EphrinB2 activation enhances angiogenesis, reduces amyloid-β deposits and secondary damage in thalamus at the early stage after cortical infarction in hypertensive rats

Xing, Shihui; Pan, Nannan; Xu, Wei; Zhang, Jian; Li, Jingjing; Dang, Chao; Liu, Gang; Pei, Zhong

doi:10.1177/0271678x18769188

Cited by 20 publications

(15 citation statements)

References 47 publications

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“…Some of the target genes in our circRNA-miRNA-mRNA network, such as EphB2, Wnt3, and Twist1, are mainly involved in inflammation and angiogenesis. It was reported previously that activation of EphrinB2 enhanced angiogenesis and reduced neuronal loss and gliosis in the ipsilateral thalamus in rats with MCAO [ 40 ]. The present study revealed the possible mechanism of ephrinB2 in the secondary thalamic neurodegeneration and self-remodeling after cerebral infarction from the perspective of circRNA.…”

Section: Discussionmentioning

confidence: 99%

Altered circular RNA expression profiles in the non-ischemic thalamus in focal cortical infarction mice

et al. 2020

Aging

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Focal cerebral infarction leads to secondary changes in non-ischemic areas remote from but connected to the infarct site. Circular RNAs (circRNAs) are involved in the pathophysiological processes of many diseases. However, the expression and roles of circRNAs in non-ischemic remote regions after ischemic stroke remain unknown. In this study, adult male C57BL/6J mice were subjected to permanent distal middle cerebral artery occlusion (MCAO) to establish focal cortical infarction. High-throughput sequencing was used to profile the circRNA expression in the mouse ipsilateral thalamus at 7 and 14 d after MCAO. Bioinformatics analyses were conducted to predict the function of the differential expressed circRNAs’ host and target genes. Compared with sham group, a total of 2659 circRNAs were significantly altered in the ipsilateral thalamus at 7 or 14 d after MCAO in mice. Among them, 73 circRNAs were significantly altered at both two time points after stroke. GO and KEGG analyses indicated that circRNAs plays important roles in secondary thalamic neurodegeneration and remodeling after focal cortical infarction. This is the first study to profile the circRNA expression in non-ischemic region of ischemic stroke, suggesting that circRNAs may be therapeutic targets for reducing post-stroke secondary remote neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Altered circular RNA expression profiles in the non-ischemic thalamus in focal cortical infarction mice

et al. 2020

Aging

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“…Moreover, a recent study indicated that Ephrin-B2 signaling may enhance angiogenesis after stroke in hypertensive rats. 57 The roles of Ephrin-B2 signaling in vascular dysfunction and angiogenesis after stroke await further study in the future.…”

Section: Discussionmentioning

confidence: 99%

EphrinB2-EphB2 signaling for dendrite protection after neuronal ischemia in vivo and oxygen-glucose deprivation in vitro

Lan

et al. 2020

J Cereb Blood Flow Metab

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In order to rescue neuronal function, neuroprotection should be required not only for the neuron soma but also the dendrites. Here, we propose the hypothesis that ephrin-B2-EphB2 signaling may be involved in dendritic degeneration after ischemic injury. A mouse model of focal cerebral ischemia with middle cerebral artery occlusion (MCAO) method was used for EphB2 signaling test in vivo. Primary cortical neuron culture and oxygen-glucose deprivation were used to assess EphB2 signaling in vitro. siRNA and soluble ephrin-B2 ectodomain were used to block ephrin-B2-Ephb2 signaling. In the mouse model of focal cerebral ischemia and in neurons subjected to oxygen-glucose deprivation, clustering of ephrin-B2 with its receptor EphB2 was detected. Phosphorylation of EphB2 suggested activation of this signaling pathway. RNA silencing of EphB2 prevented neuronal death and preserved dendritic length. To assess therapeutic potential, we compared the soluble EphB2 ectodomain with the NMDA antagonist MK801 in neurons after oxygen-glucose deprivation. Both agents equally reduced lactate dehydrogenase release as a general marker of neurotoxicity. However, only soluble EphB2 ectodomain protected the dendrites. These findings provide a proof of concept that ephrin-B2-EphB2 signaling may represent a novel therapeutic target to protect both the neuron soma as well as dendrites against ischemic injury.

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“…Although chloral hydrate anesthesia is still used in stroke research 51 –56 , the use has been criticized for ethical and safety reasons 57 . Therefore, we would like to point out that chloral hydrate is not an optimal anesthetic for surgical procedures in rodents and the anesthesia protocol should be further refined.…”

Section: Methodsmentioning

confidence: 99%

Secondary Pathology of the Thalamus after Focal Cortical Stroke in Rats is not Associated with Thermal or Mechanical Hypersensitivity and is Not Alleviated by Intra-Thalamic Post-Stroke Delivery of Recombinant CDNF or MANF

2019

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A stroke affecting the somatosensory pathway can trigger central post-stroke pain syndrome (CPSP). The symptoms often include hyperalgesia, which has also been described in rodents after the direct damage of the thalamus. Previous studies have shown that hemorrhagic stroke or ischemia caused by vasoconstriction in the thalamus induces increased pain sensitivity. We investigated whether inducing secondary damage in the thalamus by a cortical stroke causes similar pain hypersensitivity as has previously been reported with direct ischemic injury. We induced a focal cortical ischemia-reperfusion injury in male rats, quantified the amount of secondary neurodegeneration in the thalamus, and measured whether the thalamic neurodegeneration is associated with thermal or mechanical hypersensitivity. After one month, we observed extensive neuronal degeneration and found approximately 40% decrease in the number of NeuN+ cells in the ipsilateral thalamus. At the same time, there was a massive accumulation—a 30-fold increase—of phagocytic cells in the ipsilateral thalamus. However, despite the evident damage in the thalamus, we did not observe thermal or mechanical sensitization. Thus, thalamic neurodegeneration after cortical ischemia-reperfusion does not induce CPSP-like symptoms in rats, and these results suggest that direct ischemic damage is needed for CPSP induction. Despite not observing hyperalgesia, we investigated whether administration of cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) into the ipsilateral thalamus would reduce the secondary damage. We gave a single injection (10 µg) of recombinant CDNF or MANF protein into the thalamus at 7 days post-stroke. Both CDNF and MANF treatment promoted the functional recovery but had no effect on the neuronal loss or the amount of phagocytic cells in the thalamus.

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EphrinB2 activation enhances angiogenesis, reduces amyloid-β deposits and secondary damage in thalamus at the early stage after cortical infarction in hypertensive rats

Cited by 20 publications

References 47 publications

Altered circular RNA expression profiles in the non-ischemic thalamus in focal cortical infarction mice

Altered circular RNA expression profiles in the non-ischemic thalamus in focal cortical infarction mice

EphrinB2-EphB2 signaling for dendrite protection after neuronal ischemia in vivo and oxygen-glucose deprivation in vitro

Secondary Pathology of the Thalamus after Focal Cortical Stroke in Rats is not Associated with Thermal or Mechanical Hypersensitivity and is Not Alleviated by Intra-Thalamic Post-Stroke Delivery of Recombinant CDNF or MANF

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