PMID- 28091411
OWN - NLM
STAT- MEDLINE
DCOM- 20170313
LR  - 20211022
IS  - 2542-5641 (Electronic)
IS  - 0366-6999 (Print)
IS  - 0366-6999 (Linking)
VI  - 130
IP  - 2
DP  - 2017 Jan 20
TI  - Protective Effects of Calpain Inhibition on Neurovascular Unit Injury through 
      Downregulating Nuclear Factor-kappaB-related Inflammation during Traumatic Brain 
      Injury in Mice.
PG  - 187-198
LID - 10.4103/0366-6999.198001 [doi]
AB  - 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-kappaB-related inflammation (tumor necrosis factor-alpha [TNF-alpha]: 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.
FAU - Tao, Xiao-Gang
AU  - Tao XG
AD  - Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical 
      University, Beijing 100050, China.
FAU - Shi, Jing-Hua
AU  - Shi JH
AD  - Department of Otolaryngology, Beijing Tian Tan Hospital, Capital Medical 
      University, Beijing 100050, China.
FAU - Hao, Shu-Yu
AU  - Hao SY
AD  - Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical 
      University, Beijing 100050, China.
FAU - Chen, Xue-Tao
AU  - Chen XT
AD  - Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical 
      University, Beijing 100050, China.
FAU - Liu, Bai-Yun
AU  - Liu BY
AD  - Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical 
      University, Beijing 100050; Department of Neurotrauma, Beijing Neurosurgical 
      Institute, Capital Medical University, Beijing 100050, China.
LA  - eng
PT  - Journal Article
PL  - China
TA  - Chin Med J (Engl)
JT  - Chinese medical journal
JID - 7513795
RN  - 0 (Dipeptides)
RN  - 0 (Glycoproteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (calpain inhibitors)
RN  - EC 1.11.1.7 (Peroxidase)
RN  - EC 3.4.22.- (Calpain)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - WCJ9LQ197S (calpain inhibitor III)
SB  - IM
MH  - Animals
MH  - Brain Injuries, Traumatic/*drug therapy/*metabolism
MH  - Calpain/*antagonists & inhibitors/*metabolism
MH  - Dipeptides/therapeutic use
MH  - Disease Models, Animal
MH  - Glycoproteins/therapeutic use
MH  - Inflammation/*drug therapy/*metabolism
MH  - Male
MH  - Matrix Metalloproteinase 9/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - NF-kappa B/*metabolism
MH  - Peroxidase/antagonists & inhibitors/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
PMC - PMC5282676
COIS- There are no conflicts of interest.
EDAT- 2017/01/17 06:00
MHDA- 2017/03/14 06:00
PMCR- 2017/01/20
CRDT- 2017/01/17 06:00
PHST- 2017/01/17 06:00 [entrez]
PHST- 2017/01/17 06:00 [pubmed]
PHST- 2017/03/14 06:00 [medline]
PHST- 2017/01/20 00:00 [pmc-release]
AID - ChinMedJ_2017_130_2_187_198001 [pii]
AID - CMJ-130-187 [pii]
AID - 10.4103/0366-6999.198001 [doi]
PST - ppublish
SO  - Chin Med J (Engl). 2017 Jan 20;130(2):187-198. doi: 10.4103/0366-6999.198001.