Abstract
BackgroundDipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are approved drugs for the treatment of hyperglycemia in patients with type 2 diabetes. These effects are mainly mediated by inhibiting endogenous glucagon-like peptide-1 (GLP-1) cleavage. Interestingly, gliptins can also improve stroke outcome in rodents independently from GLP1. However, the underlying mechanisms are unknown. Stromal cell-derived factor-1α (SDF-1α) is a DPP-4 substrate and CXCR4 agonist promoting beneficial effects in injured brains. However, SDF-1α involvement in gliptin-mediated neuroprotection after ischemic injury is unproven. We aimed to determine whether the gliptin linagliptin improves stroke outcome via the SDF-1α/CXCR4 pathway, and identify additional effectors behind the efficacy.MethodsMice 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 1 day before MCAO until 3 days thereafter. Stroke outcome was assessed by measuring upper-limb function, infarct volume and neuronal survival. The plasma and brain levels of active GLP-1, GIP and SDF-1α were quantified by ELISA. To identify additional gliptin-mediated molecular effectors, brain samples were analyzed by mass spectrometry.ResultsLinagliptin specifically increased active SDF-1α but not glucose-dependent insulinotropic peptide (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.ConclusionsWe showed that linagliptin improves functional stroke outcome in a SDF-1α/CXCR4-dependent manner. Considering that Calpain activity and intracellular Ca2+ regulate neurogranin and myelin basic protein detection, our data suggest a gliptin-mediated neuroprotective mechanism via the SDF-1α/CXCR4 pathway that could involve the regulation of Ca2+ homeostasis and the reduction of Calpain activity. These results provide new insights into restorative gliptin-mediated effects against stroke.
Highlights
Dipeptidyl peptidase-4 (DPP-4) inhibitors are approved drugs for the treatment of hyperglycemia in patients with type 2 diabetes
Treatment with linagliptin increases levels of active SDF‐1a, but not of active GLP‐1 and active glucose-dependent insulinotropic peptide (GIP) in the brain (Study 2) The results showed that sustained linagliptin treatment significantly increased levels of all three peptides in serum (Fig. 2a–c)
To test the potential involvement of the Stromal cell-derived factor-1α (SDF-1α)/CXCR4 pathway on this beneficial effect mediated by linagliptin, AMD3100 was administered from Day 1 before stroke until this time point
Summary
Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are approved drugs for the treatment of hyperglycemia in patients with type 2 diabetes These effects are mainly mediated by inhibiting endogenous glucagon-like peptide-1 (GLP-1) cleavage. Several reports have shown that gliptins mediate positive pleiotropic effects in animal models of Alzheimer’s disease (AD) [3,4,5,6,7] and in diabetic patients with AD [8] Translation of these positive functional results to diabetic (and non-diabetic) individuals affected by stroke remains to be demonstrated since large clinical studies have not yet evaluated the potential of gliptins in improving functional stroke outcomes [9]. These studies assessed gliptins’ efficacy to prevent cardiovascular events (including stroke) and to decrease mortality in people with diabetes with basically neutral results [2, 10, 11]
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