sphingosine-1-phosphate and Ischemic-Attack--Transient

Cerebrovascular function is critical for brain health, and endogenous vascular protective pathways may provide therapeutic targets for neurological disorders. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs, and S1P. To address roles and mechanisms of engagement of endothelial cell S1P. Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P. This study provides genetic evidence to support a pivotal role for the endothelium in maintaining perfusion and microvascular patency in the ischemic penumbra that is coordinated by S1P signaling and can be harnessed for neuroprotection with blood-brain barrier-penetrating S1P

Topics: Animals; Blood-Brain Barrier; Cerebral Arteries; Cerebrovascular Circulation; Disease Models, Animal; Endothelial Cells; Female; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Ischemic Stroke; Lysophospholipids; Male; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Microcirculation; Neuroprotective Agents; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; Vascular Patency

Sphingosine-1-phosphate (S1P) is a sphingolipid molecule produced by the action of sphingosine kinases (SphK) on sphingosine. It possesses various intracellular functions through its interactions with intracellular proteins or via its action on five G-protein-coupled cell membrane receptors. Following transient global cerebral ischemia (tGCI), only the CA1 subregion of the hippocampus undergoes apoptosis. In this study, we evaluated S1P levels and S1P-processing enzyme expression in different hippocampal areas following tGCI in rats. We found that S1P was upregulated earlier in CA3 than in CA1. This was associated with upregulation of SphK1 in both regions; however, SphK2 was downregulated quickly in CA3. S1P lyase was also downregulated in CA3, but not in CA1. Spinster 2, the S1P exporter, was upregulated early in both regions, but was quickly downregulated in CA3. Together, these effects explain the variable levels of S1P in the CA1 and CA3 areas and indicate that S1P levels play a role in the preferential resistance of the CA3 subregion to tGCI-induced ischemia. FTY720 did not improve neuronal survival in the CA1 subregion, indicating that these effects were due to intracellular S1P accumulation. In conclusion, the findings suggest that intracellular S1P levels affect neuronal cell fate following tGCI.

Topics: Animals; Apoptosis; Down-Regulation; Hippocampus; Ischemic Attack, Transient; Lysophospholipids; Male; Neurons; PC12 Cells; Rats; Rats, Sprague-Dawley; Sphingosine; Up-Regulation