Effects of the PPARγ activator pioglitazone on p38 MAP kinase and IκBα in the spinal cord of a transgenic mouse model of amyotrophic lateral sclerosis
Effects of the PPARγ activator pioglitazone on p38 MAP kinase and IκBα in the spinal cord of a transgenic mouse model of amyotrophic lateral sclerosis
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DOI：
10.1111/j.1440-1789.2008.00890.x
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发表时间：
2008-08-01
期刊：
影响因子：
2.3
通讯作者：
Kobayashi, Makio
中科院分区：
文献类型：
--
作者：
Shibata, Noriyuki;Kawaguchi-Niida, Motoko;Kobayashi, Makio
新的证据表明程序性细胞死亡和炎症与肌萎缩侧索硬化症（ALS）有关。为了评估抗炎过氧化物酶体增殖物激活受体-γ（PPARγ）激动剂吡格列酮对 ALS 的分子病理学作用，我们验证了吡格列酮治疗组和未治疗组小鼠脊髓腰段腹角中神经元、星形胶质细胞和小胶质细胞数量的变化。 G93A 突变型人超氧化物歧化酶-1 (SOD1)（ALS 小鼠）和非转基因同窝小鼠（对照小鼠）的转基因，对 PPAR γ、磷酸化 p38 丝裂原激活蛋白激酶 (p-p38) 的活性形式和核因子 kappaB 抑制剂进行免疫组织化学和免疫印迹分析 (NF-kappa B)-alpha (I kappa B alpha) 在脊髓中，并比较不同组之间的结果。图像分析显示，症状前和晚期 ALS 小鼠的未治疗组中 NeuN 免疫反应性神经元的光密度显着低于年龄匹配对照小鼠的未治疗组，并通过吡格列酮治疗恢复，并且 GFAP 免疫反应性星形胶质细胞和 Iba1 免疫反应性小胶质细胞的光密度 未治疗的晚期 ALS 小鼠组明显高于未治疗的对照小鼠组，并通过吡格列酮治疗恢复。免疫组织化学分析表明，PPAR γ 和 p-p38 的免疫反应性主要位于神经元中，I kappa B α 免疫反应性主要位于星形胶质细胞和小胶质细胞中。免疫印迹分析表明，吡格列酮治疗导致核 PPAR γ 免疫反应密度没有显着变化，胞质 p-p38 免疫反应密度显着降低，胞质 I kappa B α 免疫反应密度显着增加。我们的结果表明，吡格列酮通过 PPAR γ 独立机制保护运动神经元免受 p38 介导的神经元死亡和 NF-κ B 介导的神经胶质炎症。
Emerging evidence suggests the involvement of programmed cell death and inflammation in amyotrophic lateral sclerosis (ALS). To assess molecular pathological effects of the anti-inflammatory peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonist pioglitazone in ALS, we verified changes in the population of neurons, astrocytes, and microglia in the ventral horns of spinal cord lumbar segments from the pioglitazone-treated and non-treated groups of mice carrying a transgene for G93A mutant human superoxide dismutase-1 (SOD1) (ALS mice) and non-transgenic littermates (control mice), performed immunohistochemical and immunoblot analyses of PPAR gamma, active form of phosphorylated p38 mitogen-activated protein kinase (p-p38) and inhibitor of nuclear factor-kappaB (NF-kappa B)-alpha (I kappa B alpha) in the spinal cords, and compared the results between the different groups. Image analysis revealed that optical density of NeuN-immunoreactive neurons was significantly lower in the non-treated groups of presymptomatic and advanced ALS mice than in the non-treated groups of age-matched control mice and was recovered with pioglitazone treatment, and that optical densities of GFAP-immunoreactive astrocytes and Iba1-immunoreactive microglia were significantly higher in the non-treated group of advanced ALS mice than in the non-treated group of control mice and were recovered with pioglitazone treatment. Immunohistochemical analysis demonstrated that immunoreactivities for PPAR gamma and p-p38 were mainly localized in neurons, and that I kappa B alpha immunoreactivity was mainly localized in astrocytes and microglia. Immunoblot analysis showed that pioglitazone treatment resulted in no significant change in nuclear PPAR gamma-immunoreactive density, a significant decrease in cytosolic p-p38-immunoreactive density, and a significant increase in cytosolic I kappa B alpha-immunoreactive density. Our results suggest that pioglitazone protects motor neurons against p38-mediated neuronal death and NF-kappa B-mediated glial inflammation via a PPAR gamma-independent mechanism.