PMID- 34675988
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220427
IS  - 1741-427X (Print)
IS  - 1741-4288 (Electronic)
IS  - 1741-427X (Linking)
VI  - 2021
DP  - 2021
TI  - Inhibition of the Immunoproteasome Subunit LMP7 Ameliorates Cerebral White Matter 
      Demyelination Possibly via TGFbeta/Smad Signaling.
PG  - 6426225
LID - 10.1155/2021/6426225 [doi]
LID - 6426225
AB  - OBJECTIVES: Chronic cerebral hypoperfusion induces white matter ischemic injury 
      and cognitive impairment, whereas the mechanism remains unclear. 
      Immunoproteasomes have been implicated in the pathogenesis of acute ischemia 
      stroke and multiple sclerosis. However, the expression and role of 
      immunoproteasomes in the brain of chronic cerebral hypoperfusion remain to be 
      clarified. METHODS: Chronic white matter ischemic injury mice models were induced 
      by bilateral carotid artery stenosis (BCAS). A selective immunoproteasome subunit 
      low-molecular-mass peptide-7 (LMP7) inhibitor PR957 was administered to mice. 
      Cognitive function, white matter integrity, and potential pathways were assessed 
      after BCAS. RESULTS: The present study found that chronic cerebral hypoperfusion 
      following BCAS induced cerebral white matter demyelination and cognitive 
      impairment, accompanied with elevated expression of the immunoproteasomes LMP2 
      and LMP7, activation of astrocytes and microglia, and increased production of 
      inflammatory cytokines (e.g., interleukin-1beta (IL-1beta), tumor necrosis factor-alpha 
      (TNF-alpha), IL-10, transforming growth factor-beta1 (TGFbeta1), and insulin-like growth 
      factor-1 (IGF-1)). However, inhibition of LMP7 with the specific proteasome 
      inhibitor PR957 significantly mitigated the histological damage of the white 
      matter, suppressed inflammatory response, and paralleled by an improvement of 
      cognitive function. Furthermore, treatment of PR957 significantly upregulated the 
      level of TGFbeta1, the total expression level, and the phosphorylation level of 
      Smad2/3 and promoted brain remyelination. Surprisingly, PR957 alone had no 
      effects on the neuroinflammation response and the activation of TGFbeta/Smad 
      signaling in the sham-operated (BCAS-nonoperated) mice. CONCLUSIONS: The possible 
      mechanism underlying this was attributed to that the immunoproteasome regulates 
      TGFbeta/Smad signaling-mediated neuroinflammation and oligodendrocyte remyelination.
CI  - Copyright (c) 2021 Xingyong Chen et al.
FAU - Chen, Xingyong
AU  - Chen X
AUID- ORCID: 0000-0001-7364-5414
AD  - Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical 
      College of Fujian Medical University, Fuzhou 350001, China.
FAU - Yao, Nannan
AU  - Yao N
AUID- ORCID: 0000-0001-6169-7233
AD  - Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical 
      College of Fujian Medical University, Fuzhou 350001, China.
FAU - Lin, Zejing
AU  - Lin Z
AUID- ORCID: 0000-0002-8870-7072
AD  - Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical 
      College of Fujian Medical University, Fuzhou 350001, China.
FAU - Wang, Yinzhou
AU  - Wang Y
AUID- ORCID: 0000-0002-9595-2244
AD  - Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical 
      College of Fujian Medical University, Fuzhou 350001, China.
AD  - Fujian Academy of Medical Science, Fuzhou 350001, China.
LA  - eng
PT  - Journal Article
DEP - 20211012
PL  - United States
TA  - Evid Based Complement Alternat Med
JT  - Evidence-based complementary and alternative medicine : eCAM
JID - 101215021
PMC - PMC8526201
COIS- The authors declare no conflicts of interest.
EDAT- 2021/10/23 06:00
MHDA- 2021/10/23 06:01
PMCR- 2021/10/12
CRDT- 2021/10/22 06:49
PHST- 2021/06/06 00:00 [received]
PHST- 2021/08/12 00:00 [revised]
PHST- 2021/09/13 00:00 [accepted]
PHST- 2021/10/22 06:49 [entrez]
PHST- 2021/10/23 06:00 [pubmed]
PHST- 2021/10/23 06:01 [medline]
PHST- 2021/10/12 00:00 [pmc-release]
AID - 10.1155/2021/6426225 [doi]
PST - epublish
SO  - Evid Based Complement Alternat Med. 2021 Oct 12;2021:6426225. doi: 
      10.1155/2021/6426225. eCollection 2021.