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Sevoflurane Postconditioning-Induced Anti-Inflammation via Inhibition of the Toll-Like Receptor-4/Nuclear Factor Kappa B Pathway Contributes to Neuroprotection against Transient Global Cerebral Ischemia in Rats.

ABSTRACT: The anti-inflammatory actions of sevoflurane postconditioning are suggested as an important mechanism of sevoflurane postconditioning-induced neuroprotection against cerebral ischemia. Here, we determined whether the anti-inflammatory effects of sevoflurane postconditioning were mediated via inhibition of the toll-like receptor (TLR)-4/nuclear factor kappa B (NF-?B) pathway after global transient cerebral ischemia in rats. Forty-five rats were randomly assigned to five groups as follows: (1) control (10 min of ischemia, n = 10); (2) sevoflurane postconditioning (two periods of sevoflurane inhalation after ischemia for 10 min with a wash period of 10 min, n = 10); (3) resatorvid (intraperitoneal injection of a selective TLR-4 antagonist (3 mg/kg) 30 min before ischemia, n = 10); (4) sevoflurane postconditioning plus resatorvid (n = 10), and sham (n = 5). The numbers of necrotic and apoptotic cells in the hippocampal CA1 region, the expression levels of TLR-4, NF-?B, cleaved caspase-3, and tumor necrosis factor alpha (TNF-?) in the anterior part of each brain, and the serum levels of TNF-?, interleukin 6 (IL-6), and interleukin 1 beta (IL-1?) were assessed 1 day after ischemia. The necrotic cell counts and expression levels of TLR-4, NF-?B, caspase-3, and TNF-? in brain tissue as well as serum levels of pro-inflammatory cytokines (TNF-?, IL-6, and IL-1?) were significantly higher in the control group than in the other groups. Our findings suggest that the anti-inflammatory actions of sevoflurane postconditioning via inactivation of the TLR-4/NF-?B pathway and subsequent reduction in pro-inflammatory cytokine production, in part, contribute to sevoflurane postconditioning-induced neuroprotection after global transient cerebral ischemia in rats.

SUBMITTER: Hwang JW

PROVIDER: S-EPMC5713316 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Sevoflurane Postconditioning-Induced Anti-Inflammation via Inhibition of the Toll-Like Receptor-4/Nuclear Factor Kappa B Pathway Contributes to Neuroprotection against Transient Global Cerebral Ischemia in Rats.

Hwang Jung-Won JW Jeon Young-Tae YT Lim Young-Jin YJ Park Hee-Pyoung HP

International journal of molecular sciences 20171106 11

The anti-inflammatory actions of sevoflurane postconditioning are suggested as an important mechanism of sevoflurane postconditioning-induced neuroprotection against cerebral ischemia. Here, we determined whether the anti-inflammatory effects of sevoflurane postconditioning were mediated via inhibition of the toll-like receptor (TLR)-4/nuclear factor kappa B (NF-κB) pathway after global transient cerebral ischemia in rats. Forty-five rats were randomly assigned to five groups as follows: (1) con ...[more]

PMID: 29113143

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Project description:Mitophagy alleviates neuronal damage after cerebral ischemia by selectively removing dysfunctional mitochondria. Phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy is the most well-known type of mitophagy. However, little is known about the role of PINK1/Parkin-mediated mitophagy in ischemic tolerance induced by hypoxic postconditioning (HPC) with 8% O2 against transient global cerebral ischemia (tGCI). Hence, we aimed to test the hypothesis that HPC-mediated PINK1/Parkin-induced mitochondrial ubiquitination and promotes mitophagy, thus exerting neuroprotection in the hippocampal CA1 subregion against tGCI. We found that mitochondrial clearance was disturbed at the late phase of reperfusion after tGCI, which was reversed by HPC, as evidenced by the reduction of the translocase of outer mitochondrial membrane 20 homologs (TOMM20), translocase of inner mitochondrial membrane 23 (TIMM23) and heat shock protein 60 (HSP60) in CA1 after HPC. In addition, HPC further increased the ratio of LC3II/I in mitochondrial fraction and promoted the formation of mitophagosomes in CA1 neurons after tGCI. The administration of lysosome inhibitor chloroquine (CQ) intraperitoneally or mitophagy inhibitor (Mdivi-1) intracerebroventricularly abrogated HPC-induced mitochondrial turnover and neuroprotection in CA1 after tGCI. We also found that HPC activated PINK1/Parkin pathway after tGCI, as shown by the augment of mitochondrial PINK1 and Parkin and the promotion of mitochondrial ubiquitination in CA1. In addition, PINK1 or Parkin knockdown with small-interfering RNA (siRNA) suppressed the activation of PINK1/Parkin pathway and hampered mitochondrial clearance and attenuated neuroprotection induced by HPC, whereas PINK1 overexpression promoted PINK1/Parkin-mediated mitophagy and ameliorated neuronal damage in CA1 after tGCI. Taken together, the new finding in this study is that HPC-induced neuroprotection against tGCI through promoting mitophagy mediated by PINK1/Parkin-dependent pathway.

Project description:We previously reported that hypoxic postconditioning (HPC) ameliorated hippocampal neuronal death induced by transient global cerebral ischemia (tGCI) in adult rats. However, the mechanism of HPC-induced neuroprotection is still elusive. Notably, heat shock protein 27 (Hsp27) has recently emerged as a potent neuroprotectant in cerebral ischemia. Although its robust protective effect on stroke has been recognized, the mechanism of Hsp27-mediated neuroprotection is largely unknown. Here, we investigated the potential molecular mechanism by which HPC modulates the posttranslational regulations of Hsp27 after tGCI. We found that HPC increased expression of Hsp27 in CA1 subregion after tGCI. Inhibition of Hsp27 expression with lentivirus-mediated short hairpin RNA (shRNA) abolished the neuroprotection induced by HPC in vivo. Furthermore, pretreatment with cycloheximide, a protein synthesis inhibitor, resulted in a significant decrease in the degradation rate of Hsp27 protein in postconditioned rats, suggesting that the increase in the expression of Hsp27 after HPC might result from its decreased degradation. Next, pretreatment with leupeptin, a lysosomal inhibitor, resulted in an accumulation of Hsp27 after tGCI, indicating that autophagic pathway may be responsible for the degradation of Hsp27. We further showed that the formation of LC3-II and autophagosomes increased after tGCI. Meanwhile, the degradation of Hsp27 was suppressed and neuronal damage was reduced when blocking autophagy with 3-Methyladenine, whereas activating autophagy with rapamycin showed an opposite tendency. Lastly, we confirmed that HPC increased the expression of phosphorylated MAPKAP kinase 2 (MK2) and Hsp27 after tGCI. Also, administration of SB203580, a p38 mitogen-activated protein kinase inhibitor, decreased the expressions of phosphorylated MK2 and Hsp27. Our results suggested that inhibition of Hsp27 degradation mediated by down-regulation of autophagy may induce ischemic tolerance after HPC. Additionally, phosphorylation of Hsp27 induced by MK2 might be associated with the neuroprotection of HPC.

Project description:BackgroundOur previous study indicated that hypoxic preconditioning reduced receptor interacting protein (RIP) 3-mediated necroptotic neuronal death in hippocampal CA1 of adult rats after transient global cerebral ischemia (tGCI). Although mixed lineage kinase domain-like (MLKL) has emerged as a crucial molecule for necroptosis induction downstream of RIP3, how MLKL executes necroptosis is not yet well understood. In this study, we aim to elucidate the molecular mechanism underlying hypoxic preconditioning that inactivates MLKL-dependent neuronal necroptosis after tGCI.MethodsTransient global cerebral ischemia was induced by the four-vessel occlusion method. Twenty-four hours before ischemia, rats were exposed to systemic hypoxia with 8% O2 for 30 min. Western blotting was used to detect the expression of MLKL and interleukin-1 type 1 receptor (IL-1R1) in CA1. Immunoprecipitation was used to assess the interactions among IL-1R1, RIP3, and phosphorylated MLKL (p-MLKL). The concentration of intracellular free calcium ion (Ca2+) was measured using Fluo-4 AM. Silencing and overexpression studies were used to study the role of p-MLKL in tGCI-induced neuronal death.ResultsHypoxic preconditioning decreased the phosphorylation of MLKL both in neurons and microglia of CA1 after tGCI. The knockdown of MLKL with siRNA decreased the expression of p-MLKL and exerted neuroprotective effects after tGCI, whereas treatment with lentiviral delivery of MLKL showed opposite results. Mechanistically, hypoxic preconditioning or MLKL siRNA attenuated the RIP3-p-MLKL interaction, reduced the plasma membrane translocation of p-MLKL, and blocked Ca2+ influx after tGCI. Furthermore, hypoxic preconditioning downregulated the expression of IL-1R1 in CA1 after tGCI. Additionally, neutralizing IL-1R1 with its antagonist disrupted the interaction between IL-1R1 and the necrosome, attenuated the expression and the plasma membrane translocation of p-MLKL, thus alleviating neuronal death after tGCI.ConclusionsThese data support that the inhibition of MLKL-dependent neuronal necroptosis through downregulating IL-1R1 contributes to neuroprotection of hypoxic preconditioning against tGCI.

Dataset Information

Sevoflurane Postconditioning-Induced Anti-Inflammation via Inhibition of the Toll-Like Receptor-4/Nuclear Factor Kappa B Pathway Contributes to Neuroprotection against Transient Global Cerebral Ischemia in Rats.

Publications

Sevoflurane Postconditioning-Induced Anti-Inflammation via Inhibition of the Toll-Like Receptor-4/Nuclear Factor Kappa B Pathway Contributes to Neuroprotection against Transient Global Cerebral Ischemia in Rats.

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