Bromocriptine methylate suppresses glial inflammation and moderates disease progression in a mouse model of amyotrophic lateral sclerosis
Bromocriptine methylate suppresses glial inflammation and moderates disease progression in a mouse model of amyotrophic lateral sclerosis
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DOI：
10.1016/j.expneurol.2011.08.001
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发表时间：
2011-11
影响因子：
5.3
通讯作者：
Kazunori Tanaka;T. Kanno;Y. Yanagisawa;K. Yasutake;S. Hadano;F. Yoshii;J. Ikeda
中科院分区：
文献类型：
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作者：
Kazunori Tanaka;T. Kanno;Y. Yanagisawa;K. Yasutake;S. Hadano;F. Yoshii;J. Ikeda
肌萎缩侧索硬化症（ALS）是一种成人发病的神经退行性疾病，其特征是选择性丧失上、下运动神经元。由于氧化应激在 ALS 中观察到的运动神经元损失的进展中起着至关重要的作用，因此抗氧化剂可能是 ALS 治疗的重要治疗手段。我们之前开发了一种药物筛选系统，可以识别上调内源性神经元凋亡抑制蛋白（NAIP）（一种氧化应激诱导的细胞死亡抑制剂）的小化合物。使用该系统，我们确定多巴胺 D2 受体激动剂溴隐亭 (BRC) 是 NAIP 上调化合物之一。在本研究中，为了证明 BRC 在 ALS 中的功效，我们使用携带人类铜/锌超氧化物歧化酶 (SOD1) 基因 ALS (SOD1H46R) H46R 突变的转基因 ALS 小鼠模型，通过发病后服用 BRC 进行了一系列临床前研究。接受 BRC 的 ALS(SOD1H46R) 小鼠在发病后表现出持续的运动功能和适度延长的生存期。此外，BRC治疗延迟了晚期症状小鼠脊髓中的前角细胞损失，并减少了反应性星形胶质细胞的数量和炎症因子的水平，例如诱导型一氧化氮合酶（iNOS）和肿瘤坏死因子（TNF）-α。体外研究表明，经 BRC 处理的小鼠星形胶质细胞暴露于脂多糖 (LPS) 后，细胞外 TNF-α 水平降低。 BRC 治疗的 ALS(SOD1H46R) 小鼠还表现出脊髓氧化损伤水平降低。值得注意的是，BRC 处理导致抗氧化应激基因上调，激活转录因子 3 (ATF3) 和血红素加氧酶-1 (HO-1)，并以不依赖多巴胺受体的方式在 SH-SY5Y 培养的神经元细胞中产生谷胱甘肽 (GSH)。这些结果表明 BRC 通过抑制 ALS(SOD1H46R) 小鼠脊髓中的星形胶质细胞增生来保护运动神经元免受氧化损伤。因此，BRC 可能是治疗 ALS 的有前途的治疗剂。
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by a selective loss of upper and lower motor neurons. Since oxidative stress plays a crucial role in the progression of motor neuron loss observed in ALS, anti-oxidative agents could be an important therapeutic means for the ALS treatment. We have previously developed a drug screening system allowing the identification of small chemical compounds that upregulate endogenous neuronal apoptosis inhibitory protein (NAIP), an oxidative stress-induced cell death suppressor. Using this system, we identified the dopamine D2 receptor agonist bromocriptine (BRC) as one of NAIP-upregulating compounds. In this study, to prove the efficacy of BRC in ALS, we conducted a set of preclinical studies using a transgenic ALS mouse model carrying the H46R mutation in the human Cu/Zn superoxide dismutase (SOD1) gene ALS(SOD1H46R) by the post-onset administration of BRC. ALS(SOD1H46R) mice receiving BRC showed sustained motor functions and modest prolonged survival after onset. Further, BRC treatment delayed anterior horn cell loss, and reduced the number of reactive astrocytes and the level of inflammatory factors such as inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-α in the spinal cord of late symptomatic mice. In vitro study showed the reduced level of extracellular TNF-α after lipopolysaccharide (LPS) exposure in BRC-treated mouse astrocytes. BRC-treated ALS(SOD1H46R) mice also showed a reduced level of oxidative damage in the spinal cord. Notably, BRC treatment resulted in an upregulation of anti-oxidative stress genes, activating transcription factor 3 (ATF3) and heme oxygenase-1 (HO-1), and the generation of a glutathione (GSH) in SH-SY5Y cultured neuronal cells in a dopamine receptor-independent manner. These results imply that BRC protects motor neurons from the oxidative injury via suppression of astrogliosis in the spinal cord of ALS(SOD1H46R) mice. Thus, BRC might be a promising therapeutic agent for the treatment of ALS.