Biotransformation of nitric oxide in the cerebrospinal fluid of amyotrophic lateral sclerosis patients

Abstract

Recent findings indicate that nitric oxide (NO*) over-production might be an important factor in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS). We measured significantly higher concentrations of uric acid and thiol group-containing molecules (R-SH groups) in the cerebrospinal fluid (CSF) from SALS patients compared to controls. The above factors, together with a slightly increased free iron concentration found in the CSF, favour conditions necessary for the formation of the dinitrosyl iron complex, capable of NO* bio-transformation. Thus, we performed ex vivo saturation of CSF (from both SALS patients and controls) with NO*. A decrease in the level of R-SH was found. This was more pronounced in the CSF from SALS patients. In the CSF from SALS patients the production of nitrite and hydroxylamine was greater than that observed in the CSF from controls. Moreover, we also found increased Cu,Zn-SOD activity in the CSF from SALS patients (when compared to control subjects) but no activity corresponding to Mn-SOD in any CSF samples. As Cu,Zn-SOD can react with nitroxyl forming NO*, the conditions for a closed, but continuous, loop of NO* biotransformation are present in the CSF of ALS patients.

An exploratory study of serum urate levels in patients with amyotrophic lateral sclerosis

“…There is strong evidence that low serum urate concentrations are associated with an increased risk for Parkinson's disease (PD) [8][9][10][11][12][13], but data on the role of urate on cognitive impairment [14,15] and dementia conflict [16,17]. Similarly, the results of the few studies that have evaluated whether urate levels were associated with ALS also conflict [18][19][20].…”

The Correlation between Uric Acid Levels and Amyotrophic Lateral Sclerosis

“…Recent findings suggest that glutamate-med iated NO· overproduction and the subsequent generation of peroxynitrite play an important role in the pathogenesis of ALS [1]. Glutamate-mediated excitoto xicity is associated with adenosine triphosphate degradation, which is reflected by increased levels of extracellular hypo xanthine and xanthine and the generation of oxygen radicals.…”

“…The pathophysiology of amyotrophic lateral sclerosis (ALS) has been postulated to be related to o xidative stress fro m g lutamate-med iated excitotoxicity, especially since the discovery of Cu/Zn superoxide dis mutase (SOD) gene mutations in familial A LS and TDP -43 aggregation in sporadic ALS patients [1]. Recent findings suggest that glutamate-med iated NO· overproduction and the subsequent generation of peroxynitrite play an important role in the pathogenesis of ALS [1].…”

“…Uric acid (UA ) has the ability to react with peroxynit rite and stimulate the expression of extracellu lar SOD which may confer addit ional antio xidant protection, and has therapeutic action in mouse model of experimental autoimmune encephalomyelitis (EA E) by inactivating ONOO(-), preventing blood-brain barrier breakdown, and reducing neuroimmune responses [1]. It also stabilizes ascorbate, possibly by forming complexes with iron ions, and scavenges nitrogen radicals [2].…”

“…Glutamate-mediated excitoto xicity is associated with adenosine triphosphate degradation, which is reflected by increased levels of extracellular hypo xanthine and xanthine and the generation of oxygen radicals. As xanthine is degraded to uric acid, it has been shown that elevated levels of both xanthine and uric acid in the cerebrospinal fluid (CSF) are related to glutamate-mediated excitotoxicity in some neurological disorders [1].…”