title: Systemic administration of urocortin after intracerebral hemorrhage reduces neurological deficits and neuroinflammation in rats.
abstract: BACKGROUND
  Intracerebral hemorrhage (ICH) remains a serious clinical problem lacking effective treatment. Urocortin (UCN), a novel anti-inflammatory neuropeptide, protects injured cardiomyocytes and dopaminergic neurons. Our preliminary studies indicate UCN alleviates ICH-induced brain injury when administered intracerebroventricularly (ICV). The present study examines the therapeutic effect of UCN on ICH-induced neurological deficits and neuroinflammation when administered by the more convenient intraperitoneal (i.p.) route.
  
  
  METHODS
  ICH was induced in male Sprague-Dawley rats by intrastriatal infusion of bacterial collagenase VII-S or autologous blood. UCN (2.5 or 25 μg/kg) was administered i.p. at 60 minutes post-ICH. Penetration of i.p. administered fluorescently labeled UCN into the striatum was examined by fluorescence microscopy. Neurological deficits were evaluated by modified neurological severity score (mNSS). Brain edema was assessed using the dry/wet method. Blood-brain barrier (BBB) disruption was assessed using the Evans blue assay. Hemorrhagic volume and lesion volume were assessed by Drabkin's method and morphometric assay, respectively. Pro-inflammatory cytokine (TNF-α, IL-1β, and IL-6) expression was evaluated by enzyme-linked immunosorbent assay (ELISA). Microglial activation and neuronal loss were evaluated by immunohistochemistry.
  
  
  RESULTS
  Administration of UCN reduced neurological deficits from 1 to 7 days post-ICH. Surprisingly, although a higher dose (25 μg/kg, i.p.) also reduced the functional deficits associated with ICH, it is significantly less effective than the lower dose (2.5 μg/kg, i.p.). Beneficial results with the low dose of UCN included a reduction in neurological deficits from 1 to 7 days post-ICH, as well as a reduction in brain edema, BBB disruption, lesion volume, microglial activation and neuronal loss 3 days post-ICH, and suppression of TNF-α, IL-1β, and IL-6 production 1, 3 and 7 days post-ICH.
  
  
  CONCLUSIONS
  Systemic post-ICH treatment with UCN reduces striatal injury and neurological deficits, likely via suppression of microglial activation and inflammatory cytokine production. The low dose of UCN necessary and the clinically amenable peripheral route make UCN a potential candidate for development into a clinical treatment regimen.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Hock-Kean
authors.initials: HK
authors.lastname: Liew
authors.forename: Cheng-Yoong
authors.initials: CY
authors.lastname: Pang
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Hsu
authors.forename: Mei-Jen
authors.initials: MJ
authors.lastname: Wang
authors.forename: Ting-Yi
authors.initials: TY
authors.lastname: Li
authors.forename: Hsiao-Fen
authors.initials: HF
authors.lastname: Peng
authors.forename: Jon-Son
authors.initials: JS
authors.lastname: Kuo
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Wang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D018916:Blood-Aqueous Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D039481:CD11b Antigen / Q000378:metabolism; D002452:Cell Count; D002543:Cerebral Hemorrhage / Q000145:classification / Q000150:complications* / Q000209:etiology / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D053331:Ectodysplasins / Q000378:metabolism; D004660:Encephalitis / Q000209:etiology*; D007276:Injections, Intraventricular; D017078:Laser-Doppler Flowmetry; D008297:Male; D009422:Nervous System Diseases / Q000209:etiology*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013997:Time Factors; D054832:Urocortins / Q000008:administration & dosage*
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; D053331:Ectodysplasins; D018696:Neuroprotective Agents; D054832:Urocortins; D010751:Phosphopyruvate Hydratase