Attenuation of chronic neuroinflammation by a nitric oxide‐releasing derivative of the antioxidant ferulic acid

• Published in: Journal of neurochemistry Vol. 89; no. 2; pp. 484 - 493
• Main Authors: Wenk, Gary L., McGann‐Gramling, Kristin, Hauss‐Wegrzyniak, Beatrice, Ronchetti, Daniela, Maucci, Raffaella, Rosi, Susanna, Gasparini, Laura, Ongini, Ennio
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.04.2004; Blackwell
• Subjects: Alzheimer Disease - complications; Alzheimer Disease - drug therapy; Alzheimer Disease - pathology; Alzheimer's disease; Animals; Anti-Inflammatory Agents - pharmacology; Antioxidants - pharmacology; Biological and medical sciences; Butanes - pharmacology; Chronic Disease; Coumaric Acids - pharmacology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dentate Gyrus - drug effects; Dentate Gyrus - pathology; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Encephalitis - chemically induced; Encephalitis - pathology; Encephalitis - prevention & control; Entorhinal Cortex - drug effects; Entorhinal Cortex - pathology; ferulic acid; Isoquinolines - pharmacokinetics; Lipopolysaccharides; Male; Medical sciences; Microglia - drug effects; Microglia - pathology; NCX 2057; neuroinflammation; Neurology; nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Donors - pharmacology; Nitro Compounds - pharmacology; Rats; Rats, Inbred F344; Temporal Lobe - drug effects; Temporal Lobe - pathology; Time Factors; Treatment Outcome; Oxidative stress; Nervous system diseases; Rat; Alzheimer disease; Neuroglia; Rodentia; Inflammation; Antioxidant; Free radical; Cerebral disorder; Microglia; Ferulic acid; Vertebrata; Mammalia; neuroinflammation; Animal; Nitric oxide; Central nervous system disease; Degenerative disease; Alzheimer's disease; NCX 2057
• ISSN: 0022-3042; 1471-4159
• 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.