Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats
2012 (English)In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 122, no 9-10, 473-483 p.Article in journal (Refereed) Published
Diabetes is a strong risk factor for premature and severe stroke. The GLP-IR (glucagon-like peptide-1 receptor) agonist Ex-4 (exendin-4) is a drug for the treatment of T2D (Type 2 diabetes) that may also have neuroprotective effects. The aim of the present study was to determine the efficacy of Ex-4 against stroke in diabetes by using a diabetic animal model, a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Furthermore, we investigated inflammation and neurogenesis as potential cellular mechanisms underlying the Ex-4 efficacy. A total of seven 9-month-old Type 2 diabetic Goto-Kakizaki rats were treated peripherally for 4 weeks with Ex-4 at 0.1, 1 or 5 mu g/kg of body weight before inducing stroke by transient middle cerebral artery occlusion and for 2-4 weeks thereafter. The severity of ischaemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We also quantitatively evaluated stroke-induced inflammation, stem cell proliferation and neurogenesis. We show a profound anti-stroke efficacy of the clinical dose of Ex-4 in diabetic rats, an arrested microglia infiltration and an increase of stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4. The results show a pronounced anti-stroke, neuroprotective and anti-inflammatory effect of peripheral and chronic Ex-4 treatment in middle-aged diabetic animals in a preclinical setting that has the potential to mimic the clinical treatment. Our results should provide strong impetus to further investigate GLP-IR agonists for their neuroprotective action in diabetes, and for their possible use as anti-stroke medication in non-diabetic conditions.
Place, publisher, year, edition, pages
2012. Vol. 122, no 9-10, 473-483 p.
exendin-4 (Ex-4), Goto-Kakizaki (GK) rat, middle cerebral artery occlusion (MCAO), neurogenesis, neuroprotection
Biomedical Laboratory Science/Technology
IdentifiersURN: urn:nbn:se:su:diva-80062DOI: 10.1042/CS20110374ISI: 000303548900008OAI: oai:DiVA.org:su-80062DiVA: diva2:557269