circulation Research. 2018;122:1439-1459 [1] Darsalia et al., Diabetes 2013, 62(4):1289-1296.