title: Ethyl pyruvate protects against blood-brain barrier damage and improves long-term neurological outcomes in a rat model of traumatic brain injury.
abstract: OBJECTIVE
  Many traumatic brain injury (TBI) survivors sustain neurological disability and cognitive impairments due to the lack of defined therapies to reduce TBI-induced long-term brain damage. Ethyl pyruvate (EP) has shown neuroprotection in several models of acute brain injury. The present study therefore investigated the potential beneficial effect of EP on long-term outcomes after TBI and the underlying mechanisms.
  
  
  METHODS
  Male adult rats were subjected to unilateral controlled cortical impact injury. EP was injected intraperitoneally 15 min after TBI and again at 12, 24, 36, 48, and 60 h after TBI. Neurological deficits, blood-brain barrier (BBB) integrity, and neuroinflammation were assessed.
  
  
  RESULTS
  Ethyl pyruvate improved sensorimotor and cognitive functions and ameliorated brain tissue damage up to 28 day post-TBI. BBB breach and brain edema were attenuated by EP at 48 h after TBI. EP suppressed matrix metalloproteinase (MMP)-9 production from peripheral neutrophils and reduced the number of MMP-9-overproducing neutrophils in the spleen, and therefore mitigated MMP-9-mediated BBB breakdown. Moreover, EP exerted potent antiinflammatory effects in cultured microglia and inhibited the elevation of inflammatory mediators in the brain after TBI.
  
  
  CONCLUSIONS
  Ethyl pyruvate confers long-term neuroprotection against TBI, possibly through breaking the vicious cycle among MMP-9-mediated BBB disruption, neuroinflammation, and long-lasting brain damage.
authors.affiliation: Department of Anesthesiology of Huashan Hospital, State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China; Department of Anesthesiology of Shanghai Pulmonary Hospital, Tongji University, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Shi
authors.forename: Hai-Lian
authors.initials: HL
authors.lastname: Wang
authors.forename: Hong-Jian
authors.initials: HJ
authors.lastname: Pu
authors.forename: Ye-Jie
authors.initials: YJ
authors.lastname: Shi
authors.forename: Jia
authors.initials: J
authors.lastname: Zhang
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Zhang
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Wang
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Hu
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Yan-Qin
authors.initials: YQ
authors.lastname: Gao
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D011773:Pyruvates / Q000494:pharmacology*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D011773:Pyruvates; C046522:ethyl pyruvate; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: Blood-brain barrier; Ethyl pyruvate; Inflammation; Neuroprotection; Traumatic brain injury