title: Treatment with TO901317, a synthetic liver X receptor agonist, reduces brain damage and attenuates neuroinflammation in experimental intracerebral hemorrhage.
abstract: 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. TO901317 also reduced neuronal death, BBB disruption, and brain edema at day 4 post-ICH. These changes were associated with marked reductions in microglial activation, neutrophil infiltration, and expression levels of inflammatory mediators at 4 and 7 days. However, TO901317 had no effect on matrix metalloproteinase-9 activity. In BV2 microglial cultures, TO901317 attenuated LPS- and thrombin-stimulated nitric oxide production and reduced LPS-induced p38, JNK, MAPK, and nuclear factor-kappa B (NF-κB) signaling. Moreover, delaying administration of TO901317 to 3 h post-ICH reduced brain tissue damage and neuronal death.
  
  
  CONCLUSIONS
  Our results suggest that enhancing LXR activation may provide a potential therapy for ICH by modulating the cytotoxic functions of microglia.
authors.affiliation: Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, Republic of China.|Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: Chun-Hu
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Chien-Cheng
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, Republic of China.|Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: Chai-You
authors.initials: CY
authors.lastname: Lai
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Taipei and College of Medicine, Chang Gung University, Taipei, Taiwan, Republic of China.
authors.forename: Tai-Ho
authors.initials: TH
authors.lastname: Hung
authors.affiliation: Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Chao-Chang
authors.initials: CC
authors.lastname: Lin
authors.affiliation: School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Chao
authors.affiliation: Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, Republic of China. szufuchen@yahoo.com.tw.|Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China. szufuchen@yahoo.com.tw.
authors.forename: Szu-Fu
authors.initials: SF
authors.lastname: Chen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D001834:Body Water / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000150:complications* / Q000523:psychology; D017364:Collagenases; D005786:Gene Expression Regulation / Q000187:drug effects; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology; D000071518:Liver X Receptors / Q000819:agonists*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000893:Anti-Inflammatory Agents; D017364:Collagenases; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D018696:Neuroprotective Agents; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
keywords: Inflammation; Intracerebral hemorrhage; Liver X receptors; Microglia; Neuronal damage; TO901317