Autophagy activation and neuroprotection by progesterone in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis
Autophagy activation and neuroprotection by progesterone in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis
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DOI：
10.1016/j.nbd.2013.07.011
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发表时间：
2013-11-01
影响因子：
6.1
通讯作者：
Koh, Jae-Young
中科院分区：
文献类型：
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作者：
Kim, Jean;Kim, Tae-Youn;Koh, Jae-Young
在脑缺血、创伤性脑损伤和脊髓损伤等条件下，Progressive（PG）发挥神经保护作用。以前，我们报道PG激活自噬，一种潜在的神经保护机制，在皮质星形胶质细胞。在本研究中，我们探讨了PG通过激活脊髓细胞中的自噬来保护表达人G93 A-SOD 1（超氧化物歧化酶1）突变体的转基因（Tg）小鼠（肌萎缩侧索硬化模型）免受运动神经元变性的可能性。PG处理增加了G93 A-SOD 1 Tg脊髓星形胶质细胞培养物和小鼠中的自噬通量。此外，PG治疗降低突变体SOD 1蛋白水平和运动神经元死亡。用3-甲基腺嘌呤（3 MA）抑制自噬逆转了这些PG效应，表明自噬的激活有助于PG神经保护。从70日龄至死亡，通过腹膜内注射不同剂量的PG（2、4或8 mg/kg）或溶媒，对雄性G93 A-SOD 1 Tg小鼠的体内PG效应进行了测试。使用旋转杆试验进行的运动功能测量显示，各组间症状发作无差异，但与溶剂对照组相比，PG给药组运动功能障碍的进展显著延迟。PG注射组的平均寿命也得到延长。组织学检查显示，PG治疗大大减少了死亡的脊髓运动神经元在14周龄的突变体SOD 1 levels.Our的结果表明，PG延迟G93 A-SOD 1转基因小鼠的神经退行性疾病的进展，可能通过激活自噬在脊髓中的伴随减少。(C)版权所有© 2013 Elsevier Inc.
Progesterone (PG) exerts neuroprotective effects under conditions such as brain ischemia, traumatic brain injury, and spinal cord injury. Previously, we reported that PG activates autophagy, a potential neuroprotective mechanism, in cortical astrocytes. In the present study, we explored the possibility that PG, by activating autophagy in spinal cord cells, protects against motoneuron degeneration in transgenic (Tg) mice expressing the human G93A-SOD1 (superoxide dismutase 1) mutant, a model of amyotrophic lateral sclerosis.PG treatment increased autophagic flux in G93A-SOD1 Tg spinal cord astrocyte cultures and mice. In addition, PG treatment reduced mutant SOD1 protein levels and motoneuronal death. Inhibition of autophagy with 3-methyladenine (3MA) reversed these PG effects, indicating that activation of autophagy contributed to the PG neuroprotection. PG effects in vivo were tested by intraperitoneally injecting male G93A-SOD1 Tg mice with different doses of PG (2, 4, or 8 mg/kg) or vehicle from 70 days of age until death. Measurements of motor functions using rota-rod tests showed that the onset of symptoms was not different among groups, but the progression of motor dysfunction was significantly delayed in the PG-treated group compared with the vehicle control group. The average lifespan was also prolonged in the PG-injected group. Histological examinations revealed that PG treatment substantially reduced the death of spinal motoneurons at 14 weeks of age with a concomitant decrease in mutant SOD1 levels.Our results demonstrated that PG delays neurodegenerative progress in G93A-SOD1 transgenic mice, possibly through activation of autophagy in the spinal cord. (C) 2013 Elsevier Inc All rights reserved.