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Exendin-4 Reduces Ischemic Brain Injury in Normal and Aged Type 2 Diabetic Mice and Promotes Microglial M2 Polarization
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- Darsalia, V. (författare)
- Karolinska Institutet
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- Hua, Sansan (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology
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- Larsson, M. (författare)
- Karolinska Institutet
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- Sjoholm, A. (författare)
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- (creator_code:org_t)
- 2014-08-07
- 2014
- Engelska.
- Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8
- Tidskriftsartikel (refereegranskat)
Abstract
Ämnesord
Stäng
- 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 Exendin4 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 mg/kg Exendin-4 was administered intraperitoneally at 1.5, 3 or 4.5 hours thereafter. The treatment was continued (0.2 mg/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 proinflammatory cytokines. We show neuroprotective efficacy of 50 mg/kg Exendin-4 at 1.5 and 3 hours after stroke in both young healthy and aged diabetic/obese mice. The 5 mu g/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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Physiology (hsv//eng)
Nyckelord
- GLUCAGON-LIKE PEPTIDE-1
- TISSUE-PLASMINOGEN ACTIVATOR
- FOCAL
- CEREBRAL-ISCHEMIA
- RECEPTOR STIMULATION
- STROKE SEVERITY
- NEUROPROTECTION
- THROMBOLYSIS
- REPERFUSION
- INFARCTION
- MECHANISM
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