The Effect of Gliptins to Improve Functional Outcome after Stroke in Mice Is Mediated by the CXCR4/SDF-1α Pathway

Abstract

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 of GLP-1R. However, the underlying mechanisms are unknown. Stromal cell-derived factor-1α (SDF-1α) is a DPP-4 substrate and CXCR4 agonist that promotes beneficial effects in injured brains. However, SDF-1α involvement in gliptin-mediated neuroprotection is unproven. We aimed to determine whether gliptins improve stroke outcome via SDF-1α/CXCR4 and identify additional targets behind the efficacy. Adult, male C57bl6/j mice (n=101) underwent transient focal cerebral ischemia. Linagliptin was administered for 3 days or 3 weeks. The CXCR4-antagonist AMD3100 was administered starting a day before ischemia. Stroke outcome was assessed by measuring upper-limb function and brain tissue damage. Levels of active GLP-1, gastric inhibitory polypeptide (GIP) and SDF-1α were quantified by ELISA in serum and brain. Mass spectrometry was used to identify additional gliptin-mediated effectors in brain tissue samples. Sustained, post-ischemic treatment with linagliptin reduced motor impairment (p003C0.01) and tissue damage (p003C0.05). Linagliptin increased serum levels of GLP-1 (p003C0.0001), GIP (p003C0.05) and SDF-1α (p003C0.05). However, only SDF-1α levels were increased in the brain (p003C0.001). Linagliptin also decreased the presence of neurogranin-derived peptides and peptides from an isoform of myelin basic protein (MBG, p003C0.05). The inhibition of SDF-1α/CXCR4 pathway diminished the positive effects of linagliptin on stroke outcome (not different from vehicle). We propose a gliptin-mediated neuroprotective mechanism via SDF-1α, which could affect Ca2+ homeostasis, altering neurogranin and MBG processing and potentially decreasing calpain activity. These results provide new insights into restorative gliptin-mediated effects against stroke. Disclosure F. Chiazza: Other Relationship; Self; Boehringer Ingelheim GmbH. H. Tammen: Consultant; Self; Boehringer Ingelheim GmbH. H. Pintana: Other Relationship; Self; Boehringer Ingelheim GmbH. G. Lietzau: Other Relationship; Self; Boehringer Ingelheim GmbH. M. Collino: None. T. Nystrom: Research Support; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. V. Darsalia: Other Relationship; Self; Boehringer Ingelheim GmbH. C. Patrone: Other Relationship; Self; Boehringer Ingelheim GmbH.