Ornithine Alpha-ketoglutarate Research Articles

Nutritional interventions for preventing and treating pressure ulcers.

Nutritional interventions for preventing and treating pressure ulcers.

Alpha-ketoglutarate (AKG) inhibits proliferation of colon adenocarcinoma cells in normoxic conditions

Background and objective. Alpha-ketoglutarate (AKG), a key intermediate in Krebs cycle, is an important biological compound involved in the formation of amino acids, nitrogen transport, and oxidation reactions. AKG is already commercially available as a dietary supplement and its supplementation with glutamine, arginine, or ornithine alpha-ketoglutarate has been recently considered to improve anticancer immune functions. It is well documented that AKG treatment of Hep3B hepatoma cells in hypoxia induced HIF-alpha (hypoxia-inducible factor) degradation and reduced vascular endothelial growth factor (VEGF) synthesis. Moreover, AKG showed potent antitumor effects in murine tumor xenograft model, inhibiting tumor growth, angiogenesis, and VEGF gene expression. However, the mechanisms of its anticancer activity in normoxia have not been examined so far. Results. Here, we report that in normoxia, AKG inhibited proliferation of colon adenocarcinoma cell lines: Caco-2, HT-29, and LS-180, representing different stages of colon carcinogenesis. Furthermore, AKG influenced the cell cycle, enhancing the expression of the inhibitors of cyclin-dependent kinases p21 Waf1/Cip1 and p27 Kip1. Moreover, expression of cyclin D1, required in G1/S transmission, was decreased, which accompanied with the significant increase in cell number in G1 phase. AKG affected also one the key cell cycle regulator, Rb, and reduced its activation status. Conclusion. In this study for the first time, the antiproliferative activity of AKG on colon adenocarcinoma Caco-2, HT-29, and LS-180 cells in normoxic conditions was revealed. Taking into consideration an anticancer activity both in hypoxic and normoxic conditions, AKG may be considered as a new potent chemopreventive agent.

Advances and challenges in the treatment of branched‐chain amino/keto acid metabolic defects

Disorders of branched-chain amino/keto acid metabolism encompass diverse entities, including maple syrup urine disease (MSUD), the 'classical' organic acidurias isovaleric acidemia (IVA), propionic acidemia (PA), methylmalonic acidemia (MMA) and, among others, rarely described disorders such as 2-methylbutyryl-CoA dehydrogenase deficiency (MBDD) or isobutyryl-CoA dehydrogenase deficiency (IBDD). Our focus in this review is to highlight the biochemical basis underlying recent advances and ongoing challenges of long-term conservative therapy including precursor/protein restriction, replenishment of deficient substrates, and the use of antioxidants and anaplerotic agents which refill the Krebs cycle. Ongoing clinical assessments of affected individuals in conjunction with monitoring of disease-specific biochemical parameters remain essential. It is likely that mass spectrometry-based 'metabolomics' may be a helpful tool in the future for studying complete biochemical profiles and diverse metabolic phenotypes. Prospective studies are needed to test the effectiveness of adjunct therapies such as antioxidants, ornithine-alpha-ketoglutarate (OKG) or creatine in addition to specialized diets and to optimize current therapeutic strategies in affected individuals. With the individual life-time risk and degree of severity being unknown in asymptomatic individuals with MBDD or IBDD, instructions regarding risks for metabolic stress and fasting avoidance along with clinical monitoring are reasonable interventions at the current time. Overall, it is apparent that carefully designed prospective clinical investigations and multicenter cohort-controlled trials are needed in order to leverage that knowledge into significant breakthroughs in treatment strategies and appropriate approaches.

Effect of short-term ornithine alpha-ketoglutarate pretreatment on intestinal ischemia-reperfusion in rats

To investigate the effects of preventive enteral administration of ornithine alpha-ketoglutarate (OKG) in an ischemia-reperfusion rat model. Sixty rats were randomized into five groups (G1-G5, n = 12). Each group was divided into two subgroups (n = 6) and treated with calcium carbonate (CaCa) or OKG by gavage. Thirty minutes later, the animals were anesthetized with xylazine 15mg + ketamine 1mg ip and subjected to laparotomy. G1-G3 rats served as controls. Rats in groups G4 and G5 were subjected to ischemia for 30 minutes. Ischemia was achieved by clamping the small intestine and its mesentery, delimiting a segment of bowel 5 cm long and 5 cm apart from the ileocecal valve. In addition, G5 rats underwent reperfusion for 30 minutes. Blood samples were collected at the end of the laparotomy (G1), after 30 minutes (G2, G4) and 60 minutes (G3, G5) to determine concentrations of metabolites (pyruvate, lactate), creatine phosphokinase (CPK), thiobarbituric acid reactive substances (TBARS) and glutathione (GSH). There was a significant decrease in tissue pyruvate and lactate and plasma CPK levels in OKG-treated rats at the end of reperfusion period. GSH levels did not change significantly in ischemia and reperfusion groups. However, TBARS levels increased significantly (p<0.05) in tissue samples in OKG-treated rats subjected to ischemia for 30 minutes. Short-term pretreatment with OKG before induction of I/R decreases tissue damage, increases pyruvate utilization for energy production in the Krebs cycle and does not attenuate the oxidative stress in this animal model.

Antiosteopenic effect of ornithine alpha-ketoglutarate (OKG) administration in female turkeys

Antiosteopenic effect of ornithine alpha-ketoglutarate (OKG) administration in female turkeys

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.

Amino acids - Guidelines on Parenteral Nutrition, Chapter 4.

Protein catabolism should be reduced and protein synthesis promoted with parenteral nutrion (PN). Amino acid (AA) solutions should always be infused with PN. Standard AA solutions are generally used, whereas specially adapted AA solutions may be required in certain conditions such as severe disorders of AA utilisation or in inborn errors of AA metabolism. An AA intake of 0.8 g/kg/day is generally recommended for adult patients with a normal metabolism, which may be increased to 1.2–1.5 g/kg/day, or to 2.0 or 2.5 g/kg/day in exceptional cases. Sufficient non-nitrogen energy sources should be added in order to assure adequate utilisation of AA. A nitrogen calorie ratio of 1:130 to 1:170 (g N/kcal) or 1:21 to 1:27 (g AA/kcal) is recommended under normal metabolic conditions. In critically ill patients glutamine should be administered parenterally if indicated in the form of peptides, for example 0.3–0.4 g glutamine dipeptide/kg body weight/day (=0.2–0.26 g glutamine/kg body weight/day). No recommendation can be made for glutamine supplementation in PN for patients with acute pancreatitis or after bone marrow transplantation (BMT), and in newborns. The application of arginine is currently not warranted as a supplement in PN in adults. N-acetyl AA are only of limited use as alternative AA sources. There is currently no indication for use of AA solutions with an increased content of glycine, branched-chain AAs (BCAA) and ornithine-α-ketoglutarate (OKG) in all patients receiving PN. AA solutions with an increased proportion of BCAA are recommended in the treatment of hepatic encephalopathy (III–IV).

Efficacy and safety of ornithine alpha-ketoglutarate in heel pressure ulcers in elderly patients: Results of a randomized controlled trial

ObjectivePressure ulcers affect predominantly the elderly and nutritional status is a known risk factor. Guidelines on pressure ulcers provide recommendation on nutritional management. Ornithine alpha-ketoglutarate (OKG) is an adjuvant treatment in undernourished elderly patients or in patients with hypercatabolism states. It is a precursor of different amino-acids which play a role in the process of healing. The objective of the study is to determine the efficacy of OKG on pressure ulcer area reduction after six weeks of treatment. DesignMulti-centre, international, randomized, comparative, double blind, parallel groups, placebo-controlled study. Participants160 patients (ITT population) aged over 60 years with a heel pressure ulcer at stage II or III. InterventionPatients received OKG (n=85) or placebo (n=75) once a day for 6 weeks. MeasurementsUlcer area was measured each week, using a tracer. The primary endpoint was the percentage reduction of the surface at the final visit: [(Wound areatn — Wound areat0)/(Wound areat0)]. ResultsAt inclusion, ulcer area distribution deviated from normal distribution (median ulcer area OKG 6.6cm2, placebo 3.9 cm2, p=0.044, Mann-Whitney test). As healing is strongly related to baseline ulcer area, the abnormal distribution was a major bias. Therefore it was decided to perform the analysis on 2 sub-groups of patients according to the mean ulcer area, i.e. above or below 8cm2. The mean wound area reduction for baseline area ≤ 8 cm2 are −59. 5 ± 71.4% and −54.0 ± 69.0% for the OKG group and placebo groups respectively (p=0.477, Mann-Whitney test). In the group with baseline pressure ulcer area > 8 cm2 no between group differences on either parameter was detected. When closure rate is considered, a significant difference in favor of OKG group is observed (− 0.07 cm2/day in the OKG group and − 0.04 cm2/day in the placebo groups respectively p=0.007, Mann-Whitney test). Thirty serious adverse events were reported in 28 patients (15 allocated to OKG and 13 to placebo). None of them was considered treatment related. ConclusionThis clinical trial supports a potential benefit of OKG 10g daily in the subgroup of patients with pressure ulcers ≤ 8 cm2 surface area in elderly population when associated with debridement together with wound management according to pressure ulcer guidelines. However this study highlights methodological difficulties to perform clinical trials in old-old patients that may affect the robustness of the results for this type of study.

No effect of ornithine alphaketoglutarate on nitrogen excretion or urea synthesis rate in healthy male subjects

Summary Background & aims Ornithine alphaketoglutarate (OKG) is known for its anabolic and anticatabolic effects. Little is known about its effect on proteolysis. We studied urea formation and nitrogen excretion rates following OKG supplementation in healthy volunteers. Methods Sixteen male subjects were kept on a diet stable in protein (1 g kg−1 d−1) and aimed at maintaining body weight. They received oral supplementation of OKG (10 g) or an isonitrogenous placebo ( l -alanine) from days 4 to 6 in single daily doses in a randomised, blinded fashion. Urea kinetics were studied on day 4 from plasma urea enrichments following an oral [13C]urea bolus. Nitrogen excretion was assessed from 24-h urine collections prior to supplementation, on day 4 and day 7. Results Mean urea rate of appearance was 380±86 and 353±120 μmol kg−1 h−1 in the OKG and placebo group, respectively (p=0.62). There were no significant differences in 24-h nitrogen excretion data between groups, neither at separate time points, in overall values (p=0.40) nor in development over time (p=0.53). Conclusions A single oral dose of OKG did not affect urea production rate differently than the alanine placebo. OKG supplementation led to a temporary increase in nitrogen excretion, as did administration of placebo.

Effects of ornithine α-ketoglutarate on protein metabolism in Yoshida sarcoma-bearing rats

Ornithine alpha-ketoglutarate (OKG) is recognized to improve nutritional status in various catabolic states, such as burn injury, trauma, and sepsis. However, in wasting diseases, such as induced by cancer, the data are scarce and the precise mechanisms by which OKG acts on protein metabolism are still unclear. The aim of this study was to evaluate the ability of OKG to affect protein metabolism in an aggressive model of cancer and to modulate the ubiquitin-proteasome-dependent pathway, which in skeletal muscle is the critical degradative pathway implicated in many catabolic states, including cancer-associated cachexia. Experiments were carried out in Yoshida sarcoma-bearing and healthy pair-fed rats. Three groups of 16 young male rats were studied during 9 days following tumor implantation: two groups of tumor-bearing rats fed a balanced regimen enriched with either OKG (5 g/kg body weight/day, OKG-K) or an isonitrogenous mixture of non-essential amino acids (C-K), and one group of healthy pair-fed rats (PF). As expected, Yoshida sarcoma induced muscle atrophy, decreased nitrogen balance, enhanced 3-methylhistidine (3-MH) excretion and increased mRNA levels for ubiquitin and 14-kDa ubiquitin-conjugating enzyme E2. OKG supplementation did not improve muscle mass or protein balance and did not reduce enhanced 3-MH excretion in Yoshida sarcoma-bearing rats. Furthermore, OKG did not suppress in the cancer rats the enhanced expression of ubiquitin and 14-kDa E2, despite OKG decreased by 23% the ubiquitination rate in cancer rats (OKG-K vs. C-K, P<0.05). These data suggest that OKG action is not universal; i.e. depending upon the model under study. In the circumstances, OKG did not counteract the increase in ubiquitin-proteasome-dependent proteolysis observed in Yoshida sarcoma-bearing rats.

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

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. 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. 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. 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.

Ornithine alpha-ketoglutarate increases mineralization and mechanical properties of tibia in turkeys

Skeletal disorders in rapidly growing poultry are commonplace. This study was performed to investigate the effect of ornithine alpha-ketoglutarate (OKG) administration during the last 7 weeks of life on structural properties, mineralization, and mechanical endurance of skeleton in turkeys at slaughter. Healthy HB Medium Bronze female turkeys were randomly assigned to two weight-matched groups at the age of 12 weeks. OKG was administered orally to the experimental group ( N = 17) at the dose of 0.4 g/kg body weight per day, while the control group ( N = 16) received an equal dose of the vehicle. The turkeys were slaughtered at the age of 19 weeks and the tibiae were isolated for analysis. The effect of OKG on skeletal system development in turkeys was evaluated in relation to both geometrical and mechanical properties as well as quantitative computed tomography (QCT). Free amino acids concentrations were assessed with the use of ion-exchange chromatography. Significantly increased bone mineral density of the trabecular and the cortical bone of tibia in the turkeys given OKG for the last 7 weeks of production cycle were observed ( P < 0.05). OKG administration improved mechanical endurance of the tibia estimated by the three-point bending test ( P < 0.01). Plasma amino acid analyses showed increased level of aspartate, proline, alanine, valine, isoleucine, leucine, and ornithine (all P < 0.05) after OKG treatment, whereas cystathionine concentration was decreased ( P = 0.03). Obtained results indicate that oral OKG administration has beneficial effects on skeletal development in fast growing turkeys and this effect is connected with increased amino acid synthesis. These observations may serve to improve skeletal properties in birds, especially when considering that skeletal disorders often affect the tibia and the proper function of the skeletal system plays an essential role in animal welfare and poultry production.

Does dietary ornithine α-ketoglutarate supplementation protect the liver against ischemia–reperfusion injury?

Nutritional supplementation with glutamine, arginine and their precursors has been proposed to contribute to the protection against ischemia-reperfusion-related injuries. The aim of this study was to evaluate in an isolated perfused rat liver model the preventive effect of a 4-day oral ornithine alpha-ketoglutarate (OKG) supplementation against warm ischemia-reperfusion (I-R) injury, and the involvement of nitric oxide synthesis. Rats were fed a controlled regimen supplemented with either OKG (5 g kg(-1); n=15) or an isonitrogenous mixture of non-essential amino acids (Control; n=6) for 4 days. Livers were subsequently prepared for isolated perfusion experiments, including a 45 min no-flow ischemic period. The OKG-treated group was divided into two groups according to the absence (OKG; n=8) or presence of a NO-synthase inhibitor, L-N(omega)-nitro-arginine methyl ester (OKG L-NAME; n=7) during liver perfusion. Liver cytolysis after ischemia was demonstrated by an elevated alanine aminotransferase release during the last 15 min of reperfusion that was significantly higher in the OKG-L-NAME group. Tumor necrosis factor alpha (TNF(alpha)) production was transiently increased only in the control group just after ischemia. At the end of the reperfusion period, liver superoxide dismutase activity was significantly lower in the OKG-L-NAME group compared to control animals. Dietary OKG administration had only a limited effect in this model of mild hepatic I-R, leading mainly to reduced TNF(alpha) production. As the content of lipid peroxidation products was not modified, it seems that OKG acts on the inflammatory response rather than on oxidative reactions. This action can tentatively be attributed to the role of OKG as a glutamine precursor rather than to the synthesis of arginine and nitric oxide.

Ornithine α-Ketoglutarate as a Potent Precursor of Arginine and Nitric Oxide: A New Job for an Old Friend

Ornithine alpha-ketoglutarate (OKG) is a salt formed of 2 molecules of ornithine and 1 alpha-ketoglutarate. Its administration improves nutritional status in chronically malnourished (e.g., elderly) and acutely malnourished patients (especially burn and trauma patients). There is evidence that OKG activity is not the simple addition of the effects of ornithine (Orn) and alpha-ketoglutarate (alphaKG), because the presence of both moieties is required to induce the generation of key metabolites such as glutamine, proline, and arginine (Arg), whereas this does not occur when one or the other is given separately. This observation is related to the fact that the main feature of Orn at the whole-body level is to be metabolized through the Orn aminotransferase-dependent pathway, whereas the simultaneous administration of Orn and alphaKG saturates this pathway, diverting Orn toward metabolism into Arg. For years, OKG activity has been associated with its ability to induce the secretion of anabolic hormones, such as insulin and growth hormone, and to increase glutamine and polyamine synthesis. Recent studies using chemical inhibitors of nitric oxide synthase (NOS) suggest that nitric oxide derived from Arg could be partly involved in OKG activity. The use of genetically modified animals (i.e., knockout for NOS expression) is required to confirm this hypothesis.

A guide to understanding dietary supplements

* Foreword * Foreword * Preface * Acknowledgments * Chapter 1. Overview of the Dietary Supplement Industry and the Dietary Supplement Health and Education Act * Introduction * What Are Dietary Supplements? * Why Are Dietary Supplements So Popular? * DSHEA * Sources for Additional Information on Dietary Supplements * Chapter 2. The Product Development Process for Dietary Supplements * Introduction * Drug Development As a Model for Dietary Supplements * Consumer Product Development As a Model for Dietary Supplements * New Product Development Approaches * Adapting the NPD Process * Encouraging Creativity * Summary * Chapter 3. Critical Evaluation of Dietary Supplements * Introduction * History of Use and Safety * Claims Substantiation * Scientific Support * Third-Party Screening of Dietary Supplements * Putting Dietary Supplement Claims into the Proper Perspective * FDA Guidance on Scientific Review of Health Claims * Advertising and Claims Substantiation for Dietary Supplements * Chapter 4. Supplements for Weight Loss * Introduction * Exercise versus Diet * Step Far Away from the Cheesecake * Supplements That May Help * Summary * Conjugated Linoleic Acid (CLA) * Hydroxycitric Acid (HCA) * Chitosan * Glucomannan/Konjac * Ma Huang/Ephedra * Guarana * Synephrine/Zhi Shi * Carnitine * Pyruvate * Bladderwrack * White Willow * Chapter 5. Sports Supplements and Ergogenic Aids * Introduction * Supplements to Use with Exercise * Functional Categorization of Sports Supplements * Summary * Creatine * Ribose * Amino Acids * Branched-Chain Amino Acids (BCAAs) * Androstenedione * Dehydroepiandrosterone (DHEA) * Beta-Hydroxy Beta-Methylbutyrate (HMB) * Tribulus terrestris (Puncture Vine) * Cordyceps sinensis * Glycerol * Ornithine Alpha-Ketoglutarate (OKG) or Alpha-Ketoglutarate (AKG) * Gamma-Oryzanol/Ferulic Acid/Rice Bran Oil * Medium-Chain Triglycerides (MCTs) * Sodium Bicarbonate * Protein Supplements * Whey Protein * Carnosine * Proteolytic Enzymes * Chapter 6. Supplements for Boosting Energy Levels * Introduction * Daily Eating Strategies * Rest * Supplements * Ginseng * Royal Jelly * Bee Pollen * B-Complex Vitamins * Vitamin B1 (Thiamine) * Vitamin B2 (Riboflavin) * Rhodiola * Nicotinamide Adenine Dinucleotide (NADH) * Sea Buckthorn * Brewer's Yeast * Inosine * Chapter 7. Supplements for Bone Health * Introduction * Factors Associated with Skeletal Health * Dietary Supplements for Healthy Bones * Calcium * Magnesium * Boron * Vitamin D * Vitamin K * Chapter 8. Supplements for Joint Health * Introduction * Causes of Arthritis and Conventional Treatments * Practical Advice * Contributing Factors * Dietary Supplements * Summary * Glucosamine * Chondroitin Sulfate (CS) * Boswellia (Boswellia serrata) * Methylsulfonylmethane (MSM) * Hydrolyzed Collagen Protein (HCP)/Gelatin * Devil's Claw * Green-Lipped Mussel * Sea Cucumber * Chapter 9. Supplements for Mood and Brain Health * Introduction * The First Step--Diet and Exercise * Dietary Supplements * St. John's Wort * 5-Hydroxytryptophan (5-HTP) * Phenylalanine/D,L-Phenylalanine (DLPA) * Phosphatidylserine (PS) * Choline * Ginkgo Biloba * Huperzine A (HupA) * Vinpocetine * Kava-Kava * S-Adenosylmethionine (SAMe) * Valerian * Melatonin * Feverfew * Chapter 10. Supplements for Heart Health * Introduction * Opening Blood Vessels * Strengthening the Heart Muscle * Controlling Free Radical Damage * Summary * Red Yeast Rice (RYR) * Soy * Essential Fatty Acids and Omega-3 Fatty Acids * Garlic * Hawthorn * Coenzyme Q10 (CoQ10)/Ubiquinone * Vitamin B6 * Vitamin B12 * Folic Aci

Glutamine: clinical applications and mechanisms of action.

Supplementation of the conditionally essential amino acid glutamine may be beneficial for individuals who are highly stressed and have minimal energy and protein reserves. This includes elderly individuals, postoperative patients, individuals with cancer and very low birthweight infants. Individuals who are undergoing treatment with catabolic glucocorticoids may also benefit. Unfortunately, confusion exists as to situations in which glutamine may be beneficial because a clearly defined "glutamine deficiency syndrome" has not been described as for some other nutrients. In this review, we will discuss how glutamine affects protein metabolism under certain stressful conditions, how it affects intestinal mucosal integrity and how this might relate to sepsis and systemic inflammation. We will also discuss nutrients that are closely related to glutamine such as glutamate, nucleotides, arginine, glucosamines, and ornithine alpha-ketoglutarate and how and why they might be used as substitutes for glutamine.

Interaction between Glutamine Availability and Metabolism of Glycogen, Tricarboxylic Acid Cycle Intermediates and Glutathione

After exhaustive exercise, intravenous or oral glutamine promoted skeletal muscle glycogen storage. However, when glutamine was ingested with glucose polymer, whole-body carbohydrate storage was elevated, the most likely site being liver and not muscle, possibly due to increased glucosamine formation. The rate of tricarboxylic acid (TCA) cycle flux and hence oxidative metabolism may be limited by the availability of TCA intermediates. There is some evidence that intramuscular glutamate normally provides alpha-ketoglutarate to the mitochondrion. We hypothesized that glutamine might be a more efficient anaplerotic precursor than endogenous glutamate alone. Indeed, a greater expansion of the sum of muscle citrate, malate, fumarate and succinate concentrations was observed at the start of exercise (70% VO2(max)) after oral glutamine than when placebo or ornithine alpha-ketoglutarate was given. However, neither endurance time nor the extent of phosphocreatine depletion or lactate accumulation during the exercise was altered, suggesting either that TCA intermediates were not limiting for energy production or that the severity of exercise was insufficient for the limitation to be operational. We have also shown that in the perfused working rat heart, there is a substantial fall in intramuscular glutamine and alpha-ketoglutarate, especially after ischemia. Glutamine (but not glutamate, alpha-ketoglutarate or aspartate) was able to rescue the performance of the postischemic heart. This ability appears to be connected to the ability to sustain intracardiac ATP, phosphocreatine and glutathione.

Bacterial Dissemination and Metabolic Changes in Rats Induced by Endotoxemia following Intestinal E. coli Overgrowth Are Reduced by Ornithine α-Ketoglutarate Administration

The efficacy of ornithine alpha-ketoglutarate (OKG) in preventing bacterial translocation and dissemination, metabolic disorders and changes in mucosal enzyme activities was assessed in a model of bacterial translocation in rats. Antibiotic decontamination was performed 4 d before intragastric inoculation with an Escherichia coli strain (10(10) bacteria/kg body). Two days later, the rats were given either a lipopolysaccharide (LPS) 0127:B8 or a saline injection and were deprived of food for 24 h. Enteral nutrition, [Osmolite, 880 kJ/(kg. d)] supplemented with either OKG (LPS + OKG) or glycine (Saline + Gly or LPS + Gly), was then given for 2 d. Urinary total nitrogen losses and 3-methylhistidine excretion were determined daily. On killing at d 3, bacterial translocation to the mesenteric lymph nodes (MLN) and dissemination to the spleen and liver were evaluated, jejunal mucosa enzyme activities were assayed and tissue free amino acids in muscles were measured. Endotoxin induced translocation from the gut lumen to the MLN in all groups, whereas dissemination occurred only in LPS-treated rats. OKG significantly reduced dissemination of the bacteria in the spleen. 3-Methylhistidine excretion was greater in the LPS + Gly group (+25%, P: < 0.05) than in either the LPS + OKG or Saline + Gly group. The group fed the OKG-enriched diet had higher muscular glutamine, ornithine and arginine concentrations than did the Gly-supplemented groups (P: < 0.05). Intestinal sucrase and aminopeptidase activities were higher in the LPS + OKG group than in the LPS + Gly group (-30%, P: < 0.05). OKG supplementation limits bacterial dissemination and metabolic changes after injury in rats and thus may be useful in the prevention of gut-derived sepsis in critically ill patients.

Ornithine alpha-ketoglutarate and creatine effects on growth and plasma metabolites of nursery pigs.

Four experiments were conducted to determine the effect of dietary ornithine alpha-ketoglutarate (OKG) and creatine monohydrate on growth performance and plasma metabolites of nursery pigs. In each experiment, treatments were replicated with four to five pens of four to six pigs each. Each experiment lasted from 3 to 4 wk and Phase I (1.6% Lys) and Phase II (1.3 to 1.5% Lys) diets were fed for 9 to 16 d each. In Exp. 1, pigs (4.7 kg and 15 d of age) were fed diets containing 0, .10, or .75% OKG. Daily gain during a 13-d Phase I period and ADFI during Phase I and overall (29 d) were increased (P < .10) in pigs fed .75% OKG. Gain:feed ratio was not affected (P > .10) by diet. In Exp. 2, pigs (7.1 kg and 23 d of age) were fed 0 or .50% OKG during Phase I only. During Phase I, II, and overall, ADG and ADFI were not affected (P > .10) by OKG supplementation, but gain:feed was decreased during Phase I (P < .04), Phase II (P < .08), and overall (P < .04). Plasma urea N (PUN), glucose, and NEFA concentrations were not affected (P > .10) by OKG supplementation in this experiment. In Exp. 3, pigs (5.8 kg and 20 d of age) were fed diets containing 0, .10, or .50% creatine. Creatine tended to linearly decrease ADG (P = .11) and plasma albumin (P = .12) and PUN (P < .10) concentrations in Phase II (d 12 to 26). In Exp. 4, 850 mg of OKG or 750 mg of creatine was provided daily by oral capsule to pigs 4 d before weaning to 2 d after weaning. Pigs within a litter received either no capsule or capsules containing OKG or creatine. After weaning, pigs that received no capsule before weaning received no treatment, .50% creatine, or .50% OKG in the nursery diet. Pigs that received OKG before weaning received no treatment or .50% OKG, and pigs that received creatine before weaning received no treatment or .50% creatine in the nursery diet. Pigs weighed 3.9 kg 4 d before weaning and 4.9 kg at weaning at an average age of 20 d. The OKG provided by capsule decreased ADG (P < .02) and ADFI (P < .09) during Phase II. The OKG did not affect (P > .10) plasma NEFA, glucose, or urea N concentrations. Creatine added to the nursery diet increased (P < .02) ADFI and decreased (P < .10) gain:feed during Phase II and overall. Creatine in the nursery diet also increased (P < .01) PUN, but it did not affect plasma glucose or NEFA concentrations. Creatine and OKG have variable effects on growth performance and plasma metabolites of nursery pigs.

Modulation of immune response with ornithine A-ketoglutarate in burn injury: an arginine or glutamine dependency?

Enterally administered ornithine alpha-ketoglutarate (OKG) is an efficient complement of nutritional support in trauma situations, especially after burn injury. A typical feature observed in this intense catabolic state is insufficient production of glutamine (Gln) and arginine (Arg), two amino acids (AAs) involved in the immune response. As OKG in vivo metabolism generates these two AAs, we investigated, in burned rats, the action of OKG with regard to modulation of immunity. Male Wistar rats were randomly allocated to four groups. On day 0, 12 rats were burned with boiling water (20% body surface area). After a 24-h fast, they were enterally refed for 48 h using Osmolite, as a low-calorie low-nitrogen regimen, supplemented with either 5 g OKG x kg(-1) x d(-1) (n = 6) or an equivalent amount of nitrogen in the form of glycine (n = 6). Non-burned pair-fed controls treated with glycine (n = 6) and healthy rats fed ad libitum (n = 6) were also studied. Nitrogen balance was assessed from daily measurement of total nitrogen excretion. On day 3, thymus, Anterior tibialis muscle and proximal jejunum weights were recorded. Muscle and intestinal AA concentrations were also quantified. OKG counteracted (P<0.01) the thymic involution that occurs with burn injury, and increased the concentrations of Gln and Arg in both the muscle (P<0.01 and P<0.05, respectively) and the jejunum (P<0.01 for Gln). When all groups were taken together, a positive correlation was found between thymus weight, and Gln and Arg muscle concentrations (r = 0.71, P<0.001 and r = 0.58, P<0.01, respectively). Furthermore, as expected, OKG improved nitrogen balance. As it is known that total number of thymocytes parallels thymic weight, and as Gln and Arg are essential nutrients for activated immune cells, our results suggest that Gln and Arg derived from OKG are responsible for the immunomodulating properties of this molecule in burn injury.