Tripathy Debjani, Grammas Paula
Garrison Institute on Aging, Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.
J Neuroinflammation. 2009 Mar 16;6:10. doi: 10.1186/1742-2094-6-10.
Recent studies have demonstrated a link between the inflammatory response, increased cytokine formation, and neurodegeneration in the brain. The beneficial effects of anti-inflammatory drugs in neurodegenerative diseases, such as Alzheimer's disease (AD), have been documented. Increasing evidence suggests that acetaminophen has unappreciated anti-oxidant and anti-inflammatory properties. The objectives of this study are to determine the effects of acetaminophen on cultured brain neuronal survival and inflammatory factor expression when exposed to oxidative stress.
Cerebral cortical cultured neurons are pretreated with acetaminophen and then exposed to the superoxide-generating compound menadione (5 microM). Cell survival is assessed by MTT assay and inflammatory protein (tumor necrosis factor alpha, interleukin-1, macrophage inflammatory protein alpha, and RANTES) release quantitated by ELISA. Expression of pro- and anti-apoptotic proteins is assessed by western blots.
Acetaminophen has pro-survival effects on neurons in culture. Menadione, a superoxide releasing oxidant stressor, causes a significant (p < 0.001) increase in neuronal cell death as well as in the release of tumor necrosis factor alpha, interleukin-1, macrophage inflammatory protein alpha, and RANTES from cultured neurons. Pretreatment of neuronal cultures with acetaminophen (50 microM) increases neuronal cell survival and inhibits the expression of these cytokines and chemokines. In addition, we document, for the first time, that acetaminophen increases expression of the anti-apoptotic protein Bcl2 in brain neurons and decreases the menadione-induced elevation of the proapoptotic protein, cleaved caspase 3. We show that blocking acetaminophen-induced expression of Bcl2 reduces the pro-survival effect of the drug.
These data show that acetaminophen has anti-oxidant and anti-inflammatory effects on neurons and suggest a heretofore unappreciated therapeutic potential for this drug in neurodegenerative diseases such as AD that are characterized by oxidant and inflammatory stress.
近期研究表明，炎症反应、细胞因子生成增加与大脑神经退行性变之间存在联系。抗炎药物在神经退行性疾病如阿尔茨海默病（AD）中的有益作用已有文献记载。越来越多的证据表明，对乙酰氨基酚具有未被充分认识的抗氧化和抗炎特性。本研究的目的是确定对乙酰氨基酚在氧化应激条件下对培养的脑神经元存活及炎症因子表达的影响。
用对乙酰氨基酚预处理大脑皮质培养神经元，然后使其暴露于产超氧化物的化合物甲萘醌（5微摩尔）中。通过MTT法评估细胞存活情况，并用酶联免疫吸附测定法对炎症蛋白（肿瘤坏死因子α、白细胞介素-1、巨噬细胞炎症蛋白α和调节激活正常T细胞表达和分泌因子）的释放进行定量。通过蛋白质免疫印迹法评估促凋亡蛋白和抗凋亡蛋白的表达。
对乙酰氨基酚对培养中的神经元具有促存活作用。甲萘醌作为一种释放超氧化物的氧化应激源，可导致神经元细胞死亡显著增加（p < 0.001），同时培养神经元中肿瘤坏死因子α、白细胞介素-1、巨噬细胞炎症蛋白α和调节激活正常T细胞表达和分泌因子的释放也显著增加。用对乙酰氨基酚（50微摩尔）预处理神经元培养物可提高神经元细胞存活率，并抑制这些细胞因子和趋化因子的表达。此外，我们首次证明，对乙酰氨基酚可增加脑神经元中抗凋亡蛋白Bcl2的表达，并降低甲萘醌诱导的促凋亡蛋白裂解型半胱天冬酶3的升高。我们发现，阻断对乙酰氨基酚诱导的Bcl2表达可降低该药物的促存活作用。
这些数据表明，对乙酰氨基酚对神经元具有抗氧化和抗炎作用，并提示该药物在以氧化应激和炎症应激为特征的神经退行性疾病如AD中具有迄今未被充分认识的治疗潜力。
