Wenk Gary L, McGann-Gramling Kristin, Hauss-Wegrzyniak Beatrice, Ronchetti Daniela, Maucci Raffaella, Rosi Susanna, Gasparini Laura, Ongini Ennio
Division of Neural Systems, Memory and Aging, University of Arizona, Tucson, Arizona 85724, USA.
J Neurochem. 2004 Apr;89(2):484-93. doi: 10.1111/j.1471-4159.2004.02359.x.
Chronic neuroinflammation and oxidative stress contribute to the neurodegeneration associated with Alzheimer's disease and represent targets for therapy. Ferulic acid is a natural compound that expresses antioxidant and anti-inflammatory activities. Nitric oxide is also a key modulator of inflammatory responses. Grafting a nitric oxide-releasing moiety onto anti-inflammatory drugs results in enhanced anti-inflammatory activity. We compared the effectiveness of ferulic acid with a novel nitric oxide-releasing derivative of ferulic acid in an animal model of chronic neuroinflammation that reproduces many interesting features of Alzheimer's disease. Lipopolysaccharide was infused into the 4th ventricle of young rats for 14 days. Various doses of ferulic acid or its nitric oxide-releasing derivative were administered daily. Both drugs produced a dose-dependent reduction in microglia activation within the temporal lobe. However, the nitric oxide-releasing ferulic acid derivative was significantly more potent. If we delayed the initiation of therapy for 14 days, we found no reduction in microglial activation. In addition, both drugs demonstrated antioxidant and hydroxyl radical scavenging abilities in in vitro studies. Overall, our results predict that a treatment using nitric oxide-releasing ferulic acid may attenuate the processes that drive the pathology associated with Alzheimer's disease if the treatment is initiated before the neuroinflammatory processes can develop.
慢性神经炎症和氧化应激导致与阿尔茨海默病相关的神经退行性变，是治疗的靶点。阿魏酸是一种具有抗氧化和抗炎活性的天然化合物。一氧化氮也是炎症反应的关键调节因子。将一氧化氮释放基团嫁接到抗炎药物上可增强抗炎活性。我们在一种慢性神经炎症动物模型中比较了阿魏酸与一种新型阿魏酸一氧化氮释放衍生物的有效性，该模型再现了阿尔茨海默病的许多有趣特征。将脂多糖注入幼鼠第四脑室，持续14天。每天给予不同剂量的阿魏酸或其一氧化氮释放衍生物。两种药物均使颞叶内小胶质细胞活化呈剂量依赖性降低。然而，阿魏酸一氧化氮释放衍生物的效力明显更强。如果我们将治疗开始时间推迟14天，我们发现小胶质细胞活化没有降低。此外，两种药物在体外研究中均表现出抗氧化和清除羟自由基的能力。总体而言，我们的结果预测，如果在神经炎症过程发展之前开始治疗，使用阿魏酸一氧化氮释放衍生物进行治疗可能会减轻驱动与阿尔茨海默病相关病理过程的进程。
