Oral administration of a novel lipophilic PPARδ agonist is not neuroprotective after rodent cerebral ischemia

Peroxisome proliferator-activated receptors are regulators of inflammatory signaling. This has fostered hope that PPAR agonists might have neuroprotective potential. We hypothesized that PPARδ activation by the novel orally administered lipophilic PPARδ agonist SAR145 may improve short- and long-ter...

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Bibliographic Details
Published in:Journal of cerebral blood flow and metabolism 2018-01, Vol.38 (1), p.174-185
Main Authors: Knauss, Samuel, Endres, Matthias, Blaschke, Florian, Hindinger, Claudia, Kunz, Alexander
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Brain Ischemia - pathology
Disease Models, Animal
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Negative Results
Neuroprotective Agents - pharmacology
PPAR delta - agonists
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Summary:Peroxisome proliferator-activated receptors are regulators of inflammatory signaling. This has fostered hope that PPAR agonists might have neuroprotective potential. We hypothesized that PPARδ activation by the novel orally administered lipophilic PPARδ agonist SAR145 may improve short- and long-term outcome after focal brain ischemia. We induced ischemia by transient filamentous middle cerebral artery occlusion (MCAo) in 227 C57BL/6 mice and administered SAR145 in varying doses and time windows post-injury. Outcome was assessed by three functional tests and histologically determining ischemic lesion sizes. In a second experiment, we tested SAR145 treatment in 40 PPARδ-knockout mice using the same procedures. Three independent groups treated with 10 mg/kg bodyweight SAR145 directly after filament removal showed a mean reduction in lesion sizes of 18 ± 10% compared to vehicle-treated groups. We did not observe a consistent improvement in the long-term functional outcome by SAR145-treatment. PPARδ-knockout mice showed a significantly higher mortality after MCAo. As expected, we did not find a reduction of lesion size by SAR145-treatment in PPARδ-knockout mice. In summary, we found no evidence of a long-term neuroprotective effect of post-injury SAR145 treatment in cerebral ischemia. However, PPARδ appears to play a pathophysiologic role in acute infarct development and overall mortality after brain ischemia.
ISSN:0271-678X
1559-7016
DOI:10.1177/0271678X17743876