Imaging Hypoxic Stress and the Treatment of Amyotrophic Lateral Sclerosis with Dimethyloxalylglycine in a Mice Model
Imaging Hypoxic Stress and the Treatment of Amyotrophic Lateral Sclerosis with Dimethyloxalylglycine in a Mice Model
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DOI：
10.1016/j.neuroscience.2019.06.025
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发表时间：
2019-09
期刊：
影响因子：
3.3
通讯作者：
Emi Nomura;Y. Ohta;Koh Tadokoro;Jingwei Shang;Tian Feng;Xia Liu;Xiaowen Shi;Namiko Matsumoto;Ryo Sasaki;Keiichiro Tsunoda;Kota Sato;M. Takemoto;N. Hishikawa;T. Yamashita;T. Kuchimaru;S. Kizaka-Kondoh;K. Abe
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文献类型：
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作者：
Emi Nomura;Y. Ohta;Koh Tadokoro;Jingwei Shang;Tian Feng;Xia Liu;Xiaowen Shi;Namiko Matsumoto;Ryo Sasaki;Keiichiro Tsunoda;Kota Sato;M. Takemoto;N. Hishikawa;T. Yamashita;T. Kuchimaru;S. Kizaka-Kondoh;K. Abe
缺氧诱导因子-1 α（Hypoxia inducible factor-1α，HIF-1α）是维持氧稳态的关键转录因子。低氧应激与肌萎缩侧索硬化症（ALS）的发病机制有关，低氧诱导因子-1 α（HIF-1α）受损可导致ALS运动神经元变性。二甲基草酰甘氨酸（DMOG）上调HIF-1α表达的稳定性并显示出神经保护作用，但尚未用于ALS的抗缺氧应激治疗。本研究通过体内HIF-1 α显像技术观察了携带G93 A-人Cu/Zn超氧化物歧化酶（Cu/Zn SOD）的ALS小鼠模型的缺氧应激反应，并对ALS小鼠进行DMOG治疗。HIF-1α的表达随着疾病的进展而降低，直到126日龄。DMOG治疗组HIF-1α表达减少，脊髓运动神经元和肌纤维变性，脊髓胶质细胞增生和凋亡明显减轻。这是伴随着长期生存。本研究提示，活体生物发光共振能量转移（BRET）HIF-1α显像可用于评估ALS患者的缺氧应激，增强HIF-1α表达可作为ALS患者的治疗靶点。
Hypoxia inducible factor-1α (HIF-1α) is a key transcription factor that maintains oxygen homeostasis. Hypoxic stress is related to the pathogenesis of amyotrophic lateral sclerosis (ALS), and impaired HIF-1α induces motor neuron degeneration in ALS. Dimethyloxalylglycine (DMOG) upregulates the stability of HIF-1α expression and shows neuroprotective effects, but has not been used in ALS as an anti-hypoxic stress treatment. In the present study, we investigated hypoxic stress in ALS model mice bearing G93A-human Cu/Zn superoxide dismutase byin vivoHIF-1α imaging, and treated the ALS mice with DMOG.In vivoHIF-1α imaging analysis showed enhanced hypoxic stress in both the spinal cord and muscles of lower limbs of ALS mice, even at the pre-symptomatic stage. HIF-1α expression decreased as the disease progressed until 126 days of age. DMOG treatment significantly ameliorated the decrease in HIF-1α expression, the degeneration of both spinal motor neurons and myofibers in lower limbs, gliosis and apoptosis in the spinal cord. This was accompanied by prolonged survival. The present study suggests thatin vivobioluminescence resonance energy transfer (BRET) HIF-1α imaging is useful for evaluating hypoxic stress in ALS, and that the enhancement of HIF-1α is a therapeutic target for ALS patients.