Treatment with TO901317, a synthetic liver X receptor agonist, reduces brain damage and attenuates neuroinflammation in experimental intracerebral hemorrhage

作者：Chun‐Hu Wu, Chien-Cheng Chen, Chai-You Lai, Tai‐Ho Hung, Chao-Chang Lin, Min Chao, Szu‐Fu Chen · 发表于：Journal of Neuroinflammation · 年份：2016 · DOI：10.1186/s12974-016-0524-8 · 被引用次数：70 · 研究领域：Intracerebral and Subarachnoid Hemorrhage Research、Cholesterol and Lipid Metabolism、Alzheimer's disease research and treatments

BACKGROUND: Intracerebral hemorrhage (ICH) induces a series of inflammatory processes that contribute to neuronal damage and neurological deterioration. Liver X receptors (LXRs) are nuclear receptors that negatively regulate transcriptional processes involved in inflammatory responses, but their role in the pathology following ICH remains unclear. The present study investigated the neuroprotective effects and anti-inflammatory actions of TO901317, a synthetic LXR agonist, in a model of collagenase-induced ICH and in microglial cultures. METHODS: Mice subjected to collagenase-induced ICH injury were injected with either TO901317 (30 mg/kg) or vehicle 10 min after ICH and subsequently daily for 2 days. Behavioral studies, histology analysis, and assessments of hematoma volumes, brain water content, and blood-brain barrier (BBB) permeability were performed. The protein expression of LXR-α, LXR-β, ATP binding cassette transporter-1 (ABCA-1), and inflammatory molecules was analyzed. The anti-inflammatory mechanism of TO901317 was investigated in cultured microglia that were stimulated with either lipopolysaccharide (LPS) or thrombin. RESULTS: ICH induced an increase in LXR-α protein levels in the hemorrhagic hemisphere at 6 h whereas LXR-β expression remained unaffected. Both LXR-α and LXR-β were expressed in neurons and microglia in the peri-ICH region and but rarely in astrocytes. TO901317 significantly attenuated functional deficits and brain damage up to 28 days post-ICH. TO90...