TY - JOUR

T1 - Neuroprotective Mechanisms of Glucagon-like Peptide-1-based Therapies in Ischaemic Stroke

T2 - A Systematic Review based on Pre-Clinical Studies

AU - Marlet, Ida R

AU - Ölmestig, Joakim N E

AU - Vilsbøll, Tina

AU - Rungby, Jørgen

AU - Kruuse, Christina

N1 - © 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

PY - 2018/6

Y1 - 2018/6

N2 - Glucagon-like peptide-1 (GLP-1)-based therapies, GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is) are widely used for the treatment of type 2 diabetes. Increasing evidence suggests that they may provide neuroprotection. The aim of this MiniReview was to systematically evaluate the proposed mechanism of action for GLP-1-based therapies in ischaemic brain damage in animals. We performed a literature search using MEDLINE, EMBASE and The Cochrane Library. GLP-1-based therapies administered before, during or after experimental stroke in diabetic and non-diabetic animals were evaluated. We reviewed 27 studies comprised of 20 involving GLP-1RAs and seven involving DPP-4Is. Both GLP-1RAs and DPP-4Is affected the acute inflammatory response secondary to ischaemia by reducing inflammation, endothelial leakage and excitotoxicity. Both treatments also reduced oxidative stress and apoptosis. GLP-1RAs significantly reduced infarct volume when administered acutely, but not later after stroke. The reported effects of DPP-4Is on infarct volume were inconsistent. GLP-1-RAs reliably improved functional outcome, but the effects on cerebral blood flow were inconclusive. These neuroprotective effects were often attributed to activation of the GLP-1 receptor, but non-GLP-1R-mediated effects have also been suggested. Both GLP-1RAs and DPP-4Is significantly affected inflammation, oxidative stress and apoptosis in animal stroke models; however, data from clinical trials only report therapeutic efficacy for GLP-1RAs. Thus, GLP-1RA administration is the most promising treatment to pursue for patients at risk of stroke or immediately after stroke. Future studies should address acute and prophylactic treatments in stroke patients with and without diabetes.

AB - Glucagon-like peptide-1 (GLP-1)-based therapies, GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is) are widely used for the treatment of type 2 diabetes. Increasing evidence suggests that they may provide neuroprotection. The aim of this MiniReview was to systematically evaluate the proposed mechanism of action for GLP-1-based therapies in ischaemic brain damage in animals. We performed a literature search using MEDLINE, EMBASE and The Cochrane Library. GLP-1-based therapies administered before, during or after experimental stroke in diabetic and non-diabetic animals were evaluated. We reviewed 27 studies comprised of 20 involving GLP-1RAs and seven involving DPP-4Is. Both GLP-1RAs and DPP-4Is affected the acute inflammatory response secondary to ischaemia by reducing inflammation, endothelial leakage and excitotoxicity. Both treatments also reduced oxidative stress and apoptosis. GLP-1RAs significantly reduced infarct volume when administered acutely, but not later after stroke. The reported effects of DPP-4Is on infarct volume were inconsistent. GLP-1-RAs reliably improved functional outcome, but the effects on cerebral blood flow were inconclusive. These neuroprotective effects were often attributed to activation of the GLP-1 receptor, but non-GLP-1R-mediated effects have also been suggested. Both GLP-1RAs and DPP-4Is significantly affected inflammation, oxidative stress and apoptosis in animal stroke models; however, data from clinical trials only report therapeutic efficacy for GLP-1RAs. Thus, GLP-1RA administration is the most promising treatment to pursue for patients at risk of stroke or immediately after stroke. Future studies should address acute and prophylactic treatments in stroke patients with and without diabetes.

U2 - 10.1111/bcpt.12974

DO - 10.1111/bcpt.12974

M3 - Review

C2 - 29411931

VL - 122

SP - 559

EP - 569

JO - Basic and Clinical Pharmacology and Toxicology

JF - Basic and Clinical Pharmacology and Toxicology

SN - 1742-7835

IS - 6

ER -