Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Because of the lack of reproducible brainstem ischemia models in rodents, the temporal profile of ischemic lesions in the brainstem after transient brainstem ischemia has not been evaluated intensively. Previously, we produced a reproducible brainstem ischemia model of Mongolian gerbils. Here, we showed the temporal profile of ischemic lesions after transient brainstem ischemia.
Results: Brainstem ischemia was produced by occlusion of the bilateral vertebral arteries just before their entry into the transverse foramina of the cervical vertebrae of Mongolian gerbils. Animals were subjected to brainstem ischemia for 15 min, and then reperfused for 0 d (just after ischemia), 1 d, 3 d and 7 d (n = 4 in each group). Sham-operated animals (n = 4) were used as control. After deep anesthesia, the gerbils were perfused with fixative for immunohistochemical investigation. Ischemic lesions were detected by immunostaining for microtubule-associated protein 2 (MAP2). Just after 15-min brainstem ischemia, ischemic lesions were detected in the lateral vestibular nucleus and the ventral part of the spinal trigeminal nucleus, and these ischemic lesions disappeared one day after reperfusion in all animals examined. However, 3 days and 7 days after reperfusion, ischemic lesions appeared again and clusters of ionized calcium-binding adapter molecule-1(IBA-1)-positive cells were detected in the same areas in all animals.
Conclusion: These results suggest that delayed neuronal cell death took place in the brainstem after transient brainstem ischemia in gerbils.

DOI： 10.1186/1471-2202-11-115

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Although signal transducer and activator of transcription 3 (Stat3) plays crucial roles in the determination of neural stem cell (NSC) fate, Stat3 has multiple roles in NSC function Moreover, Stat3 plays important roles in neuronal survival and tumorigenesis. To investigate the overall effects of Stat3 on NSC fate, NSC were isolated from Stat3(flox/flox) mouse embryos (E14-15d), in which both Stat3 alleles are flanked by LoxP sites Isolated NSC was inoculated with an adenovirus vector expressing Cre recombinase (Ad nCre) or a control adenovirus vector expressing beta-galactosidase (Ad.nLz). Three days later, quantitative real-time PCR (qPCR) analysis revealed that treatment with Ad.nCre eliminated sun 3 mRNA expression in NSC Promoter assay confirmed that overexpression of nCre inhibited transactivation of acute responsive element (APRE) and blocked Stat3 function in NSC Moreover, Western blot analysis and immunocytochemical analysis revealed that elimination of Stat3 in NSC promoted neurogenesis and inhibited astrogliogenesis In addition, we investigated the effects of Stat3 elimination in NSC on the mRNA expression of Notch family members and bHLH factors Consequently, qPCR analysis showed that elimination of Stat3 in NSC promoted neurogenesis and inhibited astrogliogenesis through down-regulation of notch!, notch2 and hes5, but not hes1 mRNA expression (C) 2010 Elsevier Inc All rights reserved

DOI： 10.1016/j.bbrc.2010.03.092

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Syntaxin1 and synaptotagmin are located in the pre-synaptic terminals and play central roles in Ca(2+)-triggered neurotransmitter release. Because excessive synaptic transmission has been implicated in neuronal cell death after ischemia, we investigated the effects of cerebral ischemia on the levels of these proteins using a rat permanent focal ischemia model. Western blot analysis revealed that the protein level of syntaxin1 was significantly up-regulated in the ischemic core cortex and peri-ischemic cortex at 1 day after ischemia, while the protein level of synaptotagmin was not. Immunohistochemical analysis revealed that the protein level of syntaxin1 was markedly up-regulated in the ischemic areas where immunoreaction for MAP2 was lost. Furthermore, we showed that resident microglial cells were quite vulnerable to ischemia. Our data provide novel insights into the molecular mechanism of cerebral ischemia at the pre-synaptic terminals.

DOI： 10.1016/j.brainres.2009.03.047

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FEDERATION AMER SOC EXP BIOL  

The differentiation and proliferation of neural stem cells (NSCs) are regulated by a combination of their intrinsic properties (e.g., transcription factors, epigenetic factors, and microRNA regulation) and cell-extrinsic properties from the microenvironment around NSC (e.g., cytokines, growth factors, and cell-cell contact). Recently, there has been a great interest in clarifying the mechanism of the influence of the microenvironment on NSCs, especially cell-cell contact between NSCs and other types of cells nearby. In this study, we investigated whether microglial (Mi) cells influence the fate of NSCs. Coculture study showed that ramified Mi cells promoted astrogliogenesis and maintenance of NSCs through their paracrine effects. This microglia-induced astrogliogenesis was inhibited by AG490 and by overexpression of the dominant-negative form of Stat3 and SOCS3. Promoter assay revealed transactivation of Stat3 function in NSCs by Mi cells. Gene expression study revealed that mRNA of Notch family members (notch1-3) and sox9 in NSCs was significantly upregulated by Mi cells, and this up-regulation was inhibited by AG490. These results demonstrated that ramified Mi cells promoted astrogliogenesis and maintenance of NSCs by activating Stat3 function and via notch and sox9 signaling pathways. -Zhu, P., Hata, R., Cao, F., Gu, F., Hanakawa, Y., Hashimoto, K., Sakanaka, M. Ramified microglial cells promote astrogliogenesis and maintenance of neural stem cells through activation of Stat3 function. FASEB J. 22, 3866-3877 (2008)

DOI： 10.1096/fj.08-105908

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Language：English   Publishing type：Research paper (international conference proceedings)  

Background and aims: Idiopathic sudden hearing loss (ISHL) is usually unilateral and can be anything within a range of a slight impairment of hearing to virtual deafness. One of the most common etiologies for ISHL is circulatory disturbance (most often vertebrobasilar ischemia). Vertebrobasilar ischemia (VBI) causes deafness because most of the auditory system including the inner ears is supplied from the vertebrobasilar system. ISHL of vascular cause is important for neurologists to recognize, because it sometimes appears as a warning sign of impending vertebrobasilar ischemic stroke. Previously, we produced cochlear ischemia by occluding both vertebral arteries in gerbils and established an animal model of ISHL [1]. We also showed progressive sensory hair cell loss after cochlear ischemia [1]. Sensory hair cell loss results in the sensorineural hearing loss (SNHL) and the most common type of hearing loss in adults is SNHL. Recent advances in stem cell biology have gained interest in the hope that stem cell therapy will come closer to regenerating sensory hair cells. Transplantation of hematopoietic stem cells (HSC) is regarded to be a potential approach for promoting repair of damaged organs. Here, we investigated the influence of hematopoietic stem cells on progressive hair cell degeneration after transient cochlear ischemia in gerbils. Methods &amp
Results: Transient cochlear ischemia was produced by extracranial occlusion of the bilateral vertebral arteries just before their entry into the transverse foramen of the cervical vertebra [2]. Intrascalar injection of HSC ameliorated hearing impairment (** indicates p&lt
0.01, n=6 in each group)(Fig. A) and prevented ischemia-induced inner hair cell (IHC) degeneration while there were no apparent outer hair cell (OHC) degeneration after ischemia (** indicates p&lt
0.01, n=6 in each group)(Fig. B). We also showed that the protein level of glial cell line-derived neurotrophic factor (GDNF) in the organ of Corti was upregulated after cochlear ischemia and that treatment with HSC augmented this ischemia-induced upregulation of GDNF. A tracking study revealed that HSC injected into the cochlea were retained in the perilymphatic space of the cochlea, although they neither transdifferentiated into cochlear cell types nor fused with the injured hair cells after ischemia. Conclusions: Our results suggest that HSC may have therapeutic potential possibly through paracrine effects. Thus, we propose HSC as a potential new therapeutic strategy for hearing loss.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

Red ginseng root (Panax Ginseng CA Meyer) has been used clinically by many Asian people for thousands of years without any detrimental effects. One of the major components of Red ginseng root is ginsenoside Rb-1 (gRb1). Previously, we showed that intravenous infusion of gRb1 ameliorated ischemic brain damage through upregulation of an anti-apoptotic factor, BCI-X-L and that topical application of gRb1 to burn wound lesion facilitated wound healing through upregulation of vascular endothelial growth factor (VEGF). In the present study, we produced dihydroginsenoside Rb1 (dgRb1), a stable chemical derivative of gRb1, and showed that intravenous infusion of dgRb1 improved spinal cord injury (SCI) as well as ischemic brain damage. As we expected, the effective dose of dgRb1 was ten times lower than that of gRb1. Intravenous infusion of dgRb1 at this effective dose did not affect brain temperature, blood pressure or cerebral blood flow, suggesting that dgRb1 rescued damaged neurons without affecting systemic parameters. In subsequent in vitro studies that focused on dgRb1-induced expression of gene products responsible for neuronal death or survival, we showed that dgRb1 could upregulate the expression of not only BCI-XL, but also a potent angiogenic and neurotrophic factor, VEGF. We also showed that dgRb1-induced expression of bcl-X-L and VEGF mRNA was HRE (hypoxia response element) and STRE (signal transducers and activators of transcription 5 (Stat5) response element) dependent, respectively.

DOI： 10.1089/neu.2006.0182

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.neuroscience.2006.12.067

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/j.1471-4159.2006.03890.x

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Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

DOI： 10.1038/sj.jcbfm.9600225

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1038/sj.jcbfm.9600225

Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/jnr.10166

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