Combination of tea catechins and ornithine effectively activates the urea cycle: an in vitro and human pilot study.

PURPOSE: Accumulation of ammonia causes central and peripheral fatigue. This study aimed to investigate the synergistic effect of tea catechins and low-dose ornithine in activating the urea cycle to reduce blood ammonia levels during exercise. METHODS: We used hepatocyte-like cells derived from human-induced pluripotent stem (iPS) cells to assess the effect of tea catechins combined with ornithine on urea cycle activity. The urea production and expression of key genes involved in the metabolism of urea were investigated. We then examined the synergistic improvement in ammonia metabolism by tea catechins in combination with ornithine in a human pilot study. RESULTS: Tea catechins combined with ornithine increased urea cycle activity in hepatocyte-like cells derived from human iPS cells. Intake of 538.6 mg of tea catechins with 1592 mg of ornithine for 2 consecutive days during exercise loading suppressed the exercise-induced increase in the blood ammonia concentration as well as stabilized blood glucose levels. CONCLUSION: Controlling the levels of ammonia, a toxic waste produced in the body, is important in a variety of situations, including exercise. The present study suggests that a heterogeneous combination of polyphenols and amino acids efficiently suppresses elevated ammonia during exercise in humans by a mechanism that includes urea cycle activation. TRIAL REGISTRATION: This study was registered in the University Hospital Medical Information Network Clinical Trial Registry (No. UMIN000035484, dated January 8, 2019).

Pentachlorophenol exposure induced neurotoxicity by disrupting citrulline metabolism in larvae and adult zebrafish.

Pentachlorophenol (PCP) is a ubiquitous environmental toxicant with various adverse effects. Although its neurotoxicity has been reported, the underlying mechanism and subsequent detoxification remain unclear. In this study, embryos and adult zebrafish were exposed to PCP to determine its potential neurotoxic mechanism and protective indicators. The survival rate, heart rate, mobility time, active status and moving distance were significantly decreased in larvae after 30 µg/L PCP exposure. Likewise, the mobile time, latency to the first movement, velocity and moving distance of adult zebrafish were significantly reduced by PCP exposure. Untargeted metabolomics analysis of larvae revealed that arginine and proline metabolism was the primary pathway affected by PCP exposure, reflected by increased proline and decreased citrulline (CIT) contents, which were confirmed by quantitative data. PCP exposure suppressed the conversion from arginine to CIT in larvae by downregulating the expression of nos1 and nos2a. Ornithine content was increased in the brains and intestines of adult zebrafish after PCP exposure, which inhibited ornithine catabolism to CIT by downregulating otc, resulting in reduced CIT. Intriguingly, CIT supplementation significantly restored the neurobehavioral defects induced by PCP in larvae and adult zebrafish. CIT supplementation upregulated the expression of ef1α and tuba1 in larvae and inhibited the downregulation of ef1α in the brains of adult zebrafish. Taken together, these results indicated that CIT supplementation could protect against PCP-induced neurotoxicity by upregulating the expression of genes involved in neuronal development and function.

Review of arginase as a promising biocatalyst: characteristics, preparation, applications and future challenges.

As a committed step in the urea cycle, arginase cleaves l-arginine to form l-ornithine and urea. l-Ornithine is essential to: cell proliferation, collagen formation and other physiological functions, while the urea cycle itself converts highly toxic ammonia to urea for excretion. Recently, arginase was exploited as an efficient catalyst for the environmentally friendly synthesis of l-ornithine, an abundant nonprotein amino acid that is widely employed as a food supplement and nutrition product. It was also proposed as an arginine-reducing agent in order to treat arginase deficiency and to be a means of depleting arginine to treat arginine auxotrophic tumors. Targeting arginase inhibitors of the arginase/ornithine pathway offers great promise as a therapy for: cardiovascular, central nervous system diseases and cancers with high arginase expression. In this review, recent advances in the characteristics, structure, catalytic mechanism and preparation of arginase were summarized, with a focus being placed on the biotechnical and medical applications of arginase. In particular, perspectives have been presented on the challenges and opportunities for the environmentally friendly utilization of arginase during l-ornithine production and in therapies.

Systemic L-ornithine supplementation specifically increases ovarian putrescine levels during ovulation in mice†.

In all mammalian species examined thus far, the ovaries produce a burst of ornithine decarboxylase (ODC) and putrescine during ovulation or after application of human chorionic gonadotropin (hCG). Aged mice have significantly reduced levels of this periovulatory ODC and putrescine rise. Putrescine supplementation, in vitro during oocyte maturation or in mouse drinking water during the periovulatory period, reduces egg aneuploidies and embryo resorption, improving fertility of aged mice. These studies suggest that periovulatory putrescine supplementation may be a simple and effective therapy for reproductive aging for women. However, putrescine supplementation is expected to increase widespread tissue putrescine levels, raising concerns of nonspecific and unwanted side effects. Given that ODC is highly expressed in the ovaries during ovulation but otherwise exhibits low activity in most tissues, we hypothesized that periovulatory supplementation of L-ornithine, the substrate of ODC, might be suitable for delivering putrescine specifically to the ovaries. In this study, we have demonstrated that systemic application of L-ornithine via oral gavage or subcutaneous injection increased ovarian putrescine levels; the increase was restricted to animals that had been injected with hCG. Furthermore, L-ornithine specifically increased ovarian putrescine levels without affecting putrescine levels in any other tissues. However, our attempts to improve fertility of aged mice through L-ornithine supplementation in mouse drinking water produced either no effects (1% L-ornithine) or negative impact on fertility (4% ornithine). Our results suggest that it might not be feasible to achieve fertility-enhancing ovarian putrescine levels via L-ornithine supplementation in drinking water without encountering undesired consequences of high dose of exogenous L-ornithine.

Arginine, ornithine and citrulline supplementation in rainbow trout: Free amino acid dynamics and gene expression responses to bacterial infection.

Supplementing the diet with functional ingredients is a key strategy to improve fish performance and health in aquaculture. The amino acids of the urea and nitric oxide (NO) cycles - arginine, ornithine and citrulline - perform crucial roles in the immune response through the generation of NO and the synthesis of polyamine used for tissue repair. We previously found that citrulline supplementation improves and maintains circulating free arginine levels in rainbow trout more effectively than arginine supplementation. Here, to test whether supplementation of urea cycle amino acids modulates the immune response in rainbow trout (Oncorhynchus mykiss), we supplemented a commercial diet with high levels (2% of total diet) of either arginine, ornithine or citrulline during a 7-week feeding trial, before challenging fish with the bacterium Aeromonas salmonicida. We carried out two separate experiments to investigate fish survival and 24 h post-infection to investigate the immediate response of free amino acid levels, and transcriptional changes in genes encoding urea cycle, NO cycle and polyamine synthesis enzymes. There were no differences in percentage fish mortality between diets, however there were numerous highly significant changes in free amino acid levels and gene expression to both dietary supplementation and infection. Out of 26 amino acids detected in blood plasma, 8 were significantly changed by infection and 9 by dietary supplementation of either arginine, ornithine or citrulline. Taurine, glycine and aspartic acid displayed the largest decreases in circulating levels in infected fish, while ornithine and isoleucine were the only amino acids that increased in concentration. We investigated transcriptional responses of the enzymes involved in arginine metabolism in liver and head kidney; transcripts for polyamine synthesis enzymes showed highly significant increases in both tissues across all diets following infection. The paralogous arginase-encoding genes, Arg1a, Arg1b, Arg2a and Arg2b, displayed complex responses across tissues and also due to diet and infection. Overall, these findings improve our understanding of amino acid metabolism following infection and suggests new potential amino acid targets for improving the immune response in salmonids.

Effects of ornithine α-ketoglutarate on growth performance and gut microbiota in a chronic oxidative stress pig model induced by d-galactose.

The aim of this study was to evaluate the protective effects and underlying mechanisms of ornithine α-ketoglutarate (OKG) on d-galactose (d-gal)-induced chronic oxidative stress in a pig model. A total of 40 castrated young pigs were randomly separated into five groups, including a control group, a model group treated with 5 mg per kg body weight (BW) d-gal, and three d-gal + OKG groups in which the pigs received 0.5%, 1%, and 2% OKG (n = 8). The experiment lasted for 28 days. The growth performance, serum oxidative stress index, expression of relative intestinal genes, gut microbiota, and serum amino acid pool were determined. The results demonstrated that administration of d-gal significantly affected growth performance and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels including related mRNA expression suppression, malondialdehyde (MDA) levels enhancement, gut microbiota dysfunction, and serum amino acid alteration in pigs. However, treatment with 0.5% OKG markedly ameliorated the reduction in the growth performance, as evidenced by the reversed final body weight, average feed intake, and average body weight. Also, 0.5% OKG enhanced the SOD and GSH-Px levels including relative mRNA expression in the intestine and inhibited lipid oxidation subsequent to MDA generation. The intestinal abundances of Firmicutes were increased and those of Proteobacteria, Fusobacteria, Bacteriodetes, and Euryarchaeota were decreased in the pigs supplemented with 0.5% OKG. Meanwhile, 0.5% OKG increased the glutamate, proline, aspartate, threonine, valine, isoleucine and leucine levels in the serum. Collectively, these results indicate that d-gal induced chronic oxidative stress and also proved the positive effects of 0.5% OKG on altering the pig gut microbe, restoring serum amino acid and alleviating the growth-suppression induced by d-gal chronic oxidative stress.

Preserving Mitochondrial Structure and Motility Promotes Recovery of White Matter After Ischemia.

Stroke significantly affects white matter in the brain by impairing axon function, which results in clinical deficits. Axonal mitochondria are highly dynamic and are transported via microtubules in the anterograde or retrograde direction, depending upon axonal energy demands. Recently, we reported that mitochondrial division inhibitor 1 (Mdivi-1) promotes axon function recovery by preventing mitochondrial fission only when applied during ischemia. Application of Mdivi-1 after injury failed to protect axon function. Interestingly, L-NIO, which is a NOS3 inhibitor, confers post-ischemic protection to axon function by attenuating mitochondrial fission and preserving mitochondrial motility via conserving levels of the microtubular adaptor protein Miro-2. We propose that preventing mitochondrial fission protects axon function during injury, but that restoration of mitochondrial motility is more important to promote axon function recovery after injury. Thus, Miro-2 may be a therapeutic molecular target for recovery following a stroke.

Effects of Dietary Arginine, Ornithine, and Zeolite Supplementation on Uremic Toxins in Cats.

To test if arginine and ornithine, both components of the Krebs-Henseleit cycle, or zeolite, a potential ammonium absorber, can modulate the excretion of harmful bacterial metabolites, intestinal microbial protein fermentation was stimulated by feeding a high-protein (60.3%) diet as a single daily meal to 10 adult cats. The diet was supplemented without or with arginine (+50, 75, 100% compared to arginine in the basal diet), ornithine (+100, 150, 200% compared to arginine in the basal diet), or zeolite (0.125, 0.25, 0.375 g/kg body weight/day). The cats received each diet for 11 days. Urine, feces, and blood were collected during the last 4 days. Arginine and ornithine enhanced the postprandial increase of blood urea, but renal urea excretion was not increased. Zeolite decreased renal ammonium excretion and fecal biogenic amines. The data indicate an increased detoxification rate of ammonia by arginine and ornithine supplementation. However, as urea was not increasingly excreted, detrimental effects on renal function cannot be excluded. Zeolite had beneficial effects on the intestinal nitrogen metabolism, which should be further evaluated in diseased cats. Clinical studies should investigate whether dietary arginine and ornithine might improve hepatic ammonia detoxification or could be detrimental for renal function.

Effectiveness of arginase inhibitors against experimentally induced stroke.

Stroke is a lethal disease, but it disables more than it kills. Stroke is the second leading cause of death and the most frequent cause of permanent disability in adults worldwide, with 90% of survivors having residual deficits. The pathophysiology of stroke is complex and involves a strong inflammatory response associated with oxidative stress and activation of several proteolytic enzymes. The current study was designed to investigate the effect of arginase inhibitors (L-citruline and L-ornithine) against ischemic stroke induced in rats by middle cerebral artery occlusion (MCAO). MCAO resulted in alteration in rat behavior, brain infarct, and edema associated with disruption of the blood-brain barrier (BBB). This was mediated through overexpression of arginase I and II, inducible NOS (iNOS), malondialdehyde (MDA), advanced glycation end products (AGEs), TNF-α, and IL-1ß and downregulation of endothelial nitric oxide synthase (eNOS). Treatment with L-citruline and L-ornithine and the standard neuroprotective drug cerebrolysin ameliorated all the deleterious effects of stroke. These results indicate the possible use of arginase inhibitors in the treatment of stroke after suitable clinical trials are done.

Stachytarpheta cayennensis extract inhibits promastigote and amastigote growth in Leishmania amazonensis via parasite arginase inhibition.

ETHNOPHARMACOLOGY RELEVANCE: Stachytarpheta cayennensis is a plant that is traditionally used to treat tegumentary leishmaniasis and as an anti-inflammatory agent. AIM OF THE STUDY: This study aimed to evaluate the action of S. cayennensis extracts on the Leishmania (Leishmania) amazonensis arginase enzyme. MATERIALS AND METHODS: S. cayennensis was collected from the Brazilian Amazon region. Aqueous extracts were fractionated with n-butanol. The leishmanicidal effects of the n-butanolic fraction (BUF) were evaluated in L. (L.) amazonensis promastigotes and amastigotes. BUF was tested against recombinant arginase from both L. (L.) amazonensis and macrophage arginase. Promastigote cultures and infected macrophage cultures were supplemented with L-ornithine to verify arginase inhibition. NMR analysis was used to identify the major components of BUF. RESULTS: BUF showed an EC50 of 51 and 32µg/mL against promastigotes and amastigotes of L. (L.) amazonensis, respectively. BUF contains a mixture of verbascoside and isoverbascoside (7:3 ratio) and is a potent L. (L.) amazonensis arginase inhibitor (IC50=1.2µg/mL), while macrophage arginase was weakly inhibited (IC50>1000µg/mL). The inhibition of arginase by BUF in promastigotes and amastigotes could be demonstrated by culture media supplementation with L-ornithine, a product of the hydrolysis of L-arginine by arginase. CONCLUSIONS: Leishmanicidal effects of the S. cayennensis BUF fraction on L. (L.) amazonensis are associated with selective parasite arginase inhibition.

Effect of long-term treatment of L-ornithine on visual function and retinal histology in the rats.

L-Ornithine is a non-proteinogenic amino acid, abundant in freshwater clams and commercially available as an oral nutritional supplement. L-Ornithine is metabolized by ornithine-δ-aminotransferase. Deficiency of this enzyme causes gyrate atrophy of the choroid and retina, an autosomal recessive hereditary disease characterized by the triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy, with hyperornithinemia. However, it is unknown whether long-term L-ornithine supplementation affects visual function and retinal histology. The aim of the present study is to determine the effect of long-term supplementation of excess amounts of L-ornithine on visual function and retinal histology in rats. Male Brown Norway rats at six weeks of age were allowed free access to chow containing 4% (w/w) L-ornithine (the high ornithine diet) or that containing 4% (w/w) casein (the control diet) for 49 weeks. The dose of L-ornithine calculated from the food intake was approximately 0.8 g/d/animal, which was 100 times higher than the recommended dose for healthy humans. The amplitude of the a-wave of the scotopic rod-cone electroretinogram and the number of cells in the ganglion cell layer in the L-ornithine-treated group were larger than those in the control group 49 weeks after initiating the test diet. No functional or histological damage to the retina was seen up to 49 weeks after the start of the high-ornithine diet. The present study demonstrated that long-term supplementation of very high doses of L-ornithine for at least 49 weeks did not induce retinal damage.

A highly potent agonist to protease-activated receptor-2 reveals apical activation of the airway epithelium resulting in Ca2+-regulated ion conductance.

The airway epithelium provides a barrier that separates inhaled air and its various particulates from the underlying tissues. It provides key physiological functions in both sensing the environment and initiating appropriate innate immune defenses to protect the lung. Protease-activated receptor-2 (PAR2) is expressed both apically and basolaterally throughout the airway epithelium. One consequence of basolateral PAR2 activation is the rapid, Ca(2+)-dependent ion flux that favors secretion in the normally absorptive airway epithelium. However, roles for apically expressed PAR2 activation have not been demonstrated, in part due to the lack of specific, high-potency PAR2 ligands. In the present study, we used the newly developed PAR2 ligand 2at-LIGRLO(PEG3-Pam)-NH2 in combination with well-differentiated, primary cultured airway epithelial cells from wild-type and PAR2 (-/-) mice to examine the physiological role of PAR2 in the conducting airway after apical activation. Using digital imaging microscopy of intracellular Ca(2+) concentration changes, we verified ligand potency on PAR2 in primary cultured airway cells. Examination of airway epithelial tissue in an Ussing chamber showed that apical activation of PAR2 by 2at-LIGRLO(PEG3-Pam)-NH2 resulted in a transient decrease in transepithelial resistance that was due to increased apical ion efflux. We determined pharmacologically that this increase in ion conductance was through Ca(2+)-activated Cl(-) and large-conductance K(+) channels that were blocked with a Ca(2+)-activated Cl(-) channel inhibitor and clotrimazole, respectively. Stimulation of Cl(-) efflux via PAR2 activation at the airway epithelial surface can increase airway surface liquid that would aid in clearing the airway of noxious inhaled agents.

Glutamine and ornithine alpha-ketoglutarate supplementation on malate dehydrogenases expression in hepatectomized rats.

PURPOSE: To evaluate the relative gene expression (RGE) of cytosolic (MDH1) and mitochondrial (MDH2) malate dehydrogenases enzymes in partially hepatectomized rats after glutamine (GLN) or ornithine alpha-ketoglutarate (OKG) suplementation. METHODS: One-hundred and eight male Wistar rats were randomly distributed into six groups (n=18): CCaL, GLNL and OKGL and fed calcium caseinate (CCa), GLN and OKG, 0.5 g/Kg by gavage, 30 minutes before laparotomy. CCaH, GLNH and OKGH groups were likewise fed 30 minutes before 70% partial hepatectomy. Blood and liver samples were collected three, seven and 14 days after laparotomy/hepatectomy for quantification of MDH1/MDH2 enzymes using the real-time polymerase chain reaction (PCR) methodology. Relative enzymes expression was calculated by the 2-(ΔΔC)T method using the threshold cycle (CT) value for normalization. RESULTS: MDH1/MDH2 RGE was not different in hepatectomized rats treated with OKG compared to rats treated with CCa. However, MDH1/MDH2 RGE was greater on days 3 (321:1/26.48:1) and 7 (2.12:1/2.48:1) while MDH2 RGE was greater on day 14 (7.79:1) in hepatectomized rats treated with GLN compared to control animals. CONCLUSION: Glutamine has beneficial effects in liver regeneration in rats by promoting an up-regulation of the MDH1 and MDH2 relative gene expression.

Glutamine and ornithine alpha-ketoglutarate supplementation on malate dehydrogenases expression in hepatectomized rats

PURPOSE: To evaluate the relative gene expression (RGE) of cytosolic (MDH1) and mitochondrial (MDH2) malate dehydrogenases enzymes in partially hepatectomized rats after glutamine (GLN) or ornithine alpha-ketoglutarate (OKG) suplementation. METHODS: One-hundred and eight male Wistar rats were randomly distributed into six groups (n=18): CCaL, GLNL and OKGL and fed calcium caseinate (CCa), GLN and OKG, 0.5g/Kg by gavage, 30 minutes before laparotomy. CCaH, GLNH and OKGH groups were likewise fed 30 minutes before 70% partial hepatectomy. Blood and liver samples were collected three, seven and 14 days after laparotomy/hepatectomy for quantification of MDH1/MDH2 enzymes using the real-time polymerase chain reaction (PCR) methodology. Relative enzymes expression was calculated by the 2-ΔΔC T method using the threshold cycle (CT) value for normalization. RESULTS: MDH1/MDH2 RGE was not different in hepatectomized rats treated with OKG compared to rats treated with CCa. However, MDH1/MDH2 RGE was greater on days 3 (321:1/26.48:1) and 7 (2.12:1/2.48:1) while MDH2 RGE was greater on day 14 (7.79:1) in hepatectomized rats treated with GLN compared to control animals. CONCLUSION: Glutamine has beneficial effects in liver regeneration in rats by promoting an up-regulation of the MDH1 and MDH2 relative gene expression. .

Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis.

RATIONALE: Neutrophil extracellular trap (NET) formation promotes vascular damage, thrombosis, and activation of interferon-α-producing plasmacytoid dendritic cells in diseased arteries. Peptidylarginine deiminase inhibition is a strategy that can decrease in vivo NET formation. OBJECTIVE: To test whether peptidylarginine deiminase inhibition, a novel approach to targeting arterial disease, can reduce vascular damage and inhibit innate immune responses in murine models of atherosclerosis. METHODS AND RESULTS: Apolipoprotein-E (Apoe)(-/-) mice demonstrated enhanced NET formation, developed autoantibodies to NETs, and expressed high levels of interferon-α in diseased arteries. Apoe(-/-) mice were treated for 11 weeks with daily injections of Cl-amidine, a peptidylarginine deiminase inhibitor. Peptidylarginine deiminase inhibition blocked NET formation, reduced atherosclerotic lesion area, and delayed time to carotid artery thrombosis in a photochemical injury model. Decreases in atherosclerosis burden were accompanied by reduced recruitment of netting neutrophils and macrophages to arteries, as well as by reduced arterial interferon-α expression. CONCLUSIONS: Pharmacological interventions that block NET formation can reduce atherosclerosis burden and arterial thrombosis in murine systems. These results support a role for aberrant NET formation in the pathogenesis of atherosclerosis through modulation of innate immune responses.

Retinal risks of high-dose ornithine supplements: a review.

We reviewed the literature on ornithine supplementation and related topics. Nutritionists and physicians have reported that ornithine supplementation is useful. Paediatricians and biochemists have reported that ornithine is supplemented for NH(3) detoxification in the hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome. In contrast, ophthalmic researchers have reported retinotoxicity associated with high-dose ornithine. In vivo and in vitro experiments have shown that high concentrations of ornithine or its metabolites are toxic to the retinal pigment epithelial (RPE) cells. Long-term (exceeding a few years) and high concentrations (exceeding 600 µmol/l) of ornithine in the blood induce retinal toxicity in gyrate atrophy of the choroid and retina (GA). Intermittent high levels of ornithine do not lead to retinal lesions. Constant blood ornithine levels between 250 and 600 µmol/l do not induce retinal lesions or cause a very slowly progressive retinal degeneration. Blood ornithine levels below 250 µmol/l do not produce retinal alteration. We concluded that short-term, low-dose or transient high-dose ornithine intake is safe for the retina; its nutritional usefulness and effect on NH(3) detoxification are supported by many researchers, but the effect may be limited; and long-term, high-dose ornithine intake may be risky for the retina. Patients with GA should avoid taking ornithine; amino acid supplementation should be administered carefully for patients with the HHH syndrome, relatives of patients with GA (heterozygotes) and subjects with RPE lesions; and blood ornithine levels and retinal conditions should be evaluated in individuals taking long-term, high-dose ornithine.

Ornithine alpha-ketoglutarate: could it be a new therapeutic option for sarcopenia?

Our current knowledge on the causes of sarcopenia is still fragmentary. One of the most evident candidates to explain muscle loss in elderly includes imbalance in protein turnover, i.e. decreased muscle protein synthesis rate, notably in the post-prandial state. Nutritional strategies such as leucine supplementation, use of fast digested proteins or a pulse protein intake have been show to enhance the synthesis rate of muscle proteins in older individuals. Ornithine alpha-ketoglutarate (OKG) is a precursor of amino acids such as glutamine, arginine and proline, and increases the secretion of anabolic hormones, i.e. insulin and growth hormone. A beneficial anabolic action of OKG has been demonstrate in several pathological conditions associated with muscle loss. Therefore, OKG may be of a potential interest to modulate muscle protein metabolism and to maintain muscle mass during aging.

L-ornithine supplementation attenuates physical fatigue in healthy volunteers by modulating lipid and amino acid metabolism.

We examined the effects of L-ornithine administration on physical fatigue. In a double-blind, placebo-controlled, 2-way crossover study, 17 healthy volunteers were randomized to L-ornithine (2000 mg/d for 7 days and 6000 mg/d for 1 day as L-ornithine hydrochloride) or placebo for 8 days. The fatigue-inducing physical task consisted of workload trials on a cycle ergometer at fixed workloads for 2 hours on 2 occasions. We found that oral L-ornithine administration promoted lipid metabolism and activated the urea cycle from serum triacylglycerol, ketone bodies, free fatty acids, and blood ammonia level changing. L-ornithine significantly attenuated the subjective feeling of fatigue (measured by visual analog scale at postrecovery) compared with postload (P < .01). Moreover, in female subjects, the subjective feeling of fatigue was significantly lower compared with the placebo group (P < .05). In the physical performance test in female subjects, the decrease in mean speed for 10 seconds maximum pedaling from 0.5- to 3.5-hour trials in the group receiving L-ornithine was smaller than that in the group receiving placebo (P < .05). These results suggest that L-ornithine has an antifatigue effect by increasing the efficiency of energy consumption and promoting the excretion of ammonia. L-ornithine is a free amino acid and is not rich in meats or fish, so it is difficult to obtain amounts of L-ornithine from ordinary meals that would be sufficient to promote the antifatigue effect. We recommend L-ornithine intake as a nutritional supplement in cases of physical fatigue.

Effect of ornithine alpha-ketoglutarate on glutamine pools in burn injury: evidence of component interaction.

BACKGROUND: Ornithine alpha-ketoglutarate (OKG) has proved to be efficient in restoring glutamine (Gln) pools which are strongly depleted in hypercatabolic patients. Since its two components, alpha-ketoglutarate (alphaKG) and ornithine (Orn), give rise to glutamate (Glu), they are both considered as Gln precursors. The aim of this study was to assess the relative contributions of Orn and alphaKG to Gln generation in a rat model of burn injury. METHODS: Forty-eight young Wistar rats were scalded to give a 20% burn surface area. They were fasted for 24 h and then refed by enteral nutrition for 48 h by gavages with Osmolite (Abbott-Ross, 210 kcal/kg day(-1), 1.18 N/kg day(-1)) supplemented with either 5 g OKG/kg day(-1) (B-OKG), Orn (isomolar to OKG; B-Orn), alphaKG (isomolar to OKG; B-KG) or glycine (as an isonitrogenous control; B-Gly). Rats in the B-KG group also received glycine to make all the groups isonitrogenous. Amino acid concentrations were determined in plasma, muscles, jejunal mucosa and liver. RESULTS: The alpha-KG-enriched diet had no effect on plasma Glu content or plasma and muscle Gln content compared with the burn-injured controls. The Orn-enriched diet significantly increased (p<0.01) muscle Glu and Gln contents but not plasma Gln content. In OKG-treated animals, plasma Gln as well as muscle Glu and Gln were significantly higher than in the control (p<0.01), alpha-KG-treated (p< 0.01) and Orn-treated (p<0.05 for muscle Gln and p<0.01 for plasma Gln) animals. CONCLUSION: OKG was more efficient than Orn or alphaKG alone in restoring Gln pools in plasma and muscle, which is evidence of metabolic interaction between the two components of this molecule.