Decrease in Asymmetrical Dimethylarginine, an Endogenous Nitric Oxide Synthase Inhibitor, in Cerebrospinal Fluid during Elderly Aging and in Patients with Sporadic Form of Amyotrophic Lateral Sclerosis

Abstract

Background: Oxidative stress has been implicated in nervous system aging and the pathogenesis of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. However, the effect of asymmetrical dimethylarginine (ADMA) was previously unknown. Objective: We aimed to investigate the significance of nitric oxide (NO)-mediated neuronal death during elderly aging and in ALS. To do so, the concentration of ADMA, an endogenous NO synthase inhibitor in the cerebrospinal fluid (CSF), was determined in neurologically normal controls and in patients with ALS. Materials and Methods: There were 20 untreated patients with ALS (M/F, 12/8) and 20 age-matched controls (M/F, 9/11), with a mean age (±SD) of 66.9 ± 9.2 years for patients and 65.1 ± 13.9 years for controls. The concentrations of ADMA and L-arginine (Arg) in the CSF of ALS patients were measured by high-performance liquid chromatography using an electrochemical detector. Control subjects were neurologically normal patients who underwent lumbar spinal anesthesia for minor surgery. Results: The ADMA concentration significantly decreased with age, whereas the Arg concentration was unaltered. In patients with ALS, the ADMA concentration was significantly decreased compared with controls of a similar age (–52%, p = 0.0001). It significantly decreased with decreasing global functions of ALS (r_s = –0.74, p < 0.005), whereas the Arg concentration did not change. Conclusion: These findings suggest that ADMA may play an important role in regulating NO synthesis in the nervous systems of the elderly during aging and in ALS.

NMR analysis of the CSF and plasma metabolome of rigorously matched amyotrophic lateral sclerosis, Parkinson’s disease and control subjects

“…ADMA is an endogenous inhibitor of nitric oxide synthase (Vallance and Leiper 2004), and consequently dimethylamine can be linked to the synthesis of nitric oxide and the regulation of oxidative stress. A previous report in fact observed reduced plasma concentration of ADMA in patients with the ALS disorder (Isobe et al 2010). A reduced level of ADMA in plasma from ALS patients was also found in the same patient cohort as analyzed here, by MS-based metabolomics (Wuolikainen et al 2016).…”

NO Orchestrates the Loss of Synaptic Boutons from Adult “Sick” Motoneurons: Modeling a Molecular Mechanism

“…There is evidence that the sum of nitrites and nitrates as end-products of NO increases in the cerebrospinal fluid (CSF) [153][154][155][156] and in the serum [157] of sALS patients, suggesting overproduction of NO. This could be partially explained by the reported reduction in the CSF of asymmetrical dimethylarginine [158], a naturally occurring NOS inhibitor in the nervous system [159]. Taking into account that ex vivo measurement of nitrite and nitrate accurately correlates with the activity of NOS in the brain [160], the pronounced increase found in ALS patients, together with the reduction in endogenous NOS inhibitors, may also suggest a role for NO in the pathogenesis of this disease.…”

Endothelium-dependent control of cerebrovascular functions through age: exercise for healthy cerebrovascular aging

“…Given that ADMA-induced endothelial dysfunction of cerebral arteries (52) is robust enough to decrease CBF in healthy humans (120), we could acknowledge that ADMA accumulation with age contributes to the development of age-related cerebrovascular disorders. Nevertheless, one study reported that ADMA cerebrospinal fluid concentration decreases with age (113). In addition to a dysfunctional eNOS, a rapid inactivation of NO by reactive oxygen species (ROS) could explain the saturated cerebral vasomotor responses seen in the elderly.…”