| 1. |
- Augestad, IL, et al.
(författare)
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Regulation of Glycemia in the Recovery Phase After Stroke Counteracts the Detrimental Effect of Obesity-Induced Type 2 Diabetes on Neurological Recovery
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 69:9, s. 1961-1973
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Tidskriftsartikel (refereegranskat)abstract
- The interplay between obesity and type 2 diabetes (T2D) in poststroke recovery is unclear. Moreover, the impact of glucose control during the chronic phase after stroke is undetermined. We investigated whether obesity-induced T2D impairs neurological recovery after stroke by using a clinically relevant experimental design. We also investigated the potential efficacy of two clinically used T2D drugs: the dipeptidyl peptidase 4 inhibitor linagliptin and the sulfonylurea glimepiride. We induced transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (after 7 months of high-fat diet [HFD]) and age-matched controls. After stroke, we replaced HFD with standard diet for 8 weeks to mimic the poststroke clinical situation. Linagliptin or glimepiride were administered daily from 3 days after tMCAO for 8 weeks. We assessed neurological recovery weekly by upper-limb grip strength. Brain damage, neuroinflammation, stroke-induced neurogenesis, and atrophy of parvalbumin-positive (PV+) interneurons were quantified by immunohistochemistry. T2D/obesity impaired poststroke neurological recovery in association with hyperglycemia, neuroinflammation, and atrophy of PV+ interneurons. Both drugs counteracted these effects. In nondiabetic mice, only linagliptin accelerated recovery. These findings shed light on the interplay between obesity and T2D in stroke recovery. Moreover, they promote the use of rehabilitative strategies that are based on efficacious glycemia regulation, even if initiated days after stroke.
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| 2. |
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| 3. |
- Chiazza, F, et al.
(författare)
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The Stroke-Induced Increase of Somatostatin-Expressing Neurons is Inhibited by Diabetes: A Potential Mechanism at the Basis of Impaired Stroke Recovery
- 2021
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Ingår i: Cellular and molecular neurobiology. - : Springer Science and Business Media LLC. - 1573-6830 .- 0272-4340. ; 41:43, s. 591-603
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) hampers recovery after stroke, but the underling mechanisms are mostly unknown. In a recently published study (Pintana et al. in Clin Sci (Lond) 133(13):1367–1386, 2019), we showed that impaired recovery in T2D was associated with persistent atrophy of parvalbumin+ interneurons in the damaged striatum. In the current work, which is an extension of the abovementioned study, we investigated whether somatostatin (SOM)+ interneurons are also affected by T2D during the stroke recovery phase. C57Bl/6j mice were fed with high-fat diet or standard diet (SD) for 12 months and subjected to 30-min transient middle cerebral artery occlusion (tMCAO). SOM+ cell number/density in the striatum was assessed by immunohistochemistry 2 and 6 weeks after tMCAO in peri-infarct and infarct areas. This was possible by establishing a computer-based quantification method that compensates the post-stroke tissue deformation and the irregular cell distribution. SOM+ interneurons largely survived the stroke as seen at 2 weeks. Remarkably, 6 weeks after stroke, the number of SOM+ interneurons increased (vs. contralateral striatum) in SD-fed mice in both peri-infarct and infarct areas. However, this increase did not result from neurogenesis. T2D completely abolished this effect specifically in the in the infarct area. The results suggest that the up-regulation of SOM expression in the post-stroke phase could be related to neurological recovery and T2D could inhibit this process. We also present a new and precise method for cell counting in the stroke-damaged striatum that allows to reveal accurate, area-related effects of stroke on cell number.
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| 4. |
- Darsalia, V, et al.
(författare)
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CORRIGENDUM
- 2018
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Ingår i: Diabetes, obesity & metabolism. - : Wiley. - 1463-1326 .- 1462-8902. ; 20:4, s. 1086-1086
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Tidskriftsartikel (refereegranskat)
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| 5. |
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| 6. |
- Darsalia, V., et al.
(författare)
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Exendin-4 Reduces Ischemic Brain Injury in Normal and Aged Type 2 Diabetic Mice and Promotes Microglial M2 Polarization
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8
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Tidskriftsartikel (refereegranskat)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 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.
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| 9. |
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| 10. |
- Darsalia, V, et al.
(författare)
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Glucagon-like receptor 1 agonists and DPP-4 inhibitors: potential therapies for the treatment of stroke
- 2015
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; 35:5, s. 718-723
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Tidskriftsartikel (refereegranskat)abstract
- During the past decades, candidate drugs that have shown neuroprotective efficacy in the preclinical setting have failed in clinical stroke trials. As a result, no treatment for stroke based on neuroprotection is available today. The activation of the glucagon-like peptide 1 receptor (GLP-1) for reducing stroke damage is a relatively novel concept that has shown neuroprotective effects in animal models. In addition, clinical studies are currently ongoing. Herein, we review this emerging research field and discuss the next milestones to be achieved to develop a novel antistroke therapy.
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