why iNOS inhibition?



Someone on a forum asked why iNOS inhibitors (e.g., agmatine, anatabine) would be beneficial and my reply follows:

Too much NO generates peroxyynitrite and can cause nitrosative and oxidative stress, causing production of nitrated/oxidized alpha synuclein and oxidized dopamine. NO generated by iNOS in glial cells is particularly problematic for neurons. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408780/

This is in contrast with NO generated by the endothelium during exercise, which acts on the endothelium (autocrine signalling) which in turn produces good things like BDNF (the vascular endothelium can be thought of as an endocrine organ). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791344/ https://youtu.be/lhZZS6_-Cg4

There are lots of studies on iNOS inhibitors in models of Parkinson's and other neurodegenerative disease. https://pubmed.ncbi.nlm.nih.gov/31192483/

Tobacco use and Solanaceae vegetable consumption are associated with reduced risk of PD. If causal, the relationship may be due to nicotine, which reduces iNOS expression. Anatabine is another possible active constituent; anatabine is an iNOS inhibitor. Capsinoids have also been suggested - they work by another mechanism, via TRPV1 receptor activation. https://pubmed.ncbi.nlm.nih.gov/23661325/

Interestingly, arginine was found to inhibit protein aggregation in models of spinocerebellar ataxia and some people with SCA are taking arginine as a supplement in hopes of reducing progression. https://academic.oup.com/brain/article-abstract/143/6/1811/5841546

Dr Nathan Bryan, developer of Neo40, says not to take arginine since it is possible it could promote oxidative/nitrosative stress in some situations. https://youtu.be/ZtFsQ_-jK1g

Neo40 contains citrulline, nitrite, B12, vit C, hawthorn berry extract and beet extract. https://clinicaltrials.gov/ct2/show/NCT02934438

I am curious to know what his thoughts would be on the potential use of arginine for SCA or other neurodegenerative diseases.

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