Erythropoietin ameliorates early brain injury after subarachnoid haemorrhage by modulating microglia polarization via the EPOR/JAK2-STAT3 pathway

Wei, Shanwu; Luo, Chunxia; Yu, Shan-Ping; Gao, Jin; Liu, Chang; Wei, Zheng; Zhang, Zhiren; Wei, Ling; Yi, Bin

doi:10.1016/j.yexcr.2017.11.002

Cited by 66 publications

(50 citation statements)

References 45 publications

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“…In our model, inhibition of STAT3 phosphorylation reversed the cytoprotective effect of Epo, indicating that STAT3 is a regulator of cell death inhibition. In agreement with the present study, Wei et al (25) reported that Epo saved neuronal cells from apoptosis following brain injury by activating a JAK2/STAT3 cascade.…”

Section: Discussionsupporting

confidence: 93%

Erythropoietin promotes expression of survivin via STAT3 activation and reduces sensitivity to cisplatin in cervical cancer cells

et al. 2018

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Erythropoietin (Epo) is used for the treatment of cancer-associated anaemia. However, certain studies have identified that the administration of Epo mediates the acquisition of resistance to cisplatin, which is widely used to treat cervical cancer. Our group previously reported that cervical cancer cells express Epo receptor and that exogenous Epo induces cell proliferation and migration. However, the effect of Epo on cervical cancer cell death mediated by chemotherapeutic agents has not yet been evaluated. Thus, the aim of the present study was to assess the potential effect of Epo on the cytotoxic activity of cisplatin in cervical cancer cells. The effect of Epo was assessed in 3 cervical cancer-derived cell lines. It was observed that pre-incubation with Epo induced a significant reduction of cisplatin-induced apoptosis in vitro and in vivo. Incubation with Epo induced the expression and activation of the transcriptional factor signal transducer and activator of transcription 3 (STAT3), which in turn stimulated the expression and activation of the anti-apoptotic protein survivin. The cytotoxicity of cisplatin was partially restored by treating the cells with MY155, an inhibitor of survivin. Conversely, inhibition of STAT3 activation using sub-lethal doses of WP1066, completely abolished the cytoprotective effect of Epo. These observations indicated that Epo was able to hinder the cytotoxic effect of cisplatin in cervical cancer cells by activating anti-apoptotic responses regulated by STAT3.

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Section: Discussionsupporting

confidence: 93%

Erythropoietin promotes expression of survivin via STAT3 activation and reduces sensitivity to cisplatin in cervical cancer cells

et al. 2018

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“…) and subarachnoid haemorrhage (Wei et al . ). In the present study, cerebral ischaemia was associated with a shift in microglial morphology from a resting (ramified) appearance to the activated, amoeboid state, with no apparent effect of either rEpo or hypothermia as shown in Fig.…”

Section: Discussionmentioning

confidence: 97%

Non‐additive effects of adjunct erythropoietin therapy with therapeutic hypothermia after global cerebral ischaemia in near‐term fetal sheep

Wassink

Davidson

Fraser

et al. 2020

The Journal of Physiology

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Key points Recombinant human erythropoietin (rEpo) is neuroprotective in immature animals, but it is unclear whether the combination of high‐dose rEpo therapy with therapeutic hypothermia can further improve outcomes. Hypothermia and rEpo independently improved neuronal survival, with greater improvement with hypothermia, and similarly reduced numbers of caspase‐3 positive cells and reactive microglia after 7 days recovery. Hypothermia, but not rEpo, was associated with markedly improved EEG power, whereas both interventions improved recovery of EEG frequency. There was no significant improvement in any outcome after combined rEpo and hypothermia compared with hypothermia alone, and of concern, the combination was associated with increased numbers of cortical caspase‐3‐positive cells compared with ischaemia‐hypothermia. These data suggest that the mechanisms of neuroprotection with hypothermia and rEpo overlap and, thus, high‐dose rEpo infusion does not appear to be an effective adjunct therapy for therapeutic hypothermia. Abstract Therapeutic hypothermia for hypoxic‐ischaemic encephalopathy (HIE) provides incomplete neuroprotection. Recombinant human erythropoietin (rEpo) is neuroprotective in immature animals, but it is unclear whether adjunct rEpo therapy with therapeutic hypothermia can further improve outcomes. Near‐term fetal sheep received sham‐ischaemia (n = 9) or global cerebral ischaemia for 30 min (ischaemia‐vehicle, n = 8), followed by intravenous infusion of rEpo (ischaemia‐Epo, n = 8; 5000 U/kg loading dose, then 833.3 U/kg/h), cerebral hypothermia (ischaemia‐hypothermia, n = 8), or rEpo plus hypothermia (ischaemia‐Epo‐hypothermia, n = 8), from 3 to 72 h post ischaemia. Fetal brains were collected 7 days after cerebral ischaemia. Cerebral ischaemia was associated with severe neuronal loss and microglial induction in the parasagittal cortex and subcortical regions. Hypothermia reduced overall neuronal loss, cortical caspase‐3 and reactive microglia in the striatum and cortex, with greater recovery of electroencephalographic (EEG) power and spectral edge (SEF) from 48 h onwards. rEpo independently improved neuronal survival in the parasagittal cortex, hippocampal CA4 and thalamus, and reduced cortical caspase‐3 and activated microglia in striatal and cortical areas, with greater SEF from 120 h onwards. However, ischaemia‐Epo‐hypothermia did not further improve outcomes compared with ischaemia‐hypothermia and was associated with increased numbers of cortical caspase‐3‐positive cells. These findings suggest that although delayed, prolonged treatment with both hypothermia and rEpo are independently neuroprotective, they have overlapping anti‐inflammatory and anti‐apoptotic mechanisms, such that the delayed, high‐dose rEpo infusion for 3 days did not materially augment neuroprotection with therapeutic hypothermia.

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“…The pluripotent cytokines, erythropoietin (EPO) and melatonin (MLT), are leading candidates for neurorepair in neonates with central nervous system (CNS) injury due to their safety profile ( Robertson et al, 2012 ), and multiple and complementary, mechanisms of action on developing neural cells ( Brines et al, 2000 ; Carloni et al, 2008 ; Mazur et al, 2010 ; Jantzie et al, 2018 ). Both EPO and MLT support the genesis, survival and maturation of neural cells ( Iwai et al, 2010 ; Mazur et al, 2010 ; Jantzie et al, 2013 ; Li et al, 2017 ; Zhang et al, 2018 ), reduce excess calpain degradation ( Samantaray et al, 2008 ; Jantzie et al, 2014b , 2016 ; Robinson et al, 2016 ), limit neuroinflammation and oxidative damage ( Carloni et al, 2016 ; Ramirez-Jirano et al, 2016 ; Dominguez Rubio et al, 2017 ; McDougall et al, 2017 ; Wang et al, 2017 ; Wei et al, 2017 ; Zhou et al, 2017 ), and suppress endoplasmic reticulum stress and mitochondrial dysfunction ( Hong et al, 2012 ; Das et al, 2013 ; Carloni et al, 2014 ; Fernandez et al, 2015 ; Hadj Ayed Tka et al, 2015 ; Zhao et al, 2015 ; Hu et al, 2016 ; Hardeland, 2017 ; Mendivil-Perez et al, 2017 ; Tang et al, 2017 ; Xue et al, 2017 ). Individually, EPO and MLT are in clinical trials to ameliorate CNS injury from extremely preterm birth, demonstrating their clinical viability as therapeutics in preterm infants ( Juul et al, 2008 ; Ohls et al, 2014 , 2016 ; Fauchere et al, 2015 ; Wu et al, 2016 ; Carloni et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Extended Combined Neonatal Treatment With Erythropoietin Plus Melatonin Prevents Posthemorrhagic Hydrocephalus of Prematurity in Rats

Robinson

Conteh

Oppong

et al. 2018

Front. Cell. Neurosci.

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Posthemorrhagic hydrocephalus of prematurity (PHHP) remains a global challenge. Early preterm infants (<32 weeks gestation), particularly those exposed to chorioamnionitis (CAM), are prone to intraventricular hemorrhage (IVH) and PHHP. We established an age-appropriate, preclinical model of PHHP with progressive macrocephaly and ventriculomegaly to test whether non-surgical neonatal treatment could modulate PHHP. We combined prenatal CAM and postnatal day 1 (P1, equivalent to 30 weeks human gestation) IVH in rats, and administered systemic erythropoietin (EPO) plus melatonin (MLT), or vehicle, from P2 to P10. CAM-IVH rats developed progressive macrocephaly through P21. Macrocephaly was accompanied by ventriculomegaly at P5 (histology), and P21 (ex vivo MRI). CAM-IVH rats showed impaired performance of cliff aversion, a neonatal neurodevelopmental test. Neonatal EPO+MLT treatment prevented macrocephaly and cliff aversion impairment, and significantly reduced ventriculomegaly. EPO+MLT treatment prevented matted or missing ependymal motile cilia observed in vehicle-treated CAM-IVH rats. EPO+MLT treatment also normalized ependymal yes-associated protein (YAP) mRNA levels, and reduced ependymal GFAP-immunolabeling. Vehicle-treated CAM-IVH rats exhibited loss of microstructural integrity on diffusion tensor imaging, which was normalized in EPO+MLT-treated CAM-IVH rats. In summary, combined prenatal systemic inflammation plus early postnatal IVH caused progressive macrocephaly, ventriculomegaly and delayed development of cliff aversion reminiscent of PHHP. Neonatal systemic EPO+MLT treatment prevented multiple hallmarks of PHHP, consistent with a clinically viable, non-surgical treatment strategy.

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Erythropoietin ameliorates early brain injury after subarachnoid haemorrhage by modulating microglia polarization via the EPOR/JAK2-STAT3 pathway

Cited by 66 publications

References 45 publications

Erythropoietin promotes expression of survivin via STAT3 activation and reduces sensitivity to cisplatin in cervical cancer cells

Erythropoietin promotes expression of survivin via STAT3 activation and reduces sensitivity to cisplatin in cervical cancer cells

Non‐additive effects of adjunct erythropoietin therapy with therapeutic hypothermia after global cerebral ischaemia in near‐term fetal sheep

Extended Combined Neonatal Treatment With Erythropoietin Plus Melatonin Prevents Posthemorrhagic Hydrocephalus of Prematurity in Rats

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