Abstract
Exendin-4 is a glucagon-like receptor 1 agonist clinically used against type 2 diabetes that has also shown neuroprotective effects in experimental stroke models. However, while the neuroprotective efficacy of Exendin-4 has been thoroughly investigated if the pharmacological treatment starts before stroke, the therapeutic potential of the Exendin-4 if the treatment starts acutely after stroke has not been clearly determined. Further, a comparison of the neuroprotective efficacy in normal and aged diabetic mice has not been performed. Finally, the cellular mechanisms behind the efficacy of Exendin-4 have been only partially studied. The main objective of this study was to determine the neuroprotective efficacy of Exendin-4 in normal and aged type 2 diabetic mice if the treatment started after stroke in a clinically relevant setting. Furthermore we characterized the Exendin-4 effects on stroke-induced neuroinflammation. Two-month-old healthy and 14-month-old type 2 diabetic/obese mice were subjected to middle cerebral artery occlusion. 5 or 50 µg/kg Exendin-4 was administered intraperitoneally at 1.5, 3 or 4.5 hours thereafter. The treatment was continued (0.2 µg/kg/day) for 1 week. The neuroprotective efficacy was assessed by stroke volume measurement and stereological counting of NeuN-positive neurons. Neuroinflammation was determined by gene expression analysis of M1/M2 microglia subtypes and pro-inflammatory cytokines. We show neuroprotective efficacy of 50 µg/kg Exendin-4 at 1.5 and 3 hours after stroke in both young healthy and aged diabetic/obese mice. The 5 µg/kg dose was neuroprotective at 1.5 hour only. Proinflammatory markers and M1 phenotype were not impacted by Exendin-4 treatment while M2 markers were significantly up regulated. Our results support the use of Exendin-4 to reduce stroke-damage in the prehospital/early hospitalization setting irrespectively of age/diabetes. The results indicate the polarization of microglia/macrophages towards the M2 reparative phenotype as a potential mechanism of neuroprotection.
Highlights
Stroke is one of the major causes of death and adult disability
Several studies have shown that Ex-4 mediates neuroprotection in animal models of stroke. These studies have demonstrated proof-of-concept for Ex-4-mediated neuroprotection against ischemic brain damage [15,16,17,18,19]. In these studies the neuroprotective efficacy was achieved either by using strategies based on pretreatment [16,17], or by using experimental paradigms difficult to be translated to the clinical reality, e.g. intracerebral administration [15,18]
The intervention time usually falls between 0.5 and 4 hours and the speed of intervention has been positively correlated with favorable stroke outcome [27,28,29]
Summary
Stroke is one of the major causes of death and adult disability. The risk of stroke dramatically increases along aging and threequarters of all strokes occur in people over the age of 65 (reviewed in [1]). Type 2 diabetes (T2D) increases the risk of stroke 2-6-fold when compared with non-diabetic individuals. T2D doubles the risk of stroke recurrence and increases mortality (reviewed in [2]). Neuroprotective strategies aimed at decreasing brain damage after stroke have failed to be translated into the clinical setting along the past decades [3] [4,5]. Tissue plasminogen activator (tPA) is the only established pharmacological treatment that restores brain reperfusion [6]. There is a large un-met medical need for novel stroke therapies
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