Original article Effects of hypothermia on ex vivo microglial production of pro- and anti-inflammatory cytokines and nitric oxide in hypoxic-ischemic brain-injured mice

Matsui, Tomohiro; Kida, Hirotaka; Iha, Takuya; Obara, Tabito; Nomura, Sadahiro; Fujimiya, Tatsuya; Suzuki, Michiyasu

doi:10.5114/fn.2014.43786

Cited by 10 publications

(7 citation statements)

References 51 publications

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“…These cytokines stimulate the TLR-4 protein, which has been shown to play a role in pain development in several neuronal injury models and also in inducing NP. The results of several previous studies have revealed that TLR-4 enhances NF-κB levels, thereby inducing NP [19]. The results of the current study show that miR-1906 treatment ameliorates NF-κB and TLR-4 protein levels to reduce NP, which is consistent with the findings of previous studies [20].…”

Section: Discussionsupporting

confidence: 92%

MiR-1906 attenuates neuropathic pain in rats by regulating the TLR4/mTOR/ Akt signaling pathway

Fang

Zhou

Huang

et al. 2019

Translational Neuroscience

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Background This study determined the role of miR-1906 in neuropathic pain and proliferation in neuronal cells using a chronic constriction injury (CCI)-induced neuropathic pain (NP) rat model. Methodology NP was induced by CCI. Animals were divided into a sham group, an NP group, and a miR-1906 mimic group, which received 500 nmol/kg of a miR-1906 mimic intrathecally for 10 consecutive days following surgery. The effect of miR-1906 agomir was determined by estimating the thermal and mechanical withdrawal latency; an enzyme-linked immunosorbent assay (ELISA) was used to determine the concentration of proinflammatory mediators. Western blotting and reverse-transcription polymerase chain reaction (RT-PCR) were used to determine protein expression in the spinal tissues of the CCI-induced neuropathic pain rat model. Results Administration of miR-1906 agomir increased the mechanical and thermal withdrawal latency period and the levels of inflammatory mediators compared with the NP group. Western blotting showed that treatment with miR-1906 agomir attenuated the levels of Akt, mTOR, TLR-4, and PI3K proteins in the spinal tissues of the CCI-induced neuropathic pain model. TLR-4 and NF-κB gene expression was lower in the miR-1906 agomir group than in the NP group. Conclusion miR-1906 gene stimulation reduced neuropathic pain by enhancing Akt/nTOR/PI3K and TLR-4/NF-κB pathway regulation.

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Section: Discussionsupporting

confidence: 92%

MiR-1906 attenuates neuropathic pain in rats by regulating the TLR4/mTOR/ Akt signaling pathway

Fang

Zhou

Huang

et al. 2019

Translational Neuroscience

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“…While resident glial cells exist in a ramified state, after brain injury they migrate toward the lesion, their cell body becomes ameboid-shaped, the processes shorten, and become virtually indistinguishable from macrophages. Consistent with this, in vitro, hypothermia inhibits microglia proliferation, and attenuated microglia neurotoxicity, during and critically, after exposure to hypoxia and lipopolysaccharide [26,27,28]. Post-ischemic hypothermia also suppressed activated microglia after cerebral ischemia in fetal sheep [29].…”

Section: Discussionmentioning

confidence: 76%

Risperidone Treatment after Transient Ischemia Induces Hypothermia and Provides Neuroprotection in the Gerbil Hippocampus by Decreasing Oxidative Stress

Yang

Tae

Lee

et al. 2019

IJMS

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Compelling evidence from preclinical and clinical studies has shown that mild hypothermia is neuroprotective against ischemic stroke. We investigated the neuroprotective effect of post-risperidone (RIS) treatment against transient ischemic injury and its mechanisms in the gerbil brain. Transient ischemia (TI) was induced in the telencephalon by bilateral common carotid artery occlusion (BCCAO) for 5 min under normothermic condition (37 ± 0.2 °C). Treatment of RIS induced hypothermia until 12 h after TI in the TI-induced animals under uncontrolled body temperature (UBT) compared to that under controlled body temperature (CBT) (about 37 °C). Neuroprotective effect was statistically significant when we used 5 and 10 mg/kg doses (p < 0.05, respectively). In the RIS-treated TI group, many CA1 pyramidal neurons of the hippocampus survived under UBT compared to those under CBT. In this group under UBT, post-treatment with RIS to TI-induced animals markedly attenuated the activation of glial cells, an increase of oxidative stress markers [dihydroethidium, 8-hydroxy-2′ -deoxyguanosine (8-OHdG), and 4-Hydroxynonenal (4-HNE)], and a decrease of superoxide dismutase 2 (SOD2) in their CA1 pyramidal neurons. Furthermore, RIS-induced hypothermia was significantly interrupted by NBOH-2C-CN hydrochloride (a selective 5-HT2A receptor agonist), but not bromocriptine mesylate (a D2 receptor agonist). Our findings indicate that RIS-induced hypothermia can effectively protect neuronal cell death from TI injury through attenuation of glial activation and maintenance of antioxidants, showing that 5-HT2A receptor is involved in RIS-induced hypothermia. Therefore, RIS could be introduced to reduce body temperature rapidly and might be applied to patients for hypothermic therapy following ischemic stroke.

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“…Cooling during and after ischemic brain injury has been shown to influence microglial activation and cytokine release [33][34][35][36]. Therefore, the role of microglial activation in ischemic brain injury remains a prevailing research topic.…”

Section: Discussionmentioning

confidence: 99%

Cooling and Sterile Inflammation in an Oxygen-Glucose-Deprivation/Reperfusion Injury Model in BV-2 Microglia

Lücht

Rolfs

Wowro

et al. 2021

Mediators of Inflammation

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Objective. Cold-inducible RNA-binding protein (CIRBP) has been shown to be involved not only in cooling-induced cellular protection but also as a mediator of sterile inflammation, a critical mechanism of the innate immune response in ischemia/reperfusion (I/R) injury. The role of microglia and its activation in cerebral I/R injury warrants further investigation as both detrimental and regenerative properties have been described. Therefore, we investigated the effects of cooling, specifically viability, activation, and release of damage associated molecular patterns (DAMPs) on oxygen glucose deprivation/reperfusion- (OGD/R-) induced injury in murine BV-2 microglial cells. Methods. Murine BV-2 microglial cells were exposed to 2 to 6 h OGD (0.2% O2 in glucose- and serum-free medium) followed by up to 19 h of reperfusion, simulated by restoration of oxygen (21% O2) and nutrients. Cells were maintained at either normothermia (37°C) or cooled to 33.5°C, 1 h after experimental start. Cultured supernatants were harvested after exposure to OGD for analysis of DAMP secretions, including high-mobility group box 1 (HMGB1), heat shock protein 70 (HSP70), and CIRBP, and cytotoxicity was assessed by lactate dehydrogenase releases after exposure to OGD and reperfusion. Intracellular cold-shock proteins CIRBP and RNA-binding motif 3 (RBM3) as well as caspases 9, 8, and 3 were also analyzed via Western blot analysis. Furthermore, inducible nitric oxide synthase (iNOS), ionized calcium-binding adaptor molecule 1 (Iba1), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), interleukin-1α (IL-1α), monocyte chemotactic protein 1 (MCP-1), transforming growth factor β (TGFβ), CIRBP, and RBM3 gene expressions were assessed via reverse transcription polymerase chain reaction, and TNF-α, IL-6, and IL-1β releases into the cultured supernatants were assessed via enzyme-linked immunosorbent assays (ELISA). Results. Prolonged exposure to OGD resulted in increased BV-2 necrotic cell death, which was attenuated by cooling. Cooling also significantly induced cold-shock proteins CIRBP and RBM3 gene expressions, with CIRBP expression more rapidly regulated than RBM3 and translatable to significantly increased protein expression. DAMPs including HMGB-1, HSP70, and CIRBP could be detected in cultured supernatants after 6 h of OGD with CIRBP release being significantly attenuated by cooling. Exposure to OGD suppressed cytokine gene expressions of IL-1β, TNF-α, MCP-1, and TGFβ independently of temperature management, whereas cooling led to a significant increase in IL-1α gene expression after 6 h of OGD. In the reperfusion phase, TNF-α and MCP-1 gene expressions were increased, and cooling was associated with significantly lower TGFβ gene expression. Interestingly, cooled Normoxia groups had significant upregulations of microglial activation marker, Iba1, IL-1β, and TNF-α gene expressions. Conclusion. BV-2 microglial cells undergo necrotic cell death resulting in DAMP release due to OGD/R-induced injury. Cooling conveyed neuroprotection in OGD/R-injury as observable in increased cell viability as well as induced gene expressions of cold shock proteins. As cooling alone resulted in both upregulation of microglial activation, expression of proinflammatory cytokines, and cold shock protein transcript and protein expression, temperature management might have ambiguous effects in sterile inflammation. However, cooling resulted in a significant decrease of extracellular CIRBP, which has recently been characterized as a novel DAMP and a potent initiator and mediator of inflammation.

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Original article Effects of hypothermia on ex vivo microglial production of pro- and anti-inflammatory cytokines and nitric oxide in hypoxic-ischemic brain-injured mice

Cited by 10 publications

References 51 publications

MiR-1906 attenuates neuropathic pain in rats by regulating the TLR4/mTOR/ Akt signaling pathway

MiR-1906 attenuates neuropathic pain in rats by regulating the TLR4/mTOR/ Akt signaling pathway

Risperidone Treatment after Transient Ischemia Induces Hypothermia and Provides Neuroprotection in the Gerbil Hippocampus by Decreasing Oxidative Stress

Cooling and Sterile Inflammation in an Oxygen-Glucose-Deprivation/Reperfusion Injury Model in BV-2 Microglia

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