Targeting the sphingolipid signaling pathway in stroke.

Stroke welcomes Letters to the Editor and will publish them, if suitable, as space permits. They should not exceed 750 words (including references) and may be subject to editing or abridgment. Please submit letters in duplicate, typed double-spaced. Include a fax number for the corresponding author and a completed copyright transfer agreement form (available online at To the Editor: We congratulate Hasegawa et al 1 for their innovative and thoroughly conducted study on the neuroprotective effect of the immunomodulatory sphingosine 1-phosphate (S1P) analog FTY720 (fingolimod) in a rat stroke model. Making use of a selective agonist of S1P receptor-1 (S1P 1) and an antagonist selective for the sphingosine 1–phosphate receptors S1P 1 and S1P 3 , they identified S1P 1 as the crucial receptor that mediates the reduction of lesion size and the improved outcome after treatment with FTY720. Besides the new mechanistic insight concerning the protective signaling pathway in stroke, this study corroborates the finding that the sphingolipid mediator FTY720 has a strong neuropro-tective effect in experimental stroke, which has already been shown in mice by Shichita et al 2 and our group. 3 Also, Wacker et al 4 described that cerebral ischemia induces sphingosine kinase-2, the enzyme responsible for the phosphorylation and thus activation of FTY720, which is abundantly expressed in the brain. 5 They found that inhibition of sphingosine kinase-2 could abolish the protective effect afforded by hypoxic precondition-ing, whereas pretreatment with FTY720 before middle cerebral artery occlusion could mimic hypoxic preconditioning and co-application of hypoxic preconditioning and FTY720 led to an even greater reduction of lesion size after middle cerebral artery occlusion. These data are all the more exciting because FTY720 has already been applied to patients in clinics to treat multiple sclerosis 6 and is currently tested in phase III trials. Spurred by this success, the industry has made efforts to develop more selective S1P agonists for the 5 known S1P receptors. Hasegawa et al 1 did not discuss the strong immunosuppressive effect of FTY720 and its implications in stroke. FTY720, a synthetic derivative of the fungal metabolite myriocin, is a prodrug. To become active as a structural analog of S1P, it needs to be phosphorylated almost exclusively by sphingosine kinase-2 and acts on 4 of the known 5 S1P-receptors, which are expressed in all tissues in varying ratios. Starting in the 1990s, it was first evaluated in animal models and clinical studies of organ …