L-arginine as a medication

Background. L-arginine takes part in the ornithine cycle, in which ammonia is neutralized with urea formation. Accordingly, in the absence of L-arginine, toxic ammonia accumulates in the organism. Objective. To describe the use of L-arginine as a medication. Materials and methods. Analysis of literature sources on this topic. Results and discussion. Nitric oxide (NO) is a universal mediator in the regulation of cellular functions and intercellular communication. Deficiency of this substance is a key element of endothelial dysfunction. In the human body, NO is produced from L-arginine and performs an extremely important function of vasodilation due to the relaxation of vascular smooth muscle cells. Other physiological functions of NO include the transmission of neural signals in the central and peripheral nervous system, nervous activity, histamine secretion by mast cells, intestinal peristalsis, erection, killer action against bacteria and cancer cells. Arginine deficiency occurs in hypertension, coronary heart disease, obliterating disease of peripherl arteries, primary pulmonary hypertension, obstetric and perinatal pathological conditions. Potential ways to eliminate NO deficiency include the administration of its precursor – L-arginine (Tivortin, “Yuria-Pharm”) or its donors (molsidomine, nitrates). Tivortin has antioxidant and detoxifying effects, reduces endothelial dysfunction, activates urea synthesis, promotes glucose utilization, increases blood insulin. Conclusions. 1. NO deficiency is a key element of endothelial dysfunction. 2. Physiological functions of NO are vasodilation, transmission of neural signals, intestinal motility, etc. 3. In the human body NO is formed from L-arginine. 4. Arginine deficiency occurs in hypertension, coronary heart disease, obliterating disease of the peripheral arteries, primary pulmonary hypertension, obstetric and perinatal pathological conditions. 5. L-arginine (Tivortin) prescription is one of the ways to eliminate NO deficiency. 6. Tivortin has antioxidant and detoxifying effects, reduces endothelial dysfunction, and promotes glucose utilization.

Alteration of serum amino acid profiles by dietary adenine supplementation inhibits fatty liver development in rats

Studies on animal models have demonstrated that feeding a low-arginine diet inhibits triacylglycerol (TAG) secretion from the liver, resulting in marked fatty liver development in rats. Here, we first showed that culturing hepatocytes in the medium mimicking the serum amino acid profile of low-arginine diet-fed rats induced TAG accumulation in the cells, indicating that the specific amino acid profile caused TAG accumulation in hepatocytes. Dietary adenine supplementation completely recovered hepatic TAG secretion and abolished hepatic TAG accumulation in rats. A comprehensive non-linear analysis revealed that inhibition of hepatic TAG accumulation by dietary adenine supplementation could be predicted using only serum amino acid concentration data. Comparison of serum amino acid concentrations indicated that histidine, methionine, and branched-chain amino acid (BCAA) concentrations were altered by adenine supplementation. Furthermore, when the serum amino acid profiles of low-arginine diet-fed rats were altered by modifying methionine or BCAA concentrations in their diets, their hepatic TAG accumulation was abolished. Altogether, these results suggest that an increase in methionine and BCAA levels in the serum in response to dietary arginine deficiency is a key causative factor for hepatic TAG accumulation, and dietary adenine supplementation could disrupt this phenomenon by altering serum amino acid profiles.

Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells

Arginine deprivation therapy (ADT) is a new metabolic targeting approach with high therapeutic potential for various solid cancers. Combination of ADT with low doses of the natural arginine analog canavanine effectively sensitizes malignant cells to irradiation. However, the molecular mechanisms determining the sensitivity of intrinsically non-auxotrophic cancers to arginine deficiency are still poorly understood. We here show for the first time that arginine deficiency is accompanied by global metabolic changes and protein/membrane breakdown, and results in the induction of specific, more or less pronounced (severe vs. mild) ER stress responses in head and neck squamous cell carcinoma (HNSCC) cells that differ in their intrinsic ADT sensitivity. Combination of ADT with canavanine triggered catastrophic ER stress via the eIF2α-ATF4(GADD34)-CHOP pathway, thereby inducing apoptosis; the same signaling arm was irrelevant in ADT-related radiosensitization. The particular strong supra-additive effect of ADT, canavanine and irradiation in both intrinsically more and less sensitive cancer cells supports the rational of ER stress pathways as novel target for improving multi-modal metabolic anti-cancer therapy.

Hyperammonemia in azotemic cats

Objectives Hyperammonemia occurs in cats with hepatobiliary and nutritional (cobalamin and arginine deficiency) disorders, and has also been documented in four cats with renal azotemia. We hypothesized that in cats with renal azotemia, fasting hyperammonemia would correlate with indices of worsening kidney function, and would be independent of cobalamin, potassium, systemic inflammation or urinary tract infection (UTI) with urease-producing bacteria. Methods A fasted blood sample was prospectively collected for ammonia and cobalamin analysis from 18 client-owned cats with renal azotemia (creatinine [Cr] ⩾1.6 mg/dl, urine specific gravity <1.030 or documentation of historical chronic kidney disease [CKD]). Correlations between blood ammonia and selected biochemical parameters were analyzed using Pearson’s correlation coefficient. Results Seven castrated males and 11 spayed females with a median age of 12 years (range 4–19 years) were enrolled. Ten of 18 (56%) cats presented for acute kidney injury (AKI) or acute on chronic kidney disease (AoCKD), and 8/18 (44%) presented for progressive CKD. The median Cr was 5.9 mg/dl (range 1.9–24.7 mg/dl). Hyperammonemia was documented in 4/18 (22%) cats, with a median of 95 µmol/dl (range 85–98 µmol/dl), and all four of these cats were classified as AKI/AoCKD. Blood ammonia concentrations had a significant moderate positive correlation between blood urea nitrogen (BUN) ( r = 0.645, P = 0.003), Cr ( r = 0.578, P = 0.012) and serum phosphorus ( r = 0.714, P = 0.0009) but not with cobalamin, potassium or white blood cell count. No cats had UTIs with urease-producing bacteria. Conclusions and relevance A correlation exists between blood ammonia and BUN, Cr and phosphorus in cats with renal azotemia. Future studies are warranted in a larger population of cats to determine the true prevalence, etiology and potential therapeutic effect of medical management of hyperammonemia on long-term prognosis in cats with kidney disease.

Citrulline supplementation improves spatial memory in a murine model for Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) correlates with the dysfunction of metabolic pathways that translates into neurological symptoms. An arginine deficiency, a precursor of nitric oxide (NO), has been reported for AD patients.ObjectiveWe aimed to evaluate the effect of citrulline oral supplementation on cognitive decline in an AD murine model.MethosThree-month citrulline or water supplementation was blindly given to male and female wild type and 3xTg-AD mice trained and tested in the Morris Water Maze (MWM). Cerebrospinal fluid and brain tissue were collected. Ultra Performance Liquid Chromatography was used for arginine determinations while the Griess method was used for NO.ResultsEight-month-old male 3xTg-AD mice supplemented with citrulline performed significantly better in the MWM task; arginine levels increased in cerebrospinal fluid although no changes were seen in brain tissue and only a tendency of increase of NO was observed.ConclusionsCitrulline oral administration is a viable treatment for memory improvement in the early stages of AD pointing to NO as a viable, efficient target for memory dysfunction in AD.

Metabolomic Profiling of Plasma and Erythrocytes in Sickle Mice Points to Altered Nociceptive Pathways

Few data-driven metabolomic approaches have been reported in sickle cell disease (SCD) to date. We performed a metabo-lipidomic study on the plasma and red blood cells of a steady-state mouse model carrying the homozygous human hemoglobin SS, compared with AS and AA genotypes. Among the 188 metabolites analyzed by a targeted quantitative metabolomic approach, 153 and 129 metabolites were accurately measured in the plasma and red blood cells, respectively. Unsupervised PCAs (principal component analyses) gave good spontaneous discrimination between HbSS and controls, and supervised OPLS-DAs (orthogonal partial least squares-discriminant analyses) provided highly discriminant models. These models confirmed the well-known deregulation of nitric oxide synthesis in the HbSS genotype, involving arginine deficiency and increased levels of dimethylarginines, ornithine, and polyamines. Other discriminant metabolites were newly evidenced, such as hexoses, alpha-aminoadipate, serotonin, kynurenine, and amino acids, pointing to a glycolytic shift and to the alteration of metabolites known to be involved in nociceptive pathways. Sharp remodeling of lysophosphatidylcholines, phosphatidylcholines, and sphingomyelins was evidenced in red blood cells. Our metabolomic study provides an overview of the metabolic remodeling induced by the sickle genotype in the plasma and red blood cells, revealing a biological fingerprint of altered nitric oxide, bioenergetics and nociceptive pathways.

Arginine deficiency is involved in thrombocytopenia and immunosuppression in severe fever with thrombocytopenia syndrome

Severe fever with thrombocytopenia syndrome (SFTS) caused by a recently identified bunyavirus, SFTSV, is an emerging infectious disease with extensive geographical distribution and high mortality. Progressive viral replication and severe thrombocytopenia are key features of SFTSV infection and fatal outcome, whereas the underlying mechanisms are unknown. We revealed arginine deficiency in SFTS cases by performing metabolomics analysis on two independent patient cohorts, suggesting that arginine metabolism by nitric oxide synthase and arginase is a key pathway in SFTSV infection and consequential death. Arginine deficiency was associated with decreased intraplatelet nitric oxide (Plt-NO) concentration, platelet activation, and thrombocytopenia. An expansion of arginase-expressing granulocytic myeloid-derived suppressor cells was observed, which was related to T cell CD3-ζ chain down-regulation and virus clearance disturbance, implicating a role of arginase activity and arginine depletion in the impaired anti-SFTSV T cell function. Moreover, a comprehensive measurement of arginine bioavailability, global arginine bioavailability ratio, was shown to be a good prognostic marker for fatal prediction in early infection. A randomized controlled trial demonstrated that arginine administration was correlated with enhanced Plt-NO concentration, suppressed platelet activation, and elevated CD3-ζ chain expression and eventually associated with an accelerated virus clearance and thrombocytopenia recovery. Together, our findings revealed the arginine catabolism pathway–associated regulation of platelet homeostasis and T cell dysregulation after SFTSV infection, which not only provided a functional mechanism underlying SFTS pathogenesis but also offered an alternative therapy choice for SFTS.

Intracerebroventricular administration of L-arginine improves spatial memory acquisition in triple transgenic mice via reduction of oxidative stress and apoptosis

Arginine is one of the most versatile semi-essential amino acids. Further to the primary role in protein biosynthesis, arginine is involved in the urea cycle, and it is a precursor of nitric oxide. Arginine deficiency is associated with neurodegenerative diseases such as Parkinson’s, Huntington’s and Alzheimer’s diseases (AD). In this study, we administer arginine intracerebroventricularly in a murine model of AD and evaluate cognitive functions in a set of behavioral tests. In addition, the effect of arginine on synaptic plasticity was tested electrophysiologically by assessment of the hippocampal long-term potentiation (LTP). The effect of arginine on β amyloidosis was tested immunohistochemically. A role of arginine in the prevention of cytotoxicity and apoptosis was evaluated in vitro on PC-12 cells. The results indicate that intracerebroventricular administration of arginine improves spatial memory acquisition in 3xTg-AD mice, however, without significantly reducing intraneuronal β amyloidosis. Arginine shows little or no impact on LTP and does not rescue LTP deterioration induced by Aβ. Nevertheless, arginine possesses neuroprotective and antiapoptotic properties.