title: Protective Effects of Calpain Inhibition on Neurovascular Unit Injury through Downregulating Nuclear Factor-κB-related Inflammation during Traumatic Brain Injury in Mice.
abstract: BACKGROUND
  In addition to neurons, all components of the neurovascular unit (NVU), such as glial, endothelial, and basal membranes, are destroyed during traumatic brain injury (TBI). Previous studies have shown that excessive stimulation of calpain is crucial for cerebral injury after traumatic insult. The objective of this study was to investigate whether calpain activation participated in NVU disruption and edema formation in a mouse model of controlled cortical impact (CCI).
  
  
  METHODS
  One hundred and eight mice were divided into three groups: the sham group, the control group, and the MDL28170 group. MDL28170 (20 mg/kg), an efficient calpain inhibitor, was administered intraperitoneally at 5 min, 3 h, and 6 h after experimental CCI. We then measured neurobehavioral deficits, calpain activity, inflammatory mediator levels, blood-brain barrier (BBB) disruption, and NVU deficits using electron microscopy and histopathological analysis at 6 h and 24 h after CCI.
  
  
  RESULTS
  The MDL28170 treatment significantly reduced the extent of both cerebral contusion (MDL28170 vs. vehicle group, 16.90 ± 1.01 mm΃ and 17.20 ± 1.17 mm΃ vs. 9.30 ± 1.05 mm΃ and 9.90 ± 1.17 mm΃, both P < 0.001) and edema (MDL28170 vs. vehicle group, 80.76 ± 1.25% and 82.00 ± 1.84% vs. 82.55 ± 1.32% and 83.64 ± 1.25%, both P < 0.05), improved neurological scores (MDL28170 vs. vehicle group, 7.50 ± 0.45 and 6.33 ± 0.38 vs. 12.33 ± 0.48 and 11.67 ± 0.48, both P < 0.001), and attenuated NVU damage resulting (including tight junction (TJ), basement membrane, BBB, and neuron) from CCI at 6 h and 24 h. Moreover, MDL28170 markedly downregulated nuclear factor-κB-related inflammation (tumor necrosis factor-α [TNF-α]: MDL28170 vs. vehicle group, 1.15 ± 0.07 and 1.62 ± 0.08 vs. 1.59 ± 0.10 and 2.18 ± 0.10, both P < 0.001; inducible nitric oxide synthase: MDL28170 vs. vehicle group, 4.51 ± 0.23 vs. 6.23 ± 0.12, P < 0.001 at 24 h; intracellular adhesion molecule-1: MDL28170 vs. vehicle group, 1.45 ± 0.13 vs. 1.70 ± 0.12, P < 0.01 at 24 h) and lessened both myeloperoxidase activity (MDL28170 vs. vehicle group, 0.016 ± 0.001 and 0.016 ± 0.001 vs. 0.024 ± 0.001 and 0.023 ± 0.001, P < 0.001 and 0.01, respectively) and matrix metalloproteinase-9 (MMP-9) levels (MDL28170 vs. vehicle group, 0.87 ± 0.13 and 1.10 ± 0.10 vs. 1.17 ± 0.13 and 1.25 ± 0.12, P < 0.001 and 0.05, respectively) at 6 h and 24 h after CCI.
  
  
  CONCLUSIONS
  These findings demonstrate that MDL28170 can protect the structure of the NVU by inhibiting the inflammatory cascade, reducing the expression of MMP-9, and supporting the integrity of TJ during acute TBI.
authors.affiliation: Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Xiao-Gang
authors.initials: XG
authors.lastname: Tao
authors.affiliation: Department of Otolaryngology, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Jing-Hua
authors.initials: JH
authors.lastname: Shi
authors.affiliation: Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Hao
authors.affiliation: Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Xue-Tao
authors.initials: XT
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050; Department of Neurotrauma, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
authors.forename: Bai-Yun
authors.initials: BY
authors.lastname: Liu
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000378:metabolism*; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004151:Dipeptides / Q000627:therapeutic use; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004151:Dipeptides; D006023:Glycoproteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C039304:calpain inhibitors; D009195:Peroxidase; D002154:Calpain; D020780:Matrix Metalloproteinase 9; C058076:calpain inhibitor III