brief notes - uric acid, peroxynitrite, mannitol, eythritol

Got into a discussion about the U-shaped or J-shaped mortality curve for serum urate. U or J, there's an inflection point, and the lowest mortality is not at the extreme lower end. Could this be due to impaired kidney function causing both high mortality and low serum urate levels? Or is it because very low levels are harmful?

People with mutations in the urate transporter (URAT1) gene SLC22A12 have low levels of serum urate due to low resorption rate and have endothelial dysfunction, likely due to oxidative stress.

- Extremely Low Levels of Serum Uric Acid Are Associated With Endothelial Dysfunction in Humans https://www.jstage.jst.go.jp/article/circj/79/5/79_CJ-15-0232/_pdf/-char/en

Primates have evolved higher serum urate levels as the result of positive selection pressure through loss of the uricase gene and also increase in efficiency of the urate transporter.

 - Coevolution of URAT1 and Uricase during Primate Evolution:Implications for Serum Urate Homeostasis and Gout https://pubmed.ncbi.nlm.nih.gov/27352852/

This is despite the deleterious effects of high serum urate (it activates the NLRP3 inflammasome and increases risk of kidney stones, gout, cardiovascular disease and metabolic syndrome). Several theories have been proposed to explain this adaptation; there does not presently appear to be consensus on which is best. It is widely accepted that urate / uric acid is the main peroxynitrite scavenger in vivo; there is also experimental evidence indicating it has neuroprotective effects. This topic is of interest due to the association of low serum urate and risk of neurodegenerative diseases, e.g., Parkinson, Alzheimer, and multiple sclerosis. It's possible reverse causation is at work - the disease process causes increased oxidative stress which consumes UA - but assuming this is true, this indicates potential benefit to use of a peroxynitrite scavenger (or an agent that reduces generation of peroxynitrite, such as agmatine).

For some reason I thought perhaps erythritol might be a peroxynitrite scavenger; this article turned up in a search:

- Multi-Targeted Mechanisms Underlying the Endothelial Protective Effects of the Diabetic-Safe Sweetener Erythritol 

https://pubmed.ncbi.nlm.nih.gov/23755276/

"Another indication of the involvement of NO in endothelial cell death was found when HUVECs were incubated with the peroxynitrite generator SIN-1. We showed that SIN-1induced cell death, which was attenuated by ERT. Specifically for endothelial cells during diabetes, this is an important finding since peroxynitrite formation is likely to be increased during diabetes. Peroxynitrite is generated by the reaction of superoxide radicals with nitric oxide [37], the production of these precursors is known to be increased during diabetes [38,39]. Peroxynitrite can induce lipid peroxidation and protein nitrosylation and thus plays a role in diabetes related tissue damage [40]. In a previous study, ERT was shown to have peroxynitrite scavenging activity in an in vitro system[41]."

 

Nope, it was mannitol in Ref 41. Hope the rest of the article is accurate. (Note the protective effect of erythritol was only with exposure to high glucose levels.)

Ref 41:

 - OH-radical-type reactive oxygen species derived from superoxide and nitric oxide: a sensitive method for their determination and differentiation 

https://pubmed.ncbi.nlm.nih.gov/9462930/

"SIN-l-driven ethene release from KMB is inhibited to different degrees by SOD, hemoglobin,
BSA, uric acid, desferal, mannitol and formate, where hemoglobin is the best inhibitor by blocking the reaction by more than 95% (Fig. 3a). Catalase and EDTA are essentially without influence. The strong inhibition by desferal is more than surprising: this chelator is estimated as specific inhibitor for reactions including Fe2+/Fe3+-redox cycling and has been used as such for years by numerous workers and groups."

Does it work in vivo? Seems to:

- Iron-induced lipid peroxidation in spinal cord: protection with mannitol and methylprednisolone 

https://pubmed.ncbi.nlm.nih.gov/3013972/

"The ability of the free radical scavenger, mannitol, and the synthetic glucocorticoid, methylprednisolone sodium succinate (MPSS) to reverse the effects of iron catalyzed free radical induced lipid peroxidation was assessed in the feline spinal cord. Ferrous chloride (100 mM) was infused into the gray matter of lumbar spinal cord, the region frozen in situ, removed, and homogenates of the gray matter analyzed for activity of Na+,K+-ATPase and levels of malondialdehyde (MDA). ATPase activity had declined to approximately 30% of control by 2 h after FeCl2 infusion and remained at this level through 24 h. Malondialdehyde values were elevated almost twofold at 2 h. Mannitol essentially reversed the effects of FeCl2 infusion on Na+,K+-ATPase activity and MDA production. These results may implicate the hydroxyl radical (. OH), or an oxidizing species with . OH-like reactivity, as the initiating radical species in this model of lipid peroxidation."

  

Some people with Parkinson's have reported lessening of non-motor symptoms with mannitol consumption - mainly improvement in sense of smell. The mechanism of action is thought to be through osmotic stress induction of HSP70, a molecular chaperone, which reduces alpha synuclein aggregation: https://scienceofparkinsons.com/2018/05/30/mannitol/

Turqoise killifish (Nothobranchius furzeri)have been proposed as a natural model of PD; in the wild, they live in temporary pools and where experience drastic changes in osmolarity over the course of their lifespan. They are perhaps the shortest lived vertebrate species https://www.sciencedirect.com/science/article/pii/S2211124719300233