Introduction: There 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 anti-apoptotic signaling. Heparin is a pleiotropic drug that antagonizes many pathophysiological mechanisms. In this study, we evaluated if heparin prevents EBI after SAH by anti-apoptotic mechanisms including SphK1.
Methods: This 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 + 10U heparin pretreatment (n = 11), SAH + 30U heparin pretreatment (n = 14), SAH + 10U heparin posttreatment (n = 30), and SAH + 30U 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 deoxynucleoti¬dyl transferase–mediated uridine 5’-triphosphate-biotin nick end-labeling staining.
Results: Low-dose heparin pre- and post- treatment 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.
Conclusions: Low-dose heparin posttreatment may decrease the development of post-SAH EBI through an¬ti-apoptotic mechanisms including sphingosine-related pathway activation, implying its efficacy for early prevention of brain injury after acute aneurysm rupture in a clinical setting.
Patient Care: Low-dose heparin posttreatment may decrease the development of post-SAH EBI through anti-apoptotic mechanisms including sphingosine-related pathway activation.
Learning Objectives: 1)Early prevention of brain injury after acute aneurysm rupture is important for lifesaving in a clinical setting.
2)Low-dose heparin effect mechanism may implicate with sphingosine-related pathway activation.
3)Low-dose heparin posttreatment may decrease the development of post-SAH EBI through anti-apoptotic mechanisms including sphingosine-related pathway activation