G-1 exerts neuroprotective effects through G protein-coupled estrogen receptor 1 following spinal cord injury in mice

Cheng, Qiang; Meng, Jia; Wang, Xin‐shang; Kang, Wen-bo; Tian, Zhen; Zhang, Kun; Liu, Gang; Zhao, Jianning

doi:10.1042/bsr20160134

Cited by 28 publications

(25 citation statements)

References 47 publications

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“…GPR30 activation also induced the activation of PI3-kinase/Akt-dependent signaling and transactivation of the epidermal growth factor receptor via Src protein kinase [ 33 – 35 ]. Moreover, GPR30 increased Bcl-2 and BDNF by regulating the PI3K/Akt and MAPK/ERK signaling pathways [ 36 ]. Whether these second messenger signaling molecules are required for the GPR30-mediated downregulation of TLR4 in microglia needs to be determined.…”

Section: Discussionmentioning

confidence: 99%

The novel estrogenic receptor GPR30 alleviates ischemic injury by inhibiting TLR4-mediated microglial inflammation

Zhang

Qin

Deng

et al. 2018

J Neuroinflammation

152

110

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BackgroundThe steroid hormone estrogen (17-β-estradiol, E2) provides neuroprotection against cerebral ischemic injury by activating estrogen receptors. The novel estrogen receptor G protein-coupled receptor 30 (GPR30) is highly expressed in the brain and provides acute neuroprotection against stroke. However, the underlying mechanisms remain unclear.MethodsIn this study, ovariectomized female mice were subjected to middle cerebral artery occlusion (MCAO), and E2, G1, and ICI182780 were administered immediately upon reperfusion. The infarction volume, neurological scores, and neuronal injuries were examined. Primary microglial cells were subjected to oxygen-glucose deprivation (OGD), and the drugs were administered immediately upon reintroduction. The pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in penumbra and microglia were assessed by ELISA. The cell viability and lactose dehydrogenase (LDH) release of neurons co-cultured with microglia were analyzed using cell counting kit-8 (CCK8) and LDH release assays. Microglial activation as well as GPR30, Iba1, and Toll-like receptor 4 (TLR4) protein expression and TLR4 mRNA expression were detected. Additionally, NF-κB activity was detected in lipopolysaccharide (LPS)-activated microglia after the activation of GPR30.ResultsGPR30 was highly expressed in microglia and significantly increased after ischemic injury. The activation of GPR30 significantly reduced the infarction volume, improved the neurological deficit, and alleviated neuronal injuries. Moreover, GPR30 activation significantly reduced the release of TNF-α, IL-1β, and IL-6 from ischemic penumbra and microglia subjected to OGD and alleviated neuronal injury as assessed using the CCK8 and LDH assays. Finally, the activation of GPR30 relieved microglial activation, reduced Iba1 and TLR4 protein expression and TLR4 mRNA levels, and inhibited NF-κB activity.ConclusionsMicroglial GPR30 exerts acute neuroprotective effects by inhibiting TLR4-mediated microglial inflammation, which indicates that GPR30 may be a potential target for the treatment of ischemic stroke.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1246-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The novel estrogenic receptor GPR30 alleviates ischemic injury by inhibiting TLR4-mediated microglial inflammation

Zhang

Qin

Deng

et al. 2018

J Neuroinflammation

152

110

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“…Two of the crucial downstream proteins of PI3K/AKT are Bax and Bcl-2, which are related to apoptosis. Cheng et al found that promotion of AKT phosphorylation could increase Bcl-2 expression, thus decreasing the levels of Bax and cleaved caspase-3 in SCI 24. Moreover, PI3K/AKT pathway is also involved with autophagy 25.…”

Section: Discussionmentioning

confidence: 99%

Icariin Inhibits Endoplasmic Reticulum Stress-induced Neuronal Apoptosis after Spinal Cord Injury through Modulating the PI3K/AKT Signaling Pathway

Zhang

et al. 2019

Int. J. Biol. Sci.

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Endoplasmic reticulum (ER) stress-induced neuronal apoptosis is a crucial pathological process of spinal cord injury (SCI). In our previous study, icariin (ICA) showed neuroprotective effects in SCI. However, the relationships between ER stress and ICA in SCI are unclear yet. Therefore, whether ICA could ameliorate SCI via attenuating ER stress was investigated in vitro and in vivo. Adult mice were established SCI model and received vehicle solution or ICA by gavage once per day in vivo. The primary cultured cells were treated with or without thapsigargin (TG), ICA or LY294002 to induce ER stress in vitro. Motor dysfunction, neuronal apoptosis, tissue damage and inhibition of PI3K/AKT pathway were induced by ER stress after SCI. But ICA administration significantly enhanced motor recovery and protected spinal cord tissues against infraction and hemorrhage, etc. post injury. Meanwhile, the expression of ER stress markers ATF6, IRE1α, GRP78, XBP1 and eIF2α was decreased, while the level of p-AKT/AKT was increased by ICA. Furthermore, ICA significantly inhibited the expression of ER stress apoptotic proteins caspase-12, CHOP, Bax/Bcl-2, caspase-9 and caspase-3. Moreover, immunofluorescence double staining indicated that ICA reduced GRP78, CHOP and TUNEL positive neurons following SCI. However, this beneficial effect of ICA was abolished by PI3K/AKT inhibitor LY294002 in vitro. Finally, ICA preserved the ultra-structure of ER by transmission electron microscope histologically. This study suggested that the neuroprotective effect of ICA on motor recovery and neuronal survival was related to attenuating ER stress via PI3K/AKT signaling pathway after SCI.

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“…The steroidal structure further confers anti-inflammatory and antioxidant properties, both reducing cellular toxicity and cell death (Chaovipoch et al, 2006; Cuzzocrea et al, 2008; Gupta and Hubscher, 2012; Jover-Mengual et al, 2010; Miller et al, 2005; Mosquera et al, 2014; Nilsen and Brinton, 2003; Ritz and Hausmann, 2008; Samantaray et al, 2011, 2016; Siriphorn et al, 2012; Sribnick et al, 2005, 2006, 2010; Yune et al, 2004, 2008; Zhao and Brinton, 2007). The GPER-1/GPR30 activation resulted in neuronal survival and better behavioral outcome after pathological conditions to the CNS, like SCI, traumatic brain injury and stroke (Cheng et al, 2016; Hu et al, 2012; Wang et al, 2017). The GPER-1 activation by G-1 (GPER-1 selective agonist) was shown to mediate a sexually dimorphic response after middle cerebral artery occlusion (MCAo) (Broughton et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Continuous tamoxifen delivery improves locomotor recovery 6 h after spinal cord injury by neuronal and glial mechanisms in male rats

Colón

González

Cajigas

et al. 2018

Experimental Neurology

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No treatment is available for patients with spinal cord injury (SCI). Patients often arrive to the hospital hours after SCI suggesting the need of a therapy that can be used on a clinically relevant window. Previous studies showed that Tamoxifen (TAM) treatment 24h after SCI benefits locomotor recovery in female rats. Tamoxifen exerts beneficial effects in male and female rodents but a gap of knowledge exists on: the therapeutic window of TAM, the spatio-temporal mechanisms activated and if this response is sexually dimorphic. We hypothesized that TAM will favor locomotor recovery when administered up-to 24h after SCI in male Sprague-Dawley rats. Rats received a thoracic (T10) contusion using the MACSIS impactor followed by placebo or TAM (15mg/21days) pellets in a therapeutic window of 0, 6, 12, or 24h. Animals were sacrificed at 2, 7, 14, 28 or 35days post injury (DPI) to study the molecular and cellular changes in the acute and chronic stages. Immediate or delayed therapy (t=6h) improved locomotor function, increased white matter spared tissue, and neuronal survival. TAM reduced reactive gliosis during chronic stages and increased the expression of Olig-2. A significant difference was observed in estrogen receptor alpha between male and female rodents from 2 to 28 DPI suggesting a sexually dimorphic characteristic that could be related to the behavioral differences observed in the therapeutic window of TAM. This study supports the use of TAM in the SCI setting due to its neuroprotective effects but with a significant sexually dimorphic therapeutic window.

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G-1 exerts neuroprotective effects through G protein-coupled estrogen receptor 1 following spinal cord injury in mice

Cited by 28 publications

References 47 publications

The novel estrogenic receptor GPR30 alleviates ischemic injury by inhibiting TLR4-mediated microglial inflammation

The novel estrogenic receptor GPR30 alleviates ischemic injury by inhibiting TLR4-mediated microglial inflammation

Icariin Inhibits Endoplasmic Reticulum Stress-induced Neuronal Apoptosis after Spinal Cord Injury through Modulating the PI3K/AKT Signaling Pathway

Continuous tamoxifen delivery improves locomotor recovery 6 h after spinal cord injury by neuronal and glial mechanisms in male rats

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