• Orhan Altay.
• Neurosurgery. 2015 Aug 1;62 Suppl 1:217.

IntroductionThere is no proven effective therapy to prevent early brain injury (EBI) after subarachnoid hemorrhage (SAH) despite extensive research efforts. Sphingosine kinase (SphK) 1 has been reported as an important signaling node in antiapoptotic signaling. Heparin is a pleiotropic drug that antagonizes many pathophysiological mechanisms. In this study, we evaluated if heparin prevents EBI after SAH by antiapoptotic mechanisms including SphK1.MethodsThis study used 135 8-week-old male CD-1 mice. We induced SAH with endovascular perforation in mice and randomly assigned animals to sham-operated (n = 23), SAH + vehicle (n = 35), SAH + 10 U heparin pretreatment (n = 11), SAH + 30 U heparin pretreatment (n = 14), SAH + 10 U heparin posttreatment (n = 30), and SAH + 30 U heparin posttreatment (n = 22). At 24 hours post-SAH, neurological scores, brain water content, and Evans blue extravasation were evaluated. Also, the expression of SphK, phosphorylated Akt, and cleaved caspase-3 was determined by Western blotting, and neuronal cell death was examined by terminal deoxynucleotidyl transferase mediated uridine 5'-triphosphate-biotin nick end-labeling staining.ResultsLow-dose heparin pre- and posttreatment significantly improved neurobehavioral function and brain edema at 24 hours after SAH. Moreover, low-dose heparin posttreatment attenuated blood-brain barrier disruption and neuronal cell death in the cortex, associated with an increase in SphK1 and phosphorylated Akt, and a decrease in cleaved caspase-3. High-dose heparin had a tendency for increased SAH, which aggravated brain injury and therefore obscured the neuroprotective effects by heparin.ConclusionLow-dose heparin posttreatment may decrease the development of post-SAH EBI through anti-apoptotic mechanisms, including sphingosine-related pathway activation, implying its efficacy for early prevention of brain injury after acute aneurysm rupture in a clinical setting.

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