HDAC3 Inhibitor RGFP966 Ameliorated Neuroinflammation in the Cuprizone-Induced Demyelinating Mouse Model and LPS-Stimulated BV2 Cells by Downregulating the P2X7R/STAT3/NF-κB65/NLRP3 Activation
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HDAC3 Inhibitor RGFP966 Ameliorated Neuroinflammation in the Cuprizone-Induced Demyelinating Mouse Model and LPS-Stimulated BV2 Cells by Downregulating the P2X7R/STAT3/NF-κB65/NLRP3 Activation. / Sun, Wei; Zhang, Ning; Liu, Bingyi; Yang, Junrong; Loers, Gabriele; Siebert, Hans-Christian; Wen, Min; Zheng, Xuexing; Wang, Zhengping; Han, Jun; Zhang, Ruiyan.
In: ACS CHEM NEUROSCI, Vol. 13, No. 17, 07.09.2022, p. 2579-2598.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - HDAC3 Inhibitor RGFP966 Ameliorated Neuroinflammation in the Cuprizone-Induced Demyelinating Mouse Model and LPS-Stimulated BV2 Cells by Downregulating the P2X7R/STAT3/NF-κB65/NLRP3 Activation
AU - Sun, Wei
AU - Zhang, Ning
AU - Liu, Bingyi
AU - Yang, Junrong
AU - Loers, Gabriele
AU - Siebert, Hans-Christian
AU - Wen, Min
AU - Zheng, Xuexing
AU - Wang, Zhengping
AU - Han, Jun
AU - Zhang, Ruiyan
PY - 2022/9/7
Y1 - 2022/9/7
N2 - Suppression of excessive microglial overactivation can prevent the progression of multiple sclerosis (MS). Histone deacetylases 3 inhibitor (HDAC3i) has been demonstrated to exert anti-inflammatory effects by suppressing microglia (M1-liked) activation. Here, we demonstrate that the RGFP966 (a selective inhibitor of HDAC3) protects white matter after cuprizone-induced demyelination, as shown by reductions in neurological behavioral deficits and increases in myelin basic protein. Moreover, in this study, we found that RGFP966 caused a significant reduction in the levels of inflammatory cytokines, including IL-1β, TNF-α, as well as iNOS, and inhibited microglial (M1-liked) activation in the experimental cuprizone model and LPS-stimulated BV2 cells. Meanwhile, RGFP966 alleviated apoptosis of LPS-induced BV2 cells in vitro. Furthermore, RGFP966 suppressed the expression of P2X7R, NLRP3, ASC, IL-18, IL-1β, and caspase-1, inhibited the ratio of phosphorylated-STAT3/STAT3 and phosphorylated NF-κB p65/NF-κB p65, as well as increased acetylated NF-κB p65 in vitro and in vivo. Furthermore, we confirmed that brilliant blue G (antagonists of P2X7R) suppressed the expression of microglial NLRP3, IL-18, IL-1β, caspase-1, NF-κB p65 (including phosphorylated NF-κB p65), and STAT3 (including phosphorylated STAT3) in vitro. These findings demonstrated that RFFP966 alleviated the inflammatory response and exerted a neuroprotective effect possibly by modulating P2X7R/STAT3/NF-κB65/NLRP3 signaling pathways. Thus, HDAD3 might be considered a promising intervention target for neurodegenerative diseases, such as MS.
AB - Suppression of excessive microglial overactivation can prevent the progression of multiple sclerosis (MS). Histone deacetylases 3 inhibitor (HDAC3i) has been demonstrated to exert anti-inflammatory effects by suppressing microglia (M1-liked) activation. Here, we demonstrate that the RGFP966 (a selective inhibitor of HDAC3) protects white matter after cuprizone-induced demyelination, as shown by reductions in neurological behavioral deficits and increases in myelin basic protein. Moreover, in this study, we found that RGFP966 caused a significant reduction in the levels of inflammatory cytokines, including IL-1β, TNF-α, as well as iNOS, and inhibited microglial (M1-liked) activation in the experimental cuprizone model and LPS-stimulated BV2 cells. Meanwhile, RGFP966 alleviated apoptosis of LPS-induced BV2 cells in vitro. Furthermore, RGFP966 suppressed the expression of P2X7R, NLRP3, ASC, IL-18, IL-1β, and caspase-1, inhibited the ratio of phosphorylated-STAT3/STAT3 and phosphorylated NF-κB p65/NF-κB p65, as well as increased acetylated NF-κB p65 in vitro and in vivo. Furthermore, we confirmed that brilliant blue G (antagonists of P2X7R) suppressed the expression of microglial NLRP3, IL-18, IL-1β, caspase-1, NF-κB p65 (including phosphorylated NF-κB p65), and STAT3 (including phosphorylated STAT3) in vitro. These findings demonstrated that RFFP966 alleviated the inflammatory response and exerted a neuroprotective effect possibly by modulating P2X7R/STAT3/NF-κB65/NLRP3 signaling pathways. Thus, HDAD3 might be considered a promising intervention target for neurodegenerative diseases, such as MS.
KW - Acrylamides
KW - Animals
KW - Caspase 1/metabolism
KW - Cuprizone/metabolism
KW - Disease Models, Animal
KW - Enzyme Inhibitors/pharmacology
KW - Histone Deacetylases/metabolism
KW - Interleukin-18/metabolism
KW - Lipopolysaccharides/toxicity
KW - Mice
KW - Microglia
KW - NF-kappa B/metabolism
KW - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
KW - Neuroinflammatory Diseases
KW - Phenylenediamines
U2 - 10.1021/acschemneuro.1c00826
DO - 10.1021/acschemneuro.1c00826
M3 - SCORING: Journal article
C2 - 35947794
VL - 13
SP - 2579
EP - 2598
JO - ACS CHEM NEUROSCI
JF - ACS CHEM NEUROSCI
SN - 1948-7193
IS - 17
ER -