Dual PPARα/γ agonist aleglitazar confers stroke protection in a model of mild focal brain ischemia in mice
| Autor: | Golo Kronenberg, Stephanie Wegner, Matthew Blake Wright, Matthias Endres, Ria Uhlemann, Valérie Boujon, Karen Gertz, Ulrich Laufs |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
PPARγ
metabolism [PPAR alpha] prevention & control [Brain Ischemia] metabolism [Stroke] Pharmacology PPARα Brain Ischemia Brain ischemia chemistry.chemical_compound Mice 0302 clinical medicine Neuroinflammation Drug Discovery Glucose homeostasis pharmacology [Thiophenes] Oxazoles Genetics (clinical) Aleglitazar biology Microglia Stroke medicine.anatomical_structure Molecular Medicine Original Article metabolism [PPAR gamma] prevention & control [Stroke] Agonist medicine.drug_class metabolism [Brain Ischemia] Thiophenes pathology [Brain Ischemia] Proinflammatory cytokine 03 medical and health sciences medicine Animals PPAR alpha ddc:610 business.industry medicine.disease PPAR gamma Disease Models Animal agonists [PPAR alpha] chemistry biology.protein pathology [Stroke] pharmacology [Oxazoles] NeuN business agonists [PPAR gamma] 030215 immunology |
| Zdroj: | Journal of molecular medicine 97(8), 1127-1138 (2019). doi:10.1007/s00109-019-01801-0 Journal of Molecular Medicine (Berlin, Germany) |
| DOI: | 10.1007/s00109-019-01801-0 |
| Popis: | Peroxisome proliferator-activated receptors (PPARs) control the expression of genes involved in glucose homeostasis, lipid metabolism, inflammation, and cell differentiation. Here, we analyzed the effects of aleglitazar, a dual PPARα and PPARγ agonist with balanced affinity for either subtype, on subacute stroke outcome. Healthy young adult mice were subjected to transient 30 min middle cerebral artery occlusion (MCAo)/reperfusion. Daily treatment with aleglitazar was begun on the day of MCAo and continued until sacrifice. Blood glucose measurements and lipid profile did not differ between mice receiving aleglitazar and mice receiving vehicle after MCAo. Aleglitazar reduced the size of the ischemic lesion as assessed using NeuN immunohistochemistry on day 7. Sensorimotor performance on the rotarod was impaired during the first week after MCAo, an effect that was significantly attenuated by treatment with aleglitazar. Smaller lesion volume in mice treated with aleglitazar was accompanied by a decrease in mRNA transcription of IL-1β, Vcam-1, and Icam-1, suggesting that reduced proinflammatory signaling and reduced vascular inflammation in the ischemic hemisphere contribute to the beneficial effects of aleglitazar during the first week after stroke. Further experiments in primary murine microglia confirmed that aleglitazar reduces key aspects of microglia activation including NO production, release of proinflammatory cytokines, migration, and phagocytosis. In aggregate, a brief course of PPARα/γ agonist aleglitazar initiated post-event affords stroke protection and functional recovery in a model of mild brain ischemia. Our data underscores the theme of delayed injury processes such as neuroinflammation as promising therapeutic targets in stroke. Key messages PPARα/γ agonist aleglitazar improves stroke outcome after transient brain ischemia.Aleglitazar attenuates inflammatory responses in post-ischemic brain.Aleglitazar reduces microglia migration, phagocytosis, and release of cytokines.Beneficial effects of aleglitazar independent of glucose regulation.Aleglitazar provides extended window of opportunity for stroke treatment. |
| Databáze: | OpenAIRE |
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