Sphingosine Kinase 2 Mediates Cerebral Preconditioning and Protects the Mouse Brain Against Ischemic Injury

Content Provider	Scilit
Author	Yung, Lai Ming Wei, Ying Qin, Tao Wang, Yumei Smith, Charles D. Waeber, Christian
Copyright Year	2012
Description	Journal: Stroke Cerebral preconditioning provides insights into endogenous mechanisms that protect the brain from ischemic injury. Hypoxia and the anesthetic isoflurane are powerful preconditioning agents. Recent data show that sphingosine 1-phosphate receptor stimulation improves outcome in rodent models of stroke. Endogenous sphingosine 1-phosphate levels are controlled by the expression and activity of sphingosine kinases (SPK). We hypothesize that SPK upregulation mediates preconditioning induced by isoflurane and hypoxia and reduces ischemic injury. Male wild-type C57BL/J, SPK1$ ^{−/−}$ and SPK2$ ^{−/−}$ mice were exposed to isoflurane or hypoxia preconditioning before transient middle cerebral artery occlusion. Infarct volume and neurological outcome were measured 24 hours later. SPK inhibitors (SKI-II and ABC294640) were used to test the involvement of SPK2. Expressions of SPK1, SPK2, and hypoxia-inducible factor 1α were determined. Primary cultures of mouse cortical neurons were exposed to isoflurane before glutamate- or hydrogen peroxide-induced cell death. Isoflurane preconditioning and hypoxia preconditioning significantly reduced infarct volume and improved neurological outcome in wild-type and SPK1$ ^{−/−}$ mice but not in SPK2$ ^{−/−}$ mice. Pretreatment with SKI-II or ABC294640 abolished the isoflurane preconditioning-induced tolerance. Western blot showed a rapid and sustained increase in SPK2 level, whereas SPK1 level was similar between preconditioned mice and controls. Hypoxia-inducible factor 1α was upregulated in wild-type isoflurane-preconditioned mice but not in SPK2$ ^{−/−}$ . Isoflurane preconditioning protected primary neurons against cell death, which was abolished in ABC294640-treated cells. Applying genetic and pharmacological approaches, we demonstrate that neuronal SPK2 isoform plays an important role in cerebral preconditioning.
Related Links	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246529/pdf https://www.ahajournals.org/doi/pdf/10.1161/STROKEAHA.111.626911
Ending Page	204
Page Count	6
Starting Page	199
ISSN	00392499
e-ISSN	15244628
DOI	10.1161/strokeaha.111.626911
Journal	Stroke
Issue Number	1
Volume Number	43
Language	English
Publisher	Ovid Technologies (Wolters Kluwer Health)
Publisher Date	2012-01-01
Access Restriction	Open
Subject Keyword	Sphingosine Kinase 2 Cerebral Ischemia
Content Type	Text
Resource Type	Article
Subject	Cardiology and Cardiovascular Medicine Neuroscience Advanced and Specialized Nursing Neurology (clinical)