Ukai Wataru, Hashimoto Eri, Yoshinaga Toshihiro, Ishii Takao, Tateno Masaru, Ono Takafumi, Watanabe Kimihiko, Saito Satoshi, Saito Toshikazu
Department of Neuropsychiatry, Sapporo Medical University, School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543 Japan.
Nihon Shinkei Seishin Yakurigaku Zasshi. 2008 Apr;28(2):69-73.
Recent clinical neuroimaging studies have revealed the possible relation between morphological brain changes, and memory, cognitive impairment in the course of alcoholism and depression. In the previous studies, we have been analyzing the mechanism of neural network disruption by ethanol using postmortem human brain and cultured cells, and identified the sensitive effect of ethanol on the neural stem cell (NSC) differentiation rather than the influence on neuronal cell survival. Furthermore, to develop a novel method for reconstruction of the neural network damaged by ethanol, we tried to analyze the usefulness of intravenous NSC transplantation in fetal alcohol syndrome spectrum disorder (FASD) model rats. In the in vitro studies, we have found the suppressive effect of ethanol on NSC differentiation to neurons, through alteration of transcription factor, CREB and NRSF/REST activities, by the cellular signaling cascade changes including trophic factors and endoplasmic reticulum (ER) function. In the in vivo studies, we have shown the effective migration of labeled NSCs into the brain of FASD model rats, and revealed the therapeutic potential of this transplantation for the treatment of anxiety/cognitive dysfunction and behavioral abnormalities in alcohol-induced brain neural network damage. We are going to the next step for analysis of transplanted NSC dynamics in the brain, which must play a pivotal role in the effective induction of behavioral recoveries.
近期的临床神经影像学研究揭示了大脑形态变化与酒精中毒和抑郁症过程中的记忆、认知障碍之间的可能关系。在之前的研究中，我们一直在使用死后的人脑和培养细胞分析乙醇破坏神经网络的机制，并确定了乙醇对神经干细胞（NSC）分化的敏感作用，而非对神经元细胞存活的影响。此外，为了开发一种重建被乙醇破坏的神经网络的新方法，我们试图分析静脉内NSC移植在胎儿酒精谱系障碍（FASD）模型大鼠中的有效性。在体外研究中，我们发现乙醇通过改变转录因子、CREB和NRSF/REST的活性，以及包括营养因子和内质网（ER）功能在内的细胞信号级联变化，对NSC向神经元的分化具有抑制作用。在体内研究中，我们展示了标记的NSC有效迁移到FASD模型大鼠的大脑中，并揭示了这种移植对治疗酒精诱导的脑神经网络损伤中的焦虑/认知功能障碍和行为异常的治疗潜力。我们将进入下一步，分析移植的NSC在大脑中的动态变化，这对于有效诱导行为恢复必定起着关键作用。
