Role of the S1P pathway and inhibition by fingolimod in preventing hemorrhagic transformation after stroke.
Angélica Salas-PerdomoFrancesc Miró-MurMattia GallizioliVanessa H BraitCarles JusticiaAnja MeissnerXabier UrraAngel ChamorroAnna M PlanasPublished in: Scientific reports (2019)
Hemorrhagic transformation (HT) is a complication of severe ischemic stroke after revascularization. Patients with low platelet counts do not receive reperfusion therapies due to high risk of HT. The immunomodulatory drug fingolimod attenuated HT after tissue plasminogen activator in a thromboembolic stroke model, but the underlying mechanism is unknown. Fingolimod acts on several sphingosine-1-phosphate (S1P) receptors, prevents lymphocyte trafficking to inflamed tissues, and affects brain and vascular cells. This study aimed to investigate changes in S1P-signaling in response to brain ischemia/reperfusion and the effects of the S1P receptor modulator fingolimod on HT. We studied brain expression of S1P signaling components, S1P concentration, and immune cell infiltration after ischemia/reperfusion in mice. We administered fingolimod after ischemia to wild-type mice, lymphocyte-deficient Rag2-/- mice, and mice with low platelet counts. Ischemia increased S1P-generating enzyme SphK1 mRNA, S1P concentration, and S1P receptor-1 (S1P1)+ T-cells in the brain. Fingolimod prevented lymphocyte infiltration, and attenuated the severity of HT in Rag2-/- mice but it was ineffective under thrombocytopenia. Fingolimod prevented β-catenin degradation but not Evans blue extravasation. Ischemia/reperfusion upregulates brain S1P signaling pathway, and fingolimod exerts local effects that attenuate HT. Although fingolimod seems to act on the brain tissue, it did not prevent blood-brain barrier leakage.
Keyphrases
- multiple sclerosis
- white matter
- cerebral ischemia
- wild type
- blood brain barrier
- resting state
- high fat diet induced
- functional connectivity
- signaling pathway
- atrial fibrillation
- peripheral blood
- type diabetes
- epithelial mesenchymal transition
- cell proliferation
- gene expression
- metabolic syndrome
- coronary artery disease
- brain injury
- subarachnoid hemorrhage
- pi k akt
- percutaneous coronary intervention
- skeletal muscle
- heart failure
- mouse model
- drug induced