sphingosine-kinase and Cerebral-Hemorrhage

The pathogenic processes of brain injury after intracerebral hemorrhage (ICH) have not yet been fully elucidated. Increasing evidence suggests that ferroptosis activation aggravates injury after ICH, but the underlying mechanism remains unclear. Sphingosine kinase 1 (Sphk1) is a key enzyme in the regulation of sphingosine metabolism involved in the ferroptosis pathway, but its role in ICH needs clarification. In this study, transcriptional changes in ICH patients were assessed by microarray data, exposing Sphk1 as a highly upregulated gene during ICH. Furthermore, Sphk1 chemical inhibitors and siRNA were used to inhibit ICH-induced Sphk1 upregulation in in vivo and in vitro models, showing that Sphk1 inhibition after protects against ferroptosis and attenuates secondary brain injury and cell death. Mechanistically, this study unveiled that sphingosine kinase 1/sphingosine 1-phosphate/extracellular-regulated protein kinases/phosphorylated extracellular-regulated protein kinases (Sphk1/S1p/ERK/p-ERK) pathway is responsible for regulation of ferroptosis leading to secondary brain injury and cell death following ICH. Collectively, this study demonstrates that ferroptosis is closely associated with ICH, and that Sphk1 has a critical role in this lethal process. These results suggest a novel unique and effective therapeutic approach for ICH prevention and treatment.

Topics: Brain Injuries; Cerebral Hemorrhage; Ferroptosis; Humans; Phosphotransferases (Alcohol Group Acceptor); Sphingosine

The present study aimed to investigate the gene functions and expression profiles in perihematomal (PH) brain regions following spontaneous intracerebral hemorrhage. The gene expression profiles were downloaded from the Gene Expression Omnibus database under accession number GSE24265, which includes 11 brain samples from different regions, including four samples from PH areas, four from contralateral grey matter (CG) and three from contralateral white matter (CW). The gene expression profiles were pre-processed and the differentially expressed genes (DEGs) between PH and CG tissue, and PH and CW tissue were identified using R packages. The expression of genes in different tissues was analyzed by hierarchical clustering. Then, the interaction network between the DEGs was constructed using String software. Finally, Gene Ontology was performed and pathway analysis was conducted using FuncAssociate and Expression Analysis Systematic Explorer to identify the gene function. As a result, 399 DEGs were obtained between PH and CG, and 756 DEGs were identified between PH and CW. There were 35 common DEGs between the two groups. These DEGs may be involved in PH edema by regulating the calcium signaling pathway [calcium channel, voltage‑dependent, T-type, α1I subunit, Ca2+/calmodulin‑dependent protein kinase II α (CAMK2A), ryanodine receptor 2 (RYR2) and inositol 1,4,5-trisphosphate receptor, type 1 (ITPR1)], cell proliferation (sphingosine kinase 1), neuron differentiation (Ephrin-A5) or extracellular matrix-receptor interaction [collagen, type I, α 2, laminin B1 (LAMB1), syndecan 2, fibronectin 1 and integrin α5 (ITGA5)]. A number of genes may cooperate to participate in the same pathway, such as ITPR1-RYR2, CAMK2A-RYR2 and ITGA5-LAMB1 interaction pairs. The present study provides several potential targets to decrease hematoma expansion and alleviate neuronal cell death following spontaneous intracerebral hemorrhage.

Topics: Aged; Aged, 80 and over; Calcium Signaling; Cerebral Hemorrhage; Cluster Analysis; Ephrin-A5; Extracellular Matrix; Female; Gene Expression Profiling; Gene Regulatory Networks; Humans; Male; Phosphotransferases (Alcohol Group Acceptor); Software