PMID- 34406990
OWN - NLM
STAT- MEDLINE
DCOM- 20220131
LR  - 20230929
IS  - 1473-558X (Electronic)
IS  - 0959-4965 (Print)
IS  - 0959-4965 (Linking)
VI  - 32
IP  - 14
DP  - 2021 Oct 6
TI  - Inhibition of immunoproteasome subunit low molecular mass polypeptide 7 with 
      ONX-0914 improves hypoxic-ischemic brain damage via PI3K/Akt signaling.
PG  - 1206-1215
LID - 10.1097/WNR.0000000000001715 [doi]
AB  - The immunoproteasome subunit low molecular mass polypeptide 7 (LMP7) leads to 
      brain injuries, such as autoimmune neuritis and ischemic stroke, by activating 
      inflammation. However, the roles and mechanisms of LMP7 in hypoxic-ischemic brain 
      damage (HIBD) remain unclear. This study explored these issues in a rat model of 
      HIBD. Pathology was evaluated using hematoxylin-eosin staining. LMP7 expression 
      was detected using western blot analysis, reverse transcription-quantitative PCR 
      (RT-qPCR), and immunohistochemical staining. The presence of proinflammatory 
      cytokines, including tumor necrosis factor-a, interleukin-6, and interleukin-1beta, 
      was tested using ELISA and RT-qPCR. Behavioral performance was evaluated using a 
      short-term neurological function score and the Morris water maze test. Compared 
      to those in the Sham group, the HIBD group exhibited obvious upregulated LMP7 and 
      pro-inflammatory cytokine levels. HIBD rats exhibited severe pathological and 
      behavioral damage. LMP7 inhibition with ONX-0914 reduced proinflammatory cytokine 
      expression, attenuated pathological damage, and enhanced behavioral performance 
      of rats with HIBD. Inhibition of phosphatidylinositol 3-kinase/protein kinase B 
      (PI3K/Akt) signaling with LY29400 increased LMP7 expression and abolished the 
      protective effects of ONX-0914 in HIBD rats. Our findings indicate that LMP7 
      aggravates brain injury by triggering inflammatory responses in HIBD rats. LMP7 
      inhibition with ONX-0914 exerts protective effects on HIBD rats, possibly via 
      PI3K/Akt signaling.
CI  - Copyright (c) 2020 The Author(s). Published by Wolters Kluwer Health, Inc.
FAU - Zhou, Yue
AU  - Zhou Y
AD  - Department of Pediatrics, Clinical Medical College and The First Affiliated 
      Hospital of Chengdu Medical College, Chengdu, Sichuan, China.
FAU - Gou, Zhixian
AU  - Gou Z
FAU - Huang, Lin
AU  - Huang L
FAU - Fan, Yang
AU  - Fan Y
FAU - Zhang, Feng
AU  - Zhang F
FAU - Lu, Liqun
AU  - Lu L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Neuroreport
JT  - Neuroreport
JID - 9100935
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Oligopeptides)
RN  - 0 (PR-957)
RN  - 0 (Proteasome Inhibitors)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.4.25.1 (LMP7 protein)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Animals
MH  - Female
MH  - Hypoxia-Ischemia, Brain/metabolism/*pathology
MH  - Male
MH  - Neuroprotective Agents/pharmacology
MH  - Oligopeptides/*pharmacology
MH  - Phosphatidylinositol 3-Kinases/drug effects/metabolism
MH  - Proteasome Endopeptidase Complex/*metabolism
MH  - Proteasome Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins c-akt/drug effects/metabolism
MH  - Random Allocation
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/*drug effects
PMC - PMC8389355
COIS- There are no conflicts of interest.
EDAT- 2021/08/19 06:00
MHDA- 2022/02/01 06:00
PMCR- 2021/08/26
CRDT- 2021/08/18 17:19
PHST- 2021/08/19 06:00 [pubmed]
PHST- 2022/02/01 06:00 [medline]
PHST- 2021/08/18 17:19 [entrez]
PHST- 2021/08/26 00:00 [pmc-release]
AID - 00001756-202110010-00007 [pii]
AID - 10.1097/WNR.0000000000001715 [doi]
PST - ppublish
SO  - Neuroreport. 2021 Oct 6;32(14):1206-1215. doi: 10.1097/WNR.0000000000001715.