Erythropoietin-mediated protection of insect brain neurons involves JAK and STAT but not PI3K transduction pathways

Miljus, Natasa; Heibeck, Saskia; Jarrar, Miriam; Micke, Michaele; Ostrowski, Daniela; Ehrenreich, Hannelore; Heinrich, Ralf

doi:10.1016/j.neuroscience.2013.11.020

Cited by 36 publications

(68 citation statements)

References 67 publications

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“…EPO operates at several levels within the central nervous system, including limiting the production of reactive oxygen species and glutamate, neurotransmission modulation, reversal of vasospasm, promoting angiogenesis, preventing apoptosis, and reduction of inflammation [8,9,18]. By using the established animal model of sepsis induced by LPS administration, we showed that treatment with EPO presented efficient therapeutic effects by reducing the first 7 days mortality rate and improving LPSinduced cognitive impairments.…”

Section: Discussionmentioning

confidence: 90%

“…In addition to its known function in erythropoiesis, EPO has been reported to exert antiapoptotic, antiinflammatory, antioxidative, and neurotrophic properties [6]. EPO is an important mediator of the adaptive response to metabolic stress, which is an endogenous mediator of neuroprotection in various central nervous system disorders [7][8][9]. Accumulating evidence has demonstrated that exogenous EPO is beneficial during systemic sepsis.…”

Section: Introductionmentioning

confidence: 99%

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Systemic Lipopolysaccharide Administration-Induced Cognitive Impairments are Reversed by Erythropoietin Treatment in Mice

et al. 2015

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Sepsis-associated encephalopathy (SAE) is a frequent complication in critically ill patients and is associated with long-term cognitive impairments. However, the pathophysiology underlying SAE is poorly understood and the pharmacologic treatment is lacking. The purpose of the present study was to investigate the effects of erythropoietin (EPO) on cognitive impairments in an animal model of SAE induced by peripheral administration of lipopolysaccharide (LPS). Mice were randomly divided into the sham + vehicle, sham + EPO, LPS + vehicle, and LPS + EPO groups. EPO was administrated 30 min after the LPS administration and daily afterward for 2 days. Behavioral tests were performed on days 6 and 7 with open field and fear conditioning tests, respectively. The survival rate was estimated by the Kaplan-Meier method. The levels of proinflammatory responses, oxidative stress, and apoptosis-related markers were measured in the hippocampus at the indicated time points. The synaptic morphometry changes in the CA1 region were observed with transmission electron microscopy. Our results showed that LPS administration resulted in high mortality rate and cognitive impairments, which were accompanied by increased expressions of interleukin-1β, malondialdehyde, cleaved caspase-3, and abnormal synaptic morphometry changes in the hippocampus. Notably, EPO treatment reversed the cognitive impairments and rescued the brain pathology induced by LPS administration. In conclusion, our data suggested that treatment with EPO reduced the mortality rate and ameliorated cognitive impairments in an animal model of SAE.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Systemic Lipopolysaccharide Administration-Induced Cognitive Impairments are Reversed by Erythropoietin Treatment in Mice

et al. 2015

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“…EPOR is associated with Janus kinase 2 tyrosine kinases with cell-specific downstream transduction pathways including signal transducers and activators of transcription-5, phosphatidylinositol-3-kinase/protein kinase B, nuclear factor kappa B, and mitogen-activated protein kinase (MAPK)51314). With EPO binding to EPOR, activation of these downstream pathways have been implicated in the regulation of gene expression leading to neuroprotection51015). Among these pathways, the MAPK signaling pathways are less well characterized, and limited information on the involvement of MAPK in the mechanisms underlying the EPO-induced neuroprotection is available.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effects of erythropoietin against hypoxic injury via modulation of the mitogen-activated protein kinase pathway and apoptosis

et al. 2017

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PurposeHypoxic-ischemic encephalopathy is a significant cause of neonatal morbidity and mortality. Erythropoietin (EPO) is emerging as a therapeutic candidate for neuroprotection. Therefore, this study was designed to determine the neuroprotective role of recombinant human EPO (rHuEPO) and the possible mechanisms by which mitogen-activated protein kinase (MAPK) signaling pathway including extracellular signal-regulated kinase (ERK1/2), JNK, and p38 MAPK is modulated in cultured cortical neuronal cells and astrocytes.MethodsPrimary neuronal cells and astrocytes were prepared from cortices of ICR mouse embryos and divided into the normoxic, hypoxia (H), and hypoxia-pretreated with EPO (H+EPO) groups. The phosphorylation of MAPK pathway was quantified using western blot, and the apoptosis was assessed by caspase-3 measurement and terminal deoxynucleotidyl transferase dUTP nick end labeling assay.ResultsAll MAPK pathway signals were activated by hypoxia in the neuronal cells and astrocytes (P<0.05). In the neuronal cells, phosphorylation of ERK-1/-2 and apoptosis were significantly decreased in the H+EPO group at 15 hours after hypoxia (P<0.05). In the astrocytes, phosphorylation of ERK-1/-2, p38 MAPK, and apoptosis was reduced in the H+EPO group at 15 hours after hypoxia (P<0.05).ConclusionPretreatment with rHuEPO exerts neuroprotective effects against hypoxic injury reducing apoptosis by caspase-dependent mechanisms. Pathologic, persistent ERK activation after hypoxic injury may be attenuateed by pretreatment with EPO supporting that EPO may regulate apoptosis by affecting ERK pathways.

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“…The research indicates that after focal cerebral ischemia, EPO starts phosphorylation of downstream factor STAT5 through mediating EPOR-JAK2-STAT5 signal transduction approach. The activated STAT5 can effectively up-regulate expression of Bcl-2, Bcl-xl and other inhibitors of apoptosis protein, benignly down-regulate expression of Bax, Caspase-3 and other pro-apoptotic protein, and effectively prevent cytochrome C from releasing from mitochondria so as to give play to the anti-apoptosis effect after cerebral ischemia [6][7][8] . The research result prompts that Acupuncturing Baihui point and Dazhui can effectively regulate expression of key target spots after cerebral ischemia and suppress neuronal apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Influence of Electric Acupuncture on Bcl-xl and Caspase-3 Expression After Cerebral Ischemia of Rats

Huang¹,

Zhang²,

Zhong³

2016

Proceedings of the 2016 6th International Conference on Machinery, Materials, Environment, Biotechnology and Computer

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Abstract. Objective: to study the influence of electric acupuncture on factors about cerebral nerve cell apoptosis: B-cell lymphocytic lymphoma-xl gene (Bcl-xl) and aspartic acid proteolytic enzyme-3 including cysteine (Caspase-3) after cerebral ischemia of rats, and discuss the possible mechanism of treating cerebral ischemia and suppressing cell apoptosis with electric acupuncture. Method: 250 healthy and adult male SD rats were chosen as the objects of study, and they were randomly divided into sham-operation group, model group, electric acupuncture group, AG490 group, and AG490 electric acupuncture group. Each group was divided into 5 sub-groups according to time bucket. There were 25 groups in total. Each group included 10 rats. AG490 right ventricle injection was conducted for AG490 group and AG490 electric acupuncture group 20min before the operation. Baihui point and Dazhui point were chosen for electric acupuncture group and AG490 electric acupuncture for electric acupuncture treatment. The number of immune positive cells of cerebral ischemia nidi of rats Bcl-xl and Caspase-3 was observed. Results: sham-operation group has no significant change in each time bucket after the operation. After cerebral ischemia for 2h, Bcl-xl and Caspase-3 expression of rats in each group rises, higher than the rats in the sham-operation group in the same time bucket. For Bcl-xl expression, the model group and the electric acupuncture group are most significant, while the expression of AG490+electric acupuncture group is lower than that of electric acupuncture group (P<0.01). Caspase-3 content has no difference for each intervention group. Bcl-xl expression of rats in each group after ischemia for 1d is basically same with the situation of rats in each group after ischemia for 2d. The electric acupuncture group presents continuous rising trend. Caspase-3 expression of each intervention group continues to rise. The model group and AG490 group are in the high level (P<0.01). AG490+electric acupuncture group is lower than the model group (P<0.05), but AG490+electric acupuncture group has no difference with AG490 group (P>0.05). The electric acupuncture group is lower than the above three groups (P<0.05). After cerebral ischemia for 3d, Bcl-xl expression of rats in each group starts to decline. High-level expression of electric acupuncture group can maintain for a long time, and the content is higher than that of model group (P<0.05). The content of AG490 group and AG490+electric acupuncture group is low (P<0.01). The content of Caspase-3 reaches the peak after cerebral ischemia for 3d. The content of AG490 group is highest (P<0.05), and the content of electric acupuncture group is lowest (P<0.01). The model group and AG490+electric acupuncture group are between the two, and the difference of the two is not significant (P>0.05). After cerebral ischemia for 7d-21d, Bcl-xl and Caspase-3 content of rats in each group continues to drop. After 21d, the differences of rats in each group are not significant (P>0.05). Conclusion: elec...

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Erythropoietin-mediated protection of insect brain neurons involves JAK and STAT but not PI3K transduction pathways

Cited by 36 publications

References 67 publications

Systemic Lipopolysaccharide Administration-Induced Cognitive Impairments are Reversed by Erythropoietin Treatment in Mice

Systemic Lipopolysaccharide Administration-Induced Cognitive Impairments are Reversed by Erythropoietin Treatment in Mice

Neuroprotective effects of erythropoietin against hypoxic injury via modulation of the mitogen-activated protein kinase pathway and apoptosis

Influence of Electric Acupuncture on Bcl-xl and Caspase-3 Expression After Cerebral Ischemia of Rats

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