Format

Send to

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

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

Author information

1
Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83, Stockholm, Sweden. fausto.chiazza@ki.se.
2
PXBioVision GmbH, Hannover, Germany.
3
Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83, Stockholm, Sweden.
4
Department of Drug Science and Technology, University of Turin, Torino, Italy.
5
Department of CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
6
Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83, Stockholm, Sweden. vladimer.darsalia@ki.se.
7
Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83, Stockholm, Sweden. cesare.patrone@ki.se.

Abstract

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

PMID:
29776406
PMCID:
PMC5960142
DOI:
10.1186/s12933-018-0702-3
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center