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The erythropoietin-derived peptide MK-X and erythropoietin have neuroprotective effects against ischemic brain damage.

ABSTRACT: Erythropoietin (EPO) has been well known as a hematopoietic cytokine over the past decades. However, recent reports have demonstrated that EPO plays a neuroprotective role in the central nervous system, and EPO has been considered as a therapeutic target in neurodegenerative diseases such as ischemic stroke. Despite the neuroprotective effect of EPO, clinical trials have shown its unexpected side effects, including undesirable proliferative effects such as erythropoiesis and tumor growth. Therefore, the development of EPO analogs that would confer neuroprotection without adverse effects has been attempted. In this study, we examined the potential of a novel EPO-based short peptide, MK-X, as a novel drug for stroke treatment in comparison with EPO. We found that MK-X administration with reperfusion dramatically reduced brain injury in an in vivo mouse model of ischemic stroke induced by middle cerebral artery occlusion, whereas EPO had little effect. Similar to EPO, MK-X efficiently ameliorated mitochondrial dysfunction followed by neuronal death caused by glutamate-induced oxidative stress in cultured neurons. Consistent with this effect, MK-X significantly decreased caspase-3 cleavage and nuclear translocation of apoptosis-inducing factor induced by glutamate. MK-X completely mimicked the effect of EPO on multiple activation of JAK2 and its downstream PI3K/AKT and ERK1/2 signaling pathways, and this signaling process was involved in the neuroprotective effect of MK-X. Furthermore, MK-X and EPO induced similar changes in the gene expression patterns under glutamate-induced excitotoxicity. Interestingly, the most significant difference between MK-X and EPO was that MK-X better penetrated into the brain across the brain-blood barrier than did EPO. In conclusion, we suggest that MK-X might be used as a novel drug for protection from brain injury caused by ischemic stroke, which penetrates into the brain faster in comparison with EPO, even though MK-X and EPO have similar protective effects against excitotoxicity.

SUBMITTER: Yoo SJ

PROVIDER: S-EPMC5596568 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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The erythropoietin-derived peptide MK-X and erythropoietin have neuroprotective effects against ischemic brain damage.

Yoo Seung-Jun SJ Cho Bongki B Lee Deokho D Son Gowoon G Lee Yeong-Bae YB Soo Han Hyung H Kim Eunjoo E Moon Chanil C Moon Cheil C

Cell death & disease 20170817 8

Erythropoietin (EPO) has been well known as a hematopoietic cytokine over the past decades. However, recent reports have demonstrated that EPO plays a neuroprotective role in the central nervous system, and EPO has been considered as a therapeutic target in neurodegenerative diseases such as ischemic stroke. Despite the neuroprotective effect of EPO, clinical trials have shown its unexpected side effects, including undesirable proliferative effects such as erythropoiesis and tumor growth. Theref ...[more]

PMID: 28817120

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Project description:Hypoxic-ischemic (HI) injury in the developing brain is a common cause of disability in children, and there are no effective treatments at this time. Erythropoietin (EPO) has recently gained interest as a neuroprotective drug, and EPO and its receptor are expressed within the central nervous system. We have recently shown that pretreatment with EPO markedly reduced brain injury caused by unilateral hypoxic-ischemic insult in 7 day old mice. EPO did not reduce early signs of neuronal injury at 6 hours, but significantly protected the neonatal brain when assessed 24 hours and 7 days after HI. The mechanism of this delayed protection is unclear, but is thought to involve transcription of neuroprotective genes, possibly subsequent to activation of NFkB. By comparing gene expression in EPO- and vehicle- (VEH) treated mice after HI, we should gain insight into the mechanisms underlying the neuroprotective effects of EPO and may identify additional targets for therapeutic interventions. We will compare gene expression patterns in 7-day old mouse forebrain after 1) VEH pretreatment plus sham surgery, 2) VEH pretreatment plus HI, and 3) EPO pretreatment plus HI. We will thus identify genes induced by HI in the developing brain and characterize changes in gene expression caused by EPO pretreatment. We will use the model of neonatal hypoxic-ischemic injury and EPO treatment parameters that were used in our prior studies demonstrating neuroprotection. Based on the time-course of neuroprotection defined in our prior study and the pharmacokinetic profile of EPO, we will examine gene expression 18 hours after HI. We hypothesize that changes in gene expression after EPO pretreatment underlie the neuroprotective effects of this cytokine after neonatal hypoxic ischemic injury. We will examine gene expression in 3 groups: 1) 1) VEH pretreatment + sham surgery, 2) VEH pretreatment + HI, and 3) EPO pretreatment + HI. EPO (5U/g, i.p.) or VEH was injected in 7 day old mice, drawn from 4 litters, with 3 to 4 pups per treatment group in each litter. One hour later, the right common carotid artery was ligated under isoflurane anesthesia, animals were allowed to recover for 90 min and were then placed in hypoxic chambers (10% oxygen, balance nitrogen) for 50 min. The animals subjected to sham surgery received isoflurane anesthesia for a comparable period, incision and dissection to visualize the common carotid artery, but no ligation and no hypoxia. Eighteen hrs later, animals were anesthetized with isoflurane and the right hemisphere was rapidly dissected and placed in RNA Later (Qiagen) at 4C. Total RNA was isolated using an RNeasy lipid tissue mini kit (QIAzol lysis and RNeasy purification, Qiagen). RNA concentrations were determined spectrophotometrically and an aliquot of each sample was examined by gel electrophoresis to screen for degradation. Samples were stored at -80C. After quality control screening, we selected 5 male and 5 female samples per treatment group (extra samples were reserved). We plan to pool 1 male and 1 female for each microarray sample and we plan to run 5 microarrays from each treatment group, for a total of 15 microarrays. We would like to have Agilent Bioanalyzer quality control assays on the individual samples carried out by the consortium before pooling. We will send 10 micrograms of each sample for Agilent QC and subsequent pooling of equimolar amounts. We would like to use Affymetrix mouse gene chips (please advise which specific chips are available; are you using the GeneChip Mouse Expression array 430A or the GeneChip Mouse Genome 430 2.0 Array?). Keywords: dose response

Project description:Oral exposure to chromium hexavalent [Cr(VI)] has disastrous impacts and affects many people worldwide. Cr(VI) triggers neurotoxicity via its high oxidation potential by generating high amount of ROS. Meanwhile, alginates are known by their chelating activity and ability to bind heavy metals and toxins, in addition to their antioxidant, anti-inflammatory, and anti-apoptotic activities. So, this study aimed to explore the neuroprotective potential of sodium alginate (SA) against cellular injury, DNA damage, macromolecule alterations, and apoptosis induced by oral ingestion of Cr. Forty Wistar male rats were divided into 4 groups; group I: standard control ingested with the vehicle solution, group II: Cr-intoxicated group received 10 mg/kg b.w. of potassium dichromate orally by gavage and kept without treatment, group III: SA group in which rats were orally exposed to 200 mg/kg b.w. of SA only, and group IV: SA-treated group that received 200 mg/kg b.w. of SA along with Cr for 28 consecutive days. Neurotransmitters such as Acetyl choline esterase (AchE), Monoamine oxidase A (MAOA) concentrations, Dopamine (DA) and 5-Hydroxytryptamine (5-HT) levels were assessed in brain homogenate tissues. Neurobiochemical markers; NAD+ and S100B protein were investigated in the brain tissues and serum, respectively. Levels of HSP70, caspase-3, protein profiling were evaluated. DNA damage was determined using the Comet assay. Results revealed a significant reduction in the AchE and MAOA concentrations, DA, 5-HT, and NAD+ levels, with an increase in the S100B protein levels. Cr(VI) altered protein pattern and caused DNA damage. High levels of HSP70 and caspase-3 proteins were observed. Fortunately, oral administration of SA prevented the accumulation of Cr in brain homogenates and significantly improved all investigated parameters. SA attenuated the ROS production and relieved the oxidative stress by its active constituents. SA can protect against cellular and DNA damage and limit apoptosis. SA could be a promising neuroprotective agent against Cr(VI)-inducing toxicity.

Project description:Expression of the 17β-estradiol (E2) synthesis enzyme aromatase is highly upregulated in astrocytes following brain injury. However, the precise role of astrocyte-derived E2 in the injured brain remains unclear. In the current study, we generated a glial fibrillary acidic protein (GFAP) promoter-driven aromatase knock-out (GFAP-ARO-KO) mouse model to deplete astrocyte-derived E2 in the brain and determine its roles after global cerebral ischemia (GCI) in male and female mice. GFAP-ARO-KO mice were viable and fertile, with normal gross brain structure, normal morphology, intensity and distribution of astrocytes, normal aromatase expression in neurons, and normal cognitive function basally. In contrast, after GCI, GFAP-ARO-KO mice: (1) lacked the normal elevation of astrocyte aromatase and hippocampal E2 levels; (2) had significantly attenuated reactive astrogliosis; and (3) displayed enhanced neuronal damage, microglia activation, and cognitive deficits. RNA-sequencing (RNA-seq) analysis revealed that the ischemic GFAP-ARO-KO mouse hippocampus failed to upregulate the "A2" panel of reactive astrocyte genes. In addition, the JAK-STAT3 pathway, which is critical for the induction of reactive astrogliosis, was significantly downregulated in the GFAP-ARO-KO hippocampus following GCI. Finally, exogenous E2 administration fully rescued the compromised JAK-STAT3 pathway and reactive astrogliosis, and reversed the enhanced neuronal damage and microglial activation in the GFAP-ARO-KO mice after GCI, suggesting that the defects in the KO mice are because of a loss of E2 rather than an increase in precursor androgens. In conclusion, the current study provides novel genetic evidence for a beneficial role of astrocyte-derived E2 in reactive astrogliosis, microglial activation, and neuroprotection following an ischemic injury to the brain.SIGNIFICANCE STATEMENT Following cerebral ischemia, reactive astrocytes express the enzyme aromatase and produce 17β-estradiol (E2), although the precise role of astrocyte-derived E2 is poorly understood. In this study, we generated a glial fibrillary acidic protein (GFAP) promoter-driven aromatase knock-out (GFAP-ARO-KO) mouse to deplete astrocyte-derived E2 and elucidate its roles after global cerebral ischemia (GCI). The GFAP-ARO-KO mice exhibited significantly attenuated reactive astrogliosis, as well as enhanced microglial activation, neuronal damage, and cognitive dysfunction after GCI. Transcriptome analysis further revealed that astrocyte-derived E2 was critical for the induction of the JAK-STAT3 signaling pathway, as well as the A2 reactive astrocyte phenotype after ischemia. Collectively, these findings indicate that astrocyte-derived E2 has a key role in the regulation of reactive astrogliosis, microglial activation, and neuroprotection after cerebral ischemia.

Project description:BackgroundInterleukin-33 (IL-33) is a well-recognized pleiotropic cytokine which plays crucial roles in immune regulation and inflammatory responses. Recent studies suggest that IL-33 and its receptor ST2 are involved in the pathogenesis of neurological diseases. Here, we explore the effect of IL-33/ST2 signaling in neonatal hypoxic-ischemic (HI) brain injury and elucidate the underlying mechanisms of action.MethodsThe brain HI model was established in neonatal C57BL/6 mice by left common carotid artery occlusion with 90 min hypoxia and treated with IL-33 at a dose of 0.2 μg/day i.p. for 3 days. TTC staining and neurobehavioral observation were used to evaluate the HI brain injury. Immunofluorescence and flow cytometry were applied to determine the expression of IL-33 and its receptor ST2 on brain CNS cells and cell proliferation and apoptosis. OGD experiment was used to assay the viability of astrocytes and neurons. RT-qPCR was used to measure the expression of neurotrophic factor-associated genes.ResultsThe expression level of IL-33 was markedly enhanced in astrocytes 24 h after cerebral HI in neonatal mice. Exogenous delivery of IL-33 significantly alleviated brain injury 7 days after HI, whereas ST2 deficiency exacerbated brain infarction and neurological deficits post HI. Flow cytometry analyses demonstrated high levels of ST2 expression on astrocytes, and the expression of ST2 was further elevated after HI. Intriguingly, IL-33 treatment apparently improved astrocyte response and attenuated HI-induced astrocyte apoptosis through ST2 signaling pathways. Further in vitro studies revealed that IL-33-activated astrocytes released a series of neurotrophic factors, which are critical for raising neuronal survival against oxygen glucose deprivation.ConclusionsThe activation of IL-33/ST2 signaling in the ischemic brain improves astrocyte response, which in turn affords protection to ischemic neurons in a glial-derived neurotrophic factor-dependent manner.

Dataset Information

The erythropoietin-derived peptide MK-X and erythropoietin have neuroprotective effects against ischemic brain damage.

Publications

The erythropoietin-derived peptide MK-X and erythropoietin have neuroprotective effects against ischemic brain damage.

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