| Summary: | 碩士 === 國防醫學院 === 生理學研究所 === 99 === Intracerebral hemorrhage (ICH) is a subtype type of stroke with high rates of mortality and morbidity, however, there is still no effective medical therapy. ICH induces a complex series of inflammatory responses that contribute to delayed neuronal damage. Liver X receptors (LXRs) are ligand-dependent transcription factor of the nuclear receptors family that regulate cholesterol and lipid metabolism. LXRs have been shown to suppress inflammatory response in animal models of various neurological diseases, but little is known about their effects in ICH. In this study we aim to investigate the functional role of LXRs in the pathogenesis of ICH by using a synthetic LXRs agonist, TO901317, which has similar affinity to LXRand LXR. In a mice ICH model of bacterial collagenase (type VII-S, 0.075 U) injection into the striatum, mice were intraperitoneally injected with TO901317 (30 mg/kg) or vehicle (DMSO) daily and for 3 days. Functional outcomes were assessed using rotarod test, beam walking test and modified neurological severity score (mNSS) after ICH. Brain injury, neuronal degeneration, neutrophil infiltration and microglia activation were measured using cresyl violet, FluoroJade-B, MPO and Iba-1 histochemistry at 4 and 28 days after ICH. Brain water content and blood brain barrier (BBB) were assessed by wet-dry method and Evans blue (EB)extraction method at 4 day. Brain hemoglobin amount, matrix metalloproteinase-9 (MMP-9) activity and protein expression of LXRs, ATP-binding cassette transporter-1 (ABCA-1), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin 6 (IL-6) and macrophage inflammatory protein-2 (MIP-2) were examined at 4 day after ICH. Our results show that ICH induced a significant in LXR protein expression, peaking at 6 hours, whereas LXRremained unchanged. Multiple-doses TO901317 (30 mg) significantly improved rotarod, beam walking performance and mNSS and reduced injury volumes up to post-ICH day 28 without affecting collagenase-induced bleeding in ICH mice. TO901317-treated mice had less injury volume, less brain atrophy and reduced neuronal death at 4 days after ICH than vehicle-treated mice. TO901317 also attenuated brain edema and BBB disruption at 4 days. Both LXRandLXR protein expression remained unaffected after TO901317-treatment, but protein expression of ABCA-1, a downstream protein of LXRs increased after administration of TO901317. The protective mechanism of LXRs was associated with marked reduction in neutrophil infiltration and microglia activation, decreased protein expression of IL-6, MIP-2, COX-2 and iNOS. Our results suggest that activation of the LXRs could be a therapeutic target in ICH.
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