Abstract: β-Sitosterol is a type of phytosterol that occurs naturally in plants. Previous studies have shown that it has anti-oxidant, anti-hyperlipidemic, anti-inflammatory, immunomodulatory, and anti-tumor effects, but it is unknown whether β-sitosterol treatment reduces the effects of ischemic stroke. Here we found that, in a mouse model of ischemic stroke induced by middle cerebral artery occlusion, β-sitosterol reduced the volume of cerebral infarction and brain edema, reduced neuronal apoptosis in brain tissue, and alleviated neurological dysfunction; moreover, β-sitosterol increased the activity of oxygen- and glucose-deprived cerebral cortex neurons and reduced apoptosis. Further investigation showed that the neuroprotective effects of β-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke. In addition, β-sitosterol showed high affinity for NPC1L1, a key transporter of cholesterol, and antagonized its activity. In conclusion, β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.

Key words: apoptosis, blood-brain barrier, β-sitosterol, cerebral ischemia/reperfusion injury, cholesterol overload, cholesterol transport, endoplasmic reticulum stress, ischemic stroke, molecular docking, NPC1L1