Abstract
Background: L-arginine is an amino acid that can be metabolized to form several bioactive molecules including Nitric Oxide (NO). In the Central Nervous System (CNS), NO regulates various and important physiological functions. However, the involvement of L-arginine metabolism –and by extension of NO- in Alzheimer’s disease (AD) pathogenesis, has been suggested. Objective: To determine the Global L-Arginine Bioavailability Ratio (GABR) and NO levels (as the sum of nitrates and nitrites, NOx) in the plasma of early-stage Alzheimer’s Disease (AD) patients in order to analyze if GABR can reflect an altered NO production, to confirm the importance of L-arginine metabolism in the development of the disease, and to evaluate the putative diagnostic/prognostic value of GABR. Method: GABR index is an indicator of the availability of L-arginine to form NO by nitric oxide synthases. It is calculated as the ratio between the levels of L-arginine and the sum of the levels of L-ornithine and L-citrulline. Plasma amino acids are measured by high-performance liquid chromatography coupled to fluorescence detection. Nitric oxide is measured in plasma as the sum of nitrates and nitrites (NOx). Results: No changes were found in L-arginine levels, whereas L-citrulline and L-ornithine levels were highly increased in AD patients. We also found that GABR decreased significantly by 47.8% in AD patients, whereas NOx levels increased significantly by 46.9%. Receiver Operator Characteristic (ROC) curve analysis for GABR showed a sensitivity of 78.1 and a specificity of 90.5. Conclusion: Low plasma GABR levels in AD patients reflect that the L-arginine-NO pathway has turned towards NO in AD, probably being related to the nitroxidative stress involved in neurodegenerative diseases. Furthermore, increased NOx could also be involved in several altered physiological functions. Therefore, GABR is proposed as a putative useful biomarker of the disease.
Highlights
The L-arginine is a semi-essential amino acid that can be metabolized to form several bioactive molecules [1] including Nitric Oxide (NO)
Since NO can only be formed from L-arginine, and L-citrulline and L-ornithine are the products resulting from the metabolism of L-arginine, the Global Arginine Bioavailability (GABR) index can be calculated as the ratio between the levels of L-arginine and the sum of the levels of L-ornithine and L-citrulline and is an indicator of the availability of L-arginine to form NO by Nitric Oxide Synthases (NOS)
We examine here the GABR in early-stage Alzheimer’s Disease (AD) patients to analyze if this parameter can reflect an altered NO production, which would confirm the importance of L-arginine metabolism, and by extension, of NO, in the development of the disease, and if so, whether there is diagnostic/prognostic significance in measuring GABR in this patients
Summary
The L-arginine is a semi-essential amino acid that can be metabolized to form several bioactive molecules [1] including Nitric Oxide (NO). L-ornithine can be used to produce glutamate that can be further metabolized to generate the amino acids Gamma-Aminobutyric Acid (GABA) and glutamine through the enzymes glutamic acid decarboxylase and glutamine synthase, respectively [1, 23, 24]. It must be taken into account that it has been described decreased levels of glutamate and GABA in brains of AD patients and increased glutamine synthase enzyme in cerebrospinal fluid [25, 26]. The involvement of L-arginine metabolism –and by extension of NO- in Alzheimer’s disease (AD) pathogenesis, has been suggested
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