Activation of sphingosine kinase 2 is an endogenous protective mechanism in cerebral ischemia

Pfeilschifter, Waltraud; Czech-Zechmeister, Bo?ena; Sujak, Marian; Mirceska, Ana; Koch, Alexander; Rami, Abdelhaq; Steinmetz, Helmuth; Foerch, Christian; Huwiler, Andrea; Pfeilschifter, Josef (2011). Activation of sphingosine kinase 2 is an endogenous protective mechanism in cerebral ischemia. Biochemical and biophysical research communications, 413(2), pp. 212-7. Orlando, Fla.: Academic Press 10.1016/j.bbrc.2011.08.070

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The two ubiquitously expressed sphingosine kinases (SphK) 1 and 2 are key regulators of the sphingolipid signaling pathway. Despite the formation of an identical messenger, i.e. sphingosine 1-phosphate (S1P), they exert strikingly different functions. Particularly, SphK2 is necessary for the phosphorylation of the sphingosine analog fingolimod (FTY720), which is protective in rodent stroke models. Using gene deficient mice lacking either SphK1 or SphK2, we investigated the role of the two lipid kinases in experimental stroke. We performed 2h transient middle cerebral artery occlusion (tMCAO) and analyzed lesion size and neurological function after 24h. Treatment groups received 1mg/kg FTY720. Neutrophil infiltration, microglia activation, mRNA and protein expression of SphK1, SphK2 and the S1P(1) receptor after tMCAO were studied. Genetic deletion of SphK2 but not SphK1 increased ischemic lesion size and worsened neurological function after tMCAO. The protective effect of FTY720 was conserved in SphK1(-/-) mice but not in SphK2(-/-) mice. This suggests that SphK2 activity is an important endogenous protective mechanism in cerebral ischemia and corroborates that the protective effect of FTY720 is mediated via phospho-FTY720.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Huwiler, Andrea

ISSN:

0006-291X

Publisher:

Academic Press

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:18

Last Modified:

17 Mar 2015 19:23

Publisher DOI:

10.1016/j.bbrc.2011.08.070

PubMed ID:

21872577

Web of Science ID:

000295443400011

URI:

https://boris.unibe.ch/id/eprint/5457 (FactScience: 210204)

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