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持续脑室内输注促红细胞生成素对神经发生增强的帕金森病大鼠模型具有神经保护/挽救作用。

Continuous intraventricular infusion of erythropoietin exerts neuroprotective/rescue effects upon Parkinson's disease model of rats with enhanced neurogenesis.

作者信息

Kadota Tomohito, Shingo Tetsuro, Yasuhara Takao, Tajiri Naoki, Kondo Akihiko, Morimoto Takamasa, Yuan Wen Ji, Wang Feifei, Baba Tanefumi, Tokunaga Koji, Miyoshi Yasuyuki, Date Isao

机构信息

Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 2-5-1, Shikata-cho, Okayama 700-8558, Japan.

出版信息

Brain Res. 2009 Feb 13;1254:120-7. doi: 10.1016/j.brainres.2008.11.094. Epub 2008 Dec 10.

Abstract

Parkinson's disease (PD) is characterized by degeneration of nigrostriatal dopaminergic neuronal systems. Several therapeutic tools for PD include medication using L-DOPA and surgeries such as deep brain stimulation are established. However, the therapies are considered as symptomatic therapy, but not basic remedy for PD and a new regenerative therapy would be desired to explore. In this study, the neuroprotective/rescue effects of erythropoietin (EPO), a well known hematopoietic hormone, on dopaminergic neurons were explored with neurogeneic potencies of EPO. EPO (100 IU/day) was continuously administered with micro-osmotic pump for a week to PD model of rats induced by intrastriatal 6-hydroxydopamine (6-OHDA) injection with subsequent behavioral and immunohistochemical investigations. The number of amphetamine-induced rotations of EPO-treated rats significantly decreased, compared to the control rats. The preservation of dopaminergic neurons of EPO-treated rats were confirmed by tyrosine hydroxylase staining and Fluoro-Gold staining. The number of bromodeoxyuridine (BrdU)/polysialic acid-neural cell adhesion molecule (PSA-NCAM) double positive cells in the subventricular zone of EPO treated rats significantly increased with migratory potencies to the damaged striatum,compared to the control rats. Furthermore, TUNEL staining and phosphorylated Akt staining revealed that the neuroprotective/rescue effects of EPO might be mediated by anti-apoptotic effects through the increase of phosphorylated Akt. These results suggest that continuous low dose infusion of EPO exerts neuroprotective/rescue effects with neurogeneic potentials. EPO might be a strong tool for PD therapy, although the further experiments should be added.

摘要

帕金森病(PD)的特征是黑质纹状体多巴胺能神经元系统的退化。目前已确立了几种针对PD的治疗方法,包括使用左旋多巴的药物治疗以及如深部脑刺激等手术。然而,这些疗法被认为是对症治疗,而非PD的根本治疗方法,因此需要探索新的再生疗法。在本研究中,探讨了著名的造血激素促红细胞生成素(EPO)对多巴胺能神经元的神经保护/挽救作用及其神经生成潜能。通过微渗透泵连续一周每天给由纹状体内注射6-羟基多巴胺(6-OHDA)诱导的PD大鼠模型注射EPO(100 IU/天),随后进行行为学和免疫组织化学研究。与对照大鼠相比,接受EPO治疗的大鼠安非他明诱导的旋转次数显著减少。通过酪氨酸羟化酶染色和荧光金染色证实了接受EPO治疗的大鼠多巴胺能神经元的保存。与对照大鼠相比,接受EPO治疗的大鼠脑室下区溴脱氧尿苷(BrdU)/多唾液酸神经细胞黏附分子(PSA-NCAM)双阳性细胞数量显著增加,且具有向受损纹状体迁移的潜能。此外,TUNEL染色和磷酸化Akt染色显示,EPO的神经保护/挽救作用可能通过磷酸化Akt的增加介导的抗凋亡作用来实现。这些结果表明,持续低剂量输注EPO具有神经保护/挽救作用及神经生成潜能。尽管还应增加进一步的实验,但EPO可能是一种强大的PD治疗工具。

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