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Dual PPARα/γ agonist aleglitazar confers stroke protection in a model of mild focal brain ischemia in mice.

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journal contribution
posted on 14.06.2019, 15:05 by V Boujon, R Uhlemann, S Wegner, MB Wright, U Laufs, M Endres, G Kronenberg, K Gertz
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.

Funding

This work was supported by the Deutsche Forschungsgemeinschaft (Exc257 to M.E.; KR 2956/4-1 to G.K.; GE 2576/2-1 to K.G.), the Bundesministerium für Bildung und Forschung (CSB to M.E., K.G. and G.K.), the German Center for Neurodegenerative Diseases (DZNE to M.E.), the German Center for Cardiovascular Research (DZHK to M.E.), the Corona Foundation (to M.E. and U.L.), and by a research grant from Roche (to M.E. and K.G.). Aleglitazar (PubChem CID: 10274777) was provided by Roche (Basel, Switzerland).

History

Citation

Journal of Molecular Medicine, 2019

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences

Version

VoR (Version of Record)

Published in

Journal of Molecular Medicine

Publisher

Springer Verlag (Germany)

eissn

1432-1440

Acceptance date

21/05/2019

Copyright date

2019

Available date

14/06/2019

Publisher version

https://link.springer.com/article/10.1007/s00109-019-01801-0

Language

en

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