NO/ONOO Cycle Uncpoupling by Resveratrol


Senior Member
The latest research on resveratrol shows that it is effective in down regulating the NO/ONOO cycle and can reduce nitric oxide uncoupling, which is the basis of Dr Martin Pall's NO/ONOO theory of the cause of CFS.

Superoxide generation is reduced and there is increased cell defence by increased levels of SOD, GPX,Catalase and most importantly reduction in the oxidation of BH4(Tetrahydrobiopterin).

People who have had the Acumen Lab tests will be familiar with the fact that CFS usually lowered these cell defences, allowing superoxide and peroxynitrite generation and the raising of the inflammatory cytokines.

J Pharmacol Exp Ther. 2010 Oct;335(1):149-54. Epub 2010 Jul 7.

Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice.
Xia N, Daiber A, Habermeier A, Closs EI, Thum T, Spanier G, Lu Q, Oelze M, Torzewski M, Lackner KJ, Mnzel T, Frstermann U, Li H.

Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany.

A crucial cause of the decreased bioactivity of nitric oxide (NO) in cardiovascular diseases is the uncoupling of the endothelial NO synthase (eNOS) caused by the oxidative stress-mediated deficiency of the NOS cofactor tetrahydrobiopterin (BH(4)). The reversal of eNOS uncoupling might represent a novel therapeutic approach. The treatment of apolipoprotein E knockout (ApoE-KO) mice with resveratrol resulted in the up-regulation of superoxide dismutase (SOD) isoforms (SOD1-SOD3), glutathione peroxidase 1 (GPx1), and catalase and the down-regulation of NADPH oxidases NOX2 and NOX4 in the hearts of ApoE-KO mice. This was associated with reductions in superoxide, 3-nitrotyrosine, and malondialdehyde levels. In parallel, the cardiac expression of GTP cyclohydrolase 1 (GCH1), the rate-limiting enzyme in BH(4) biosynthesis, was enhanced by resveratrol. This enhancement was accompanied by an elevation in BH(4) levels. Superoxide production from ApoE-KO mice hearts was reduced by the NOS inhibitor L-N(G)-nitro-arginine methyl ester, indicating eNOS uncoupling in this pathological model. Resveratrol treatment resulted in a reversal of eNOS uncoupling. Treatment of human endothelial cells with resveratrol led to an up-regulation of SOD1, SOD2, SOD3, GPx1, catalase, and GCH1. Some of these effects were preventable with sirtinol, an inhibitor of the protein deacetylase sirtuin 1. In summary, resveratrol decreased superoxide production and enhanced the inactivation of reactive oxygen species. The resulting reduction in BH(4) oxidation, together with the enhanced biosynthesis of BH(4) by GCH1, probably was responsible for the reversal of eNOS uncoupling. This novel mechanism (reversal of eNOS uncoupling) might contribute to the protective effects of resveratrol.

PMID: 20610621 [PubMed - indexed for MEDLINE
I havent read the whole study but I understand the equivelant dosage for humans in the study would be 500mg X 2 per day of resveratrol. Most supplement manufacturers dont recommend more than 200mg for humans because of possible long term side effects of high doses.