期刊
CLINICAL SCIENCE
卷 122, 期 9-10, 页码 473-483出版社
PORTLAND PRESS LTD
DOI: 10.1042/CS20110374
关键词
exendin-4 (Ex-4); Goto-Kakizaki (GK) rat; middle cerebral artery occlusion (MCAO); neurogenesis; neuroprotection
资金
- Stockholm County Council [110067]
- Diabetes Research and Wellness Foundation [0245/2010W]
- Ahlen-stiftelsen [mG8/09]
- Stroke-Riksforbundet
- European Foundation for the Study of Diabetes (EFSD)/sanofi-aventis
- Fredrik and Ingrid Thuring's Foundation
- Axel and Signe Lagermans Donation Foundation
- Loo and Hans Ostermans Foundation
- Stohnes stiftelse and the Karolinska Institutet
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.
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