Inhibition of immunoproteasome reduces infarction volume and attenuates
inflammatory reaction in a rat model of ischemic stroke
#MMPMID25633295
Chen X
; Zhang X
; Wang Y
; Lei H
; Su H
; Zeng J
; Pei Z
; Huang R
Cell Death Dis
2015[Jan]; 6
(1
): e1626
PMID25633295
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The detailed knowledge about the contribution of immunoproteasome to the
neuroinflammation in ischemic stroke is still not available. The immunoreactivity
of low molecular mass peptide 2 (LMP2) and low molecular mass peptide 7 (LMP7)
was evident in the ipsilateral ischemic cerebral cortex and striatum following
transient middle cerebral artery occlusion (MCAO). Both LMP2 and LMP7 increased
as early as 4 h after the MCAO, further increased at 24?h, peaked at 72?h and
decreased 7 days later. LMP2 and LMP7 were mainly present in astrocytes and
microglia/macrophage cells, respectively. LMP2 knockdown by shRNA (short hairpin
RNA) markedly reduced the levels of LMP2 and LMP7 protein and caused 75.5 and
78.6% decrease in the caspase-like (C-L) and chymotrypsin-like (CT-L) activities,
respectively. Compared with cont-shRNA group (39.7%, infarction volumes/total
ipsilateral hemisphere), the infarction volumes were reduced to 22.5% in
LMP2-shRNA group. Additionally, LMP2 knockdown significantly reduced activated
astrocytes and microglia, the expression nuclear factor kappa B (NF-?B) p65,
tumor necrosis factor-? (TNF-?) and interleukin-1? (IL-1?) and caused less
accumulation of ischemia-induced protein ubiquitination compared with MG132.
These findings demonstrate that inhibition of LMP2 significantly attenuates
inflammatory reaction and offers neuroprotection against focal cerebral ischemia
in rats, suggesting that selective immunoproteasome inhibitors may be a promising
strategy for stroke treatment.
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