Fingolimod Does Not Reduce Infarction After Focal Cerebral Ischemia in Mice During Active or Inactive Circadian Phases

Autor: Emiri T. Mandeville, Wenlu Li, David Quinto-Alemany, Fang Zhang, Elga Esposito, Takafumi Nakano, Joseph B. Mandeville, Janice Lee, Ji Hyun Park, Ken Arai, Christian Waeber, Ignacio Lizasoain, María Ángeles Moro, Eng H. Lo
Rok vydání: 2022
Předmět:
Zdroj: Stroke. 53:3741-3750
ISSN: 1524-4628
0039-2499
Popis: Background: It has been reported that the S1P (sphingosine 1-phosphate) receptor modulator fingolimod reduces infarction in rodent models of stroke. Recent studies have suggested that circadian rhythms affect stroke and neuroprotection. Therefore, this study revisited the use of fingolimod in mouse focal cerebral ischemia to test the hypothesis that efficacy might depend on whether experiments were performed during the inactive sleep or active wake phases of the circadian cycle. Methods: Two different stroke models were implemented in male C57Bl/6 mice—transient middle cerebral artery occlusion and permanent distal middle cerebral artery occlusion. Occlusion occurred either during inactive or active circadian phases. Mice were treated with 1 mg/kg fingolimod at 30- or 60-minute postocclusion and 1 day later for permanent and transient middle cerebral artery occlusion, respectively. Infarct volume, brain swelling, hemorrhagic transformation, and behavioral outcome were assessed at 2 or 3 days poststroke. Three independent experiments were performed in 2 different laboratories. Results: Fingolimod decreased peripheral lymphocyte number in naive mice, as expected. However, it did not significantly affect infarct volume, brain swelling, hemorrhagic transformation, or behavioral outcome at 2 or 3 days after transient or permanent focal cerebral ischemia during inactive or active circadian phases of stroke onset. Conclusions: Outcomes were not improved by fingolimod in either transient or permanent focal cerebral ischemia during both active and inactive circadian phases. These negative findings suggest that further testing of fingolimod in clinical trials may not be warranted unless translational studies can identify factors associated with fingolimod’s efficacy or lack thereof.
Databáze: OpenAIRE
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