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

Abstract

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 antiinflammatory 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 oxidereleasing 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.

Phenolic acids from malt are efficient acetylcholinesterase and butyrylcholinesterase inhibitors

“…Also, apoptotic features such as fragmentation of DNA, alterations in mitochondria and a decreased Bax (proapoptotic) to Bcl-2 (antiapoptotic) ratio in cells treated with b-amyloid were attenuated by the T. aestivum L. extract (47). Apoptotic death of the SH-SY5Y cells exposed to Ab [25][26][27][28][29][30][31][32][33][34][35] , manifested by a decrease in the mitochondrial transmembrane potential, was blocked after pretreatment with the T. aestivum extract. Also, the intracellular accumulation of reactive oxygen species was diminished by the presence of the extract.…”

“…The b-amyloid-and scopolamine-treated mice showed increased reaction times in a spatial memory test (water maze test), but the application of the T. aestivum extract reversed this effect. The total dietary fibre from T. aestivum L. effectively inhibited an Ab [25][26][27][28][29][30][31][32][33][34][35] -induced decrease in the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. The authors concluded that the attenuation of the cytotoxicity and the memory deficits caused by scopolamine could be attributed to the presence of phenolic acids in T. aestivum L.…”

“…Sodium ferulate partly reduced the decrease in phosphorylated extracellular signal-regulated kinases ERK1 and ERK2 and completely reversed the decrease in phosphorylated Akt/protein kinase B induced by b-amyloid- (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) in the hippocampal regions of the rat brain (66). Also, sodium ferulate inhibited a b-amyloid-(1-40)-induced increase in phosphorylated-p38 mitogen-activated protein kinase (MKK3/MKK6), partly prevented a decrease in phosphorylated MAPKAPK2 and Hsp27 expression, and inhibited the activation of caspase cascades (caspase-3, caspase-7 and caspase-3 activities) (67).…”

Antihypertensive effects and mechanisms of chlorogenic acids

“…57,58 Previous studies implicated that both ferulic acid and caffeic acid modulated NO pathways in the central nervous system. [59][60][61] Increased central NO had a role of restraining sympathetic outflow, 50,62,63 thereby attenuating reflex tachycardia when arterial baroreceptors were unloaded due to blood pressure reduction. 58 Although the current data on CGAs are promising, gaps in knowledge remain to be filled.…”

New organic nitrate-containing benzyloxy isonipecotanilide derivatives with vasodilatory and anti-platelet activity

“…1), i.e., 4-(ONO2)butyl esters of flurbiprofen and naproxen, respectively. HCT-1026 has been under study for its therapeutic use in a variety of conditions, including neurodegeneration and inflammation (Keeble and Moore, 2002;Scatena et al, 2005;Gasparini et al, 2005;Prosperi et al, 2004;Wenk et al, 2004Wenk et al, , 2002Ronchetti et al, 2009;Idris et al, 2004). HTC-3012, as single (S)-enantiomer, has been tested in clinical trials for the treatment of osteoarthritis (Geusens, 2009;Zhang et al, 2011).…”