Changes in the Metabolism of Sphingolipids After Subarachnoid Hemorrhage

We previously described how ceramide (Cer), a mediator of cell death, increases in the cerebrospinal fluid (CSF) of subarachnoid hemorrhage (SAH) patients. This study investigates the alterations of biochemical pathways involved in Cer homeostasis in SAH. Cer, dihydroceramide (DHC), sphingosine-1-phosphate (S1 P), and the activities of acid sphingomyelinase (ASMase), neutral sphingornyelinase (NSMase), sphingomyelinase synthase (SMS), S1P-Iyase, and glucosylceramide synthase (GCS) were determined in the CSF of SAH subjects and in brain homogenate of SAH rats. Compared with controls (n = 8), SAH patients (n = 26) had higher ASMase activity (10.0 +/- 3.5 IF/mu l min vs. 15.0 +/- 4.6 IF/mu l . min; P= 0.009) and elevated levels of Cer (11.4 +/- 8.8 pmol/ml vs. 33.3 +/- 48.3 prinol/ml; P = 0.001) and DHC (1.3 1.1 pmol/ml vs. 3.8 +/- 3.4 pmol/ml; P = 0.001) in the CSF. The activities of GCS, NSMase, and SMS in the CSF were undetectable. Brain homogenates from SAH animals had increased ASMase activity (control: 9.7 +/- 1.2 IF/mu g . min; SAH: 16.8 +/- 1.6 IF/mu g . min; P < 0.05) and Cer levels (control: 3,422 26 fmol/nmol of total lipid P; SAH: 7,073 2,467 frinol/nrinol of total lipid P; P<0.05) compared with controls. In addition, SAH was associated with a reduction of 60% in S1P levels, a 40% increase in S1P-Iyase activity, and a twofold increase in the activity of GCS. In comparison, NSMase and SMS activities were similar to controls and SMS activities similar to controls. In conclusion, our results show an activation of ASMase, S1P-Iyase, and GCS resulting in a shift in the production of protective (S1P) in favor of deleterious (Cer) sphingolipids after SAH. Additional studies are needed to determine the effect of modulators of the pathways described here in SAH. rg (C) 2015 Wiley Periodicals, Inc.