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

Cardiovasc Diabetol. 2018 May 19;17(1):60. doi: 10.1186/s12933-018-0702-3.


Background: 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. 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.

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 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.

Results: Linagliptin 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.

Conclusions: We 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.

Keywords: CXCR4/SDF-1α; DPP-4 inhibitors; Diabetes; Gliptins; Linagliptin; MCAO; Stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects*
  • Brain / enzymology
  • Brain / pathology
  • Brain / physiopathology
  • Calcium Signaling / drug effects
  • Chemokine CXCL12 / metabolism*
  • Dipeptidyl Peptidase 4 / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Disease Models, Animal
  • Infarction, Middle Cerebral Artery / drug therapy*
  • Infarction, Middle Cerebral Artery / enzymology
  • Infarction, Middle Cerebral Artery / pathology
  • Infarction, Middle Cerebral Artery / physiopathology
  • Linagliptin / pharmacology*
  • Male
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Myelin Basic Protein / metabolism
  • Neuroprotective Agents / pharmacology*
  • Receptors, CXCR4 / metabolism*
  • Recovery of Function
  • Repressor Proteins / metabolism


  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Dipeptidyl-Peptidase IV Inhibitors
  • Mbp protein, mouse
  • Myelin Basic Protein
  • Neuroprotective Agents
  • Receptors, CXCR4
  • Repressor Proteins
  • neuroguidin protein, mouse
  • Linagliptin
  • Dipeptidyl Peptidase 4
  • Dpp4 protein, mouse