Cyclooxygenase-2 (COX-2) is reported to be activated during the course of amyotrophic lateral sclerosis (ALS) development and progression. However, the roles of COX-2 in aggravating ALS and the underlying mechanism have been largely overlooked. To reveal the mechanisms, the canonical SOD1G93A mouse model was used as an experimental model for ALS in the current study. In addition, a specific inhibitor of COX-2 activity, rofecoxib, was orally administered to SOD1G93A mice. With this in vivo approach, we revealed that COX-2 proinflammatory signaling cascades were inhibited by rofecoxib in SOD1G93A mice. Specifically, the protein levels of COX-2, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α were elevated as a result of activation of astrocytes and microglia during the course of ALS development and progression. These proinflammatory reactions may contribute to the death of neurons by triggering the movement of astrocytes and microglia to neurons in the context of ALS. Treatment with rofecoxib alleviated this close association between glial cells and neurons and significantly decreased the density of inflammatory cells, which helped to restore the number of motor neurons in SOD1G93A mice. Mechanistically, rofecoxib treatment decreased the expression of COX-2 and its downstream signaling targets, including IL-1β and TNF-α, by deactivating glial cells, which in turn ameliorated the progression of SOD1G93A mice by postponing disease onset and modestly prolonging survival. Collectively, these results provide novel insights into the mechanisms of ALS and aid in the development of new drugs to improve the clinical treatment of ALS.

中文翻译：

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罗非昔布通过减轻环加氧酶 2 介导的机制减轻肌萎缩侧索硬化的发病机制

据报道，环加氧酶 2 (COX-2) 在肌萎缩侧索硬化 (ALS) 的发展和进展过程中被激活。然而，COX-2 在加重 ALS 中的作用及其潜在机制在很大程度上被忽视了。为了揭示机制，在当前的研究中使用规范的 SOD1G93A 小鼠模型作为 ALS 的实验模型。此外，将 COX-2 活性的特异性抑制剂罗非昔布口服给药至 SOD1G93A 小鼠。通过这种体内方法，我们发现在 SOD1G93A 小鼠中，罗非昔布抑制了 COX-2 促炎信号级联反应。具体而言，在 ALS 发展和进展过程中，由于星形胶质细胞和小胶质细胞的活化，COX-2、白细胞介素 (IL)-1β 和肿瘤坏死因子 (TNF)-α 的蛋白质水平升高。在 ALS 的背景下，这些促炎反应可能通过触发星形胶质细胞和小胶质细胞向神经元的运动而导致神经元的死亡。罗非昔布治疗减轻了神经胶质细胞和神经元之间的这种密切联系，并显着降低了炎症细胞的密度，这有助于恢复 SOD1G93A 小鼠运动神经元的数量。从机制上讲，罗非昔布治疗通过使神经胶质细胞失活来降低 COX-2 及其下游信号靶标（包括 IL-1β 和 TNF-α）的表达，进而通过推迟疾病发作和适度延长生存期来改善 SOD1G93A 小鼠的进展。总的来说，这些结果提供了对 ALS 机制的新见解，并有助于开发新药以改善 ALS 的临床治疗。