Attenuation of chronic neuroinflammation by a nitric oxide-releasing derivative of the antioxidant ferulic acid.
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.
Wenk
Gary L
GL
Division of Neural Systems, Memory and Aging, University of Arizona, Tucson, Arizona 85724, USA. gary@nsma.arizona.edu
McGann-Gramling
Kristin
K
Hauss-Wegrzyniak
Beatrice
B
Ronchetti
Daniela
D
Maucci
Raffaella
R
Rosi
Susanna
S
Gasparini
Laura
L
Ongini
Ennio
E
D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D002073:Butanes / Q000494:pharmacology*; D002908:Chronic Disease; D003373:Coumaric Acids / Q000494:pharmacology*; D018891:Dentate Gyrus / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004660:Encephalitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D018728:Entorhinal Cortex / Q000187:drug effects / Q000473:pathology; D007546:Isoquinolines / Q000493:pharmacokinetics; D008070:Lipopolysaccharides; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009574:Nitro Compounds / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013702:Temporal Lobe / Q000187:drug effects / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome
C484212:3-((4-hydroxy-3-methoxyphenyl)-2-propenoic acid 4-nitrooxy)butyl ester; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002073:Butanes; D003373:Coumaric Acids; D007546:Isoquinolines; D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D009569:Nitric Oxide; C004999:ferulic acid; C037850:PK 11195