Sphingosine kinase 2 mediates cerebral preconditioning and protects the mouse brain against ischemic injury.

Abstract

BACKGROUND AND PURPOSE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

Applying genetic and pharmacological approaches, we demonstrate that neuronal SPK2 isoform plays an important role in cerebral preconditioning.

• Authors: Lai Ming Yung, Ying Wei, Tao Qin, Yumei Wang, Charles D Smith, Christian Waeber
• Journal: Stroke (Stroke) Vol. 43 Issue 1 Pg. 199-204 (Jan 2012) ISSN: 1524-4628 [Electronic] United States
• PMID: 21980199 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase

Topics

• Animals
• Brain (metabolism, pathology)
• Brain Ischemia (metabolism, pathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Ischemic Preconditioning (methods)
• Male
• Mice
• Mice, Knockout
• Neurons (metabolism, pathology)
• Phosphotransferases (Alcohol Group Acceptor) (genetics, metabolism)