Therapeutic window for cinnamophilin following oxygen–glucose deprivation and transient focal cerebral ischemia

The present study investigates the role of N-methyl-D-aspartate (NMDA) receptors in a model of transient focal cerebral ischemia in normotensive rats. The left middle cerebral artery and both common carotid arteries were occluded for 60 min. Preliminary studies indicated that this gave reproducible infarctions of the cortex and striatum. These infarctions were the result of severe ischemia followed by complete reperfusion after clamp removal, as showed by striatal tissue Po2 monitoring. Microdialysis indicated that glutamate concentration increased immediately after occlusion and returned to the baseline value 40 min after clamp removal. MK-801 (1 mg kg−1 i.v.), an antagonist of the NMDA glutamatergic receptor, reduced the cortical infarct volume by 29% (p < 0.001) and the striatal infarct volume by 14% (p < 0.05) when given just prior to ischemia, but had no neuroprotective activity when given 30 min after the onset of ischemia. This short therapeutic window for MK-801 suggests that NMDA receptors play only a transient role in reversible focal ischemia in rats.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20973119 ◽

2020 ◽

pp. 0271678X2097311

Author(s):

Zhanyang Yu ◽

Wenlu Li ◽

Jing Lan ◽

Kazuhide Hayakawa ◽

Xunming Ji ◽

...

Keyword(s):

Cerebral Ischemia ◽

Mouse Model ◽

Therapeutic Potential ◽

Focal Cerebral Ischemia ◽

Ischemic Injury ◽

Glucose Deprivation ◽

Oxygen Glucose Deprivation ◽

Neuron Soma

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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A novel therapeutic approach using peripheral blood mononuclear cells preconditioned by oxygen-glucose deprivation

Scientific Reports ◽

10.1038/s41598-019-53418-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Masahiro Hatakeyama ◽

Masato Kanazawa ◽

Itaru Ninomiya ◽

Kaoru Omae ◽

Yasuko Kimura ◽

...

Keyword(s):

Cerebral Ischemia ◽

Therapeutic Strategy ◽

Mononuclear Cells ◽

Focal Cerebral Ischemia ◽

Glucose Deprivation ◽

Oxygen Glucose Deprivation ◽

Peripheral Blood Mononuclear ◽

Novel Therapeutic

AbstractCell therapies that invoke pleiotropic mechanisms may facilitate functional recovery in patients with stroke. Based on previous experiments using microglia preconditioned by oxygen-glucose deprivation, we hypothesized that the administration of peripheral blood mononuclear cells (PBMCs) preconditioned by oxygen-glucose deprivation (OGD-PBMCs) to be a therapeutic strategy for ischemic stroke. Here, OGD-PBMCs were identified to secrete remodelling factors, including the vascular endothelial growth factor and transforming growth factor-β in vitro, while intra-arterial administration of OGD-PBMCs at 7 days after focal cerebral ischemia prompted expression of such factors in the brain parenchyma at 28 days following focal cerebral ischemia in vivo. Furthermore, administration of OGD-PBMCs induced an increasing number of stage-specific embryonic antigen-3-positive cells both in vitro and in vivo. Finally, it was found to prompt angiogenesis and axonal outgrowth, and functional recovery after cerebral ischemia. In conclusion, the administration of OGD-PBMCs might be a novel therapeutic strategy against ischemic stroke.

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