title: Activation of sphingosine kinase 2 is an endogenous protective mechanism in cerebral ischemia.
abstract: 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.
authors.affiliation: Department of Neurology, University Hospital, Goethe University Frankfurt, Germany.w.pfeilschifter@med.uni-frankfurt.de
authors.forename: Waltraud
authors.initials: W
authors.lastname: Pfeilschifter
authors.forename: Bożena
authors.initials: B
authors.lastname: Czech-Zechmeister
authors.forename: Marian
authors.initials: M
authors.lastname: Sujak
authors.forename: Ana
authors.initials: A
authors.lastname: Mirceska
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.forename: Abdelhaq
authors.initials: A
authors.lastname: Rami
authors.forename: Helmuth
authors.initials: H
authors.lastname: Steinmetz
authors.forename: Christian
authors.initials: C
authors.lastname: Foerch
authors.forename: Andrea
authors.initials: A
authors.lastname: Huwiler
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D004789:Enzyme Activation; D000068876:Fingolimod Hydrochloride; D017353:Gene Deletion; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis* / Q000235:genetics; D011409:Propylene Glycols / Q000008:administration & dosage; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000099157:Sphingosine Kinase
chemical_list: D000068876:Fingolimod Hydrochloride; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D013110:Sphingosine; D000099157:Sphingosine Kinase