title: Multifaceted effects of rapamycin on functional recovery after spinal cord injury in rats through autophagy promotion, anti-inflammation, and neuroprotection.
abstract: BACKGROUND
  Spinal cord injuries (SCIs) are serious and debilitating health problems that lead to severe and permanent neurological deficits resulting from the primary mechanical impact followed by secondary tissue injury. During the acute stage after an SCI, the expression of autophagy and inflammatory responses contribute to the development of secondary injury. In the present study, we examined the multifaceted effects of rapamycin on outcomes of rats after an SCI.
  
  
  METHODS
  We used 72 female Sprague-Dawley rats for this study. In the SCI group, we performed a laminectomy at T10, followed by impact-contusion of the spinal cord. In the control group, we performed only a laminectomy without contusion. We evaluated the effects of rapamycin using the Basso, Beattie, and Bresnahan scale for functional outcomes, Western blot analyses for analyzing LC3-II, tumor necrosis factor expression, and p70S6K phosphorylation, and an immunostaining technique for localization and enumeration of microglial and neuronal cells.
  
  
  RESULTS
  Basso, Beattie, and Bresnahan scores after injury significantly improved in the rapamycin-treated group compared with the vehicle group (on Day 28 after the SCI; P < .05). The Western blot analysis demonstrated that rapamycin enhanced LC3-II expression and decreased p70S6K phosphorylation compared with the vehicle (P < .01), which implies promotion of autophagy through mammalian target of rapamycin inhibition. Furthermore, rapamycin treatment significantly attenuated tumor necrosis factor production and microglial expression (P < .05). Immunohistochemistry of NeuN (antibodies specific to neurons) showed remarkable neuronal cell preservation in the rapamycin-treated group compared with the vehicle-treated group (P < .05), which suggests a neuroprotective effect of rapamycin.
  
  
  CONCLUSIONS
  Rapamycin is a novel neuroprotectant with multifaceted effects on the rat spinal cord after injury. Use of such a clinically established drug could facilitate early clinical trials in selected cases of human SCIs.
authors.affiliation: Department of Neurosurgery, Chang Gung Memorial Hospital at Keelung, Taiwan.
authors.forename: Hsien-Chih
authors.initials: HC
authors.lastname: Chen
authors.forename: Tsorng-Harn
authors.initials: TH
authors.lastname: Fong
authors.forename: Peng-Wei
authors.initials: PW
authors.lastname: Hsu
authors.forename: Wen-Ta
authors.initials: WT
authors.lastname: Chiu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D005260:Female; D007796:Laminectomy; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D023421:Models, Animal; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology*; D013119:Spinal Cord Injuries / Q000150:complications / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D018696:Neuroprotective Agents; D020123:Sirolimus