Table 1.

Mechanisms of action of heparin to prevent delayed neurological injury associated with subarachnoid hemorrhage.

Direct chelation of hemoglobin in the subarachnoid space –Heparin binds oxidized hemoglobin that is released from damaged erythrocytes. Oxyhemoglobin is believed to have a major role in the induction of vasospasm

Decreased free-radical release –Heparin is able to directly bind to specific molecules and inhibit the formation of free radicals through the inhibition of various pro-inflammatory molecules that contribute to their formation

Inhibition of endothelin-1 (ET-1) –Inhibition of mRNA transcription of ET-1 –Inhibition of transactivation of the epidermal growth factor receptor by binding of heparin to the specific ligand –Suppression of release of intracellular calcium and inositol-triphosphate in addition to ET-1 release –Inhibition of MAP-K and prevention of DNA synthesis induced by ET-1

Prevention of K+ channel down-regulation induced by oxyhemoglobin release –Downregulation of potassium channels causes a depolarization of vascular smooth muscle cells, increased incidence of calcium influxes and increased activation causing increased vasoconstriction and neurological decline

Suppression of vascular smooth cell hyperplasia –Smooth muscle and myofibroblast proliferation, associated with cell necrosis, lead to increased vasoconstriction, ischemia, and further neurological decline. Pathological proliferation of smooth muscle cells and neovascularization may prevent further progression of neurological injury

Inhibition of neuroinflammatory pathways –Inhibition of the NF-kB pathway –Binding of chemokines, cytokines, and other inflammatory proteins