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PubMed2006

Peripheral neuropathy: pathogenic mechanisms and alternative therapies.

Peripheral neuropathy (PN), associated with diabetes, neurotoxic chemotherapy, human immunodeficiency virus (HIV)/antiretroviral drugs, alcoholism, nutrient deficiencies, heavy metal toxicity, and other etiologies, results in significant morbidity. Conventional pain medications primarily mask symptoms and have significant side effects and addiction profiles. However, a widening body of research indicates alternative medicine may offer significant benefit to this patient population. Alpha-lipoic acid, acetyl-L-carnitine, benfotiamine, methylcobalamin, and topical capsaicin are among the most well-researched alternative options for the treatment of PN. Other potential nutrient or botanical therapies include vitamin E, glutathione, folate, pyridoxine, biotin, myo-inositol, omega-3 and -6 fatty acids, L-arginine, L-glutamine, taurine, N-acetylcysteine, zinc, magnesium, chromium, and St. John's wort. In the realm of physical medicine, acupuncture, magnetic therapy, and yoga have been found to provide benefit. New cutting-edge conventional therapies, including dual-action peptides, may also hold promise.

Acquired Immunodeficiency Syndrome↗
PubMed1992

A lipoyl synthetic octadecapeptide of dihydrolipoamide acetyltransferase specifically recognized by anti-M2 autoantibodies in primary biliary cirrhosis.

Close to 95% of patients with established clinical, biochemical and histologic features of primary biliary cirrhosis (PBC) possess antimitochondrial M2 antibodies reacting with the E2 component, dihydrolipoamide acetyltransferase, of the pyruvate dehydrogenase complex. We examined the ability of synthetic peptides of E2 to be recognized in ELISA by sera from patients with PBC and autoimmune-related disorders. Sera from 14 PBC M2+ patients, 1 PBC M2- patient, 5 non-PBC M2+ patients, and 6 patients with chronic active hepatitis were studied. Among the seven E2 synthetic peptides tested (namely peptides 87-119, 167-184, 169-202, 267-302, 456-477, 498-513 and 530-543), only peptide 167-184 used as OVA conjugate and prepared with lipoic acid (LA) located on lysine 173 (natural inner lipoyl-binding site) was recognized in direct ELISA by PBC M2+ sera. The conjugated peptide 167-184 LA was not recognized in direct ELISA by non-PBC M2+ sera or by sera from patients with chronic active hepatitis. The free peptide 167-184 LA inhibited the ELISA reaction of PBC antibodies to PDH and totally abolished the typical immunofluorescence reaction of PBC sera on rat kidney, stomach and liver, or human HEp-2 cell substrates. No inhibition of ELISA or immunofluorescence reaction was found with the other E2 fragments including peptide 167-184 without LA. Our results show that the lipoyl moiety forms an integral part of a dominant conformational epitope recognized by PBC sera. Inasmuch as the peptide 167-184 LA was not recognized by non-PBC sera in direct ELISA, it could be used as a valuable probe for PBC diagnosis.

Acetyltransferases↗
PubMed1976

Comparisons of antidotal efficacy of chelating drugs upon acute toxicity of Ni(II) in rats.

Six chelating drugs were administered to rats by im injection at equimolar dosages in order to compare their relative effectiveness in prevention of death after a single parenteral injection of NiCl2. Triethylenetetramine and d-penicillamine were most effective antidotes for acute Ni (II)-toxicity. In order of decreasing antidotal effectiveness, diglycyl-L-histidine-N-methylamide, sodium diethyldithiocarbamate and calcium disodium versenate significantly reduced the acute mortality of rats following ip injection of Ni (II). Alpha-Lipoic acid was not effective as an antidote for acute Ni (II)-toxicity.

Animals↗
PubMedDate not supplied

[Hormonal regulation of lipoate-35S transport into rat liver mitochondria].

The effect of adrenalectomy, and also of adrenaline, hydrocortisone and ACTH on the rate of lipoate-35S penetration into the mitochondria of the liver was studied in rats. Bilateral adrenalectomy proved to decrease the rate of the lipoate penetration into the organellae significantly; this was more pronounced in female than in the male rats. The capacity of hepatic mitochondria to absorp the lipoic acid was restored under the effect of single adrenaline, hydrocortisone and ACTH injections. Actinomycin D administered to the animals for a period of 3 days in combination with hydrocortisone eliminated the stimulating effect of the hormone on the lipoate transport into the mitochondria of the liver of the intact and adrenalectomized rats completely. The data obtained pointed to the regulating effect of some hormones on the intensity of penetration of lipoate into the biological structures.

Adrenal Glands↗
PubMedDate not supplied

[The use of a vitamin and metabolite complex for correcting the disorders in systemic and organ hemodynamics during liver resection under conditions of acute blood loss].

The efficacy of some infusion media, vitamins, and metabolites in resection of the liver in acute blood loss was studied in experiments on dogs. Inclusion of vitamins B1, B2, and B6, lipoic acid, calcium pantothenate, nicotinamide, solution of alpha-glutamate and gamma-aminobutyric acid (aminalone) in the infusion led to a sharp increase of myocardial contractility, increase of cardiac output and total hepatic blood flow, normalization of biochemical blood values, and restoration of the activity of hepatocyte enzymes.

Acute Disease↗
PubMed1976

Lipoamide dehydrogenase in serum: a preliminary report.

Lipoamide dehydrogenase was identified in serum and the optimal conditions for its assay at 30 degrees C were defined. The pH optimum in tris(hydroxymethyl)aminomethane buffer is 7.8, and activity is inhibited if buffer concentration exceeds 100 mmol/liter. Saturating concentrations of the substrates NAD+ and lipoamide are 3 mmol/liter and 5 mmol/liter, respectively. Activity is decreased eightfold when lipoic acid is substituted for lipoamide. Activity is linearly related to enzyme concentration up to limiting absorbance change of 0.300 at 340 nm, and both within-day and day-to-day precision are satisfactory. Data suggest a normal range (2 SD) of 3-19 kU/liter. The highest value measured in serum was 473 kU/liter. A correlation with direct bilirubin concentrations (r equals 0.435, P less than 0.01) was found.

Bilirubin↗
PubMedDate not supplied

[Ribonucleotide reductase in Propionibacterium shermani].

The cell-free extract of Propionibacterium shermanii was found to contain B12-dependent ribonucleotide reductase. The extract of the cells grown under the conditions of the inhibited synthesis of vitamin B12 reduces ribonucleotides with the participation of B12-independent enzyme. The synthesis of B12-dependent apoenzyme of ribonucleotide reductase is partially maintained under these conditions. Both enzymes reduce preferably ribonucleoside diphosphates. The reducing agent of nucleotides in vitro is lipoic acid or dithiothreitol, in the B12-dependent pathway, and NADPH and thioredoxin, in the B12-independent pathway. Only B12-independent ribonucleotide reductase requires Mg2+ ions. Vitamin B12 in the coenzyme form inhibits the activity of B12-independent enzyme.

Cell-Free System↗
PubMedDate not supplied

[The effect of functionally bound vitamins and their coenzyme forms on the activity of 2-oxoacid dehydrogenases in mouse organs].

Ever-growing doses (beginning from the therapeutic up to 10-fold doses of a complex of five functionally bound vitamins (B1, FMN, nicotinamide, pantothenate, lipoic acid) being administered to F1 mice (CBA x Black) induced a constant and considerable rise of the pyruvate- and 2-oxoglutarate dehydrogenase (PDG and OGDG) activity in the mouse organs. In the in vitro experiments the addition of the corresponding coenzymes or their mixture (in the optimal concentrations) to the incubation medium containing mitochondria of the mouse liver led to a greater activation of these dehydrogenases in the group of animals which were preliminary injected the above complex of vitamins.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1989

Antimitochondrial antibodies of primary biliary cirrhosis recognize dihydrolipoamide acyltransferase and inhibit enzyme function of the branched chain alpha-ketoacid dehydrogenase complex.

Antimitochondrial antibodies (AMA) recognizing the acetyltransferase (E2) of the pyruvate dehydrogenase (PDH) complex have been previously well-documented and the immunodominant epitope mapped. In this study, we demonstrate that sera from patients with primary biliary cirrhosis (PBC) react with another lipoic acid containing acyltransferase enzyme, namely the E2 of the branched chain alpha-ketoacid dehydrogenase (BCKD) complex. Indeed, 85/120 (71%) sera from patients with PBC reacted with BCKD-E2 by immunoblotting against purified BCKD complex. In contrast, sera from patients with chronic active hepatitis or progressive sclerosing cholangitis as well as sera from healthy volunteers did not react with any component enzymes of the BCKD complex. More importantly, BCKD enzyme activity was inhibited after incubation of the BCKD complex with either PBC sera against BCKD-E2 or with affinity purified antisera to BCKD-E2. Enzyme activity was unaltered by control sera or with PBC sera that reacted with PDH-E2 but not BCKD-E2. Furthermore, immunoblots of purified mitochondria probed with PBC sera absorbed with BCKD-E2 demonstrated that BCKD-E2 and PDH-E2 are each recognized by distinct AMA populations which do not cross-react. In addition, affinity purified PBC sera against BCKD-E2 did not react with PDH-E2 nor inhibit PDH enzyme activity, thus providing further evidence that BCKD-E2 and PDH-E2 are recognized by separate AMA. These data further suggest that the BCKD-E2 epitope recognized by AMA contains, or is close to, a functional domain of this enzyme. The availability of cDNA clones encoding BCKD-E2 and PDH-E2 will allow the study of how key metabolic enzymes may be involved in the immunology and pathology of PBC.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1987

Effect of mercury on rabbit myelin CNP-ase in vitro.

2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) catalyzes hydrolysis of 2',3'-cyclic nucleotides to form the corresponding 2'-monophosphates. Rabbit myelin fraction with CNPase specific activity between 30-40 mumoles/min/mg protein was incubated in the presence of various inorganic and organic heavy metal compounds: HgCl2; (CH3Hg)OH; Pb(NO3)2; Pb(C2H302)2.3H20; (C2H5)2Pb; (C2H5)3SnCl. The enzyme has been shown to be almost exclusively sensitive to mercurials in microM concentration range. This would arise from the high solubility of mercurials in organic solvents, which allows them to penetrate into hydrophobic regions of the enzyme to react with active sulfhydryl groups. CNP-ase inhibition by methylmercury was biphasic: A reversible, non-competitive inhibition with an apparent Ki = 1 microM occurred after a 5 min preincubation time of the enzyme with the inhibitor. In the case of longer preincubation time, as well as in the presence of HgCl2, the graph of enzyme activity versus protein concentration intercepted the abscissa to the right of the origin, indicating that mercurials are irreversible inhibitors of the enzyme. After 45 min of preincubation of the inhibitors with the enzyme 1 nmol of HgCl2 completely blocks CNP-ase activity equivalent to 15.6 micrograms of myelin protein, whereas 1 nmole of Met-Hg blocks activity in 9.9 micrograms proteins. This apparently irreversible inhibition of CNP-ase activity by HgCl2 could be fully restored by the use of an excess of hydrophobic low molecular weight thiols, lipoic acid being the most efficient. Dithiothreitol, a hydrophilic complexing agent, was potent to reverse the inhibition caused by Met-Hg only during the short time experiments. Both low molecular weight thiols, and also EDTA in the case of inorganic mercury could prevent the inhibition of CNP-ase by mercurials, if preincubated for 15 min with the inhibitors, prior to the addition of the enzyme. The irreversible type of inhibition of CNP-ase by Met-Hg was only partially reversed in the presence of low molecular weight thiols. This suggests that the formation of a metal-mercaptide complex is not the only mechanism of inhibition by methylmercury. The possibility of lipid peroxidation triggered by methylmercury with subsequent inhibition of the enzyme activity was not supported by the experimental results. In fact, myelin associated CNP-ase activity appears to be very resistant to the structural membrane alterations caused by lipid peroxidation.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1986

Cytoprotective effect of free radical scavengers against mucosal damage produced by different antirheumatic drugs.

Following 200 mg aspirin, 20 mg indomethacin or 100 mg diclofenac, gastric mucosal damage was evoked after five hours in rats. By administering vitamin A, vitamin E, MTDQ (6,6-methylenebis-2,2,4-trimethyl-1,2-dihydroquinoline), vitamin C, lipoic acid and penicillamine intragastrically at the time of the application of the damaging agent, the authors studied the beneficial effect of these free-radical scavengers upon the mucosal lesions. Vitamin C and penicillamine exerted no significant protective effect. Among the other drugs, the most effective were the lipid-soluble ones: vitamin A, vitamin E and MTDQ. The authors hypothesized that the gastric damage may be connected with the degradation of the polyunsaturated fatty acid components of the cellular membranes and thus the lipid-soluble free radical scavengers were able to offer protection.

Animals↗
PubMed1986

[A variant of pathogenetic therapy in the acute period of perinatal hypoxic-traumatic brain lesions in premature infants].

The restorative potential of reparative cellular processes was studied in 39 immature infants born in hypoxia and receiving a pathogenetic treatment. In addition to the conventional treatment the test group of 24 infants received intravenously 20% piracetam solution, 1% riboflavin-mononucleotide solution, and 0.5% lipoic acid solution beginning from the first days of life. To correct the cellular metabolic processes in a control group of 15 infants, they were given 10% glucose solution, 5% ascorbic acid solution and cocarboxylase. The activity of dehydrogenases in the peripheral blood remained virtually unaltered in the control group but increased by an average of 1.5-2 times in the test group. An 18-month follow-up ascertained that the incidence of neurological complications in the infants receiving the proposed treatment was significantly lower as against the control patients.

Acute Disease↗
PubMedDate not supplied

A culture medium for cultivation of mycobacteria, probably Mycobacterium leprae from Mycobacterium leprae infected tissues.

Mycobacterium leprae suspensions were prepared from infected armadillos. The M. leprae cells were inoculated into culture media containing KH2PO4 4.7. g. Na2HPO4 2 g, sodium thioglycolate 1 g, (NH4)2SO4 2 g, MgSO4 0.1 g, ferric ammonium citrate 0.05 g, and lipoic acid (thioctic acid) 0.1 g in one liter distilled water. The solution was enriched with heat killed, sonicated leprosy derived Mycobacterium X or crude mycobactin extract from M. phlei to contain + 0.2 micrograms mycobactin per 1 ml in the final medium. Twenty ml media was distributed into each of 25 ml screw cap tubes and autoclaved for 30 minutes. Positive growth was obtained from seven out of ten specimens when incubated at 34 degrees C. The cultures developed as a sediment in the liquid media, suggesting preference for microaerophylic conditions. No growth was seen on the surface of the semi-solid agar media containing the same ingredients. Latency period of growth was estimated as 10-16 days and time of division as 6 days. Subcultures were obtained. Cells were long, acid fast, arranged side by side or end to end, with a tendency to form long spiral cords or clumps when sedimented on siliconized slides. Pyridine extraction eliminated acid fastness, but not gram positivity. Cultures did not grow on Dubos, Lowenstein or 7H10 media. They produce the disease in the foot pads of mice characteristic of M. leprae. Subcultures remain dependent on the heat killed sonicated mycobacteria, or crude mycobactin extract, and reduced oxygen tension in the media. Results suggest that cultures might be identical to M. leprae.

Ammonium Sulfate↗
PubMed1979

Strychnine treatment attempted in newborn twins with severe nonketotic hyperglycinemia.

Strychnine, a potent antagonist of glycine was given to twins suffering from nonketotic hyperglycinemia at age 73 hours. Within hours of the onset of treatment favorable effects were observed such as improvements of muscle tone, movements, defense reactions, and probably breathing. Pyridoxine, N5-formyl-tetrahydrofolate and lipoic acid were given concomitantly with strychnine but failed to alter glycine levels in plasma and cerebrospinal fluid. The therapeutic trial was terminated after 2 1/2 days because success, though considerable, was judged inadequate.

Diseases in Twins↗
PubMed1984

Glycine synthase of the purinolytic bacterium, Clostridium acidiurici. Purification of the glycine-CO2 exchange system.

When the growth medium of Clostridium acidiurici was supplemented with trace metals, glycine synthase and glycine-CO2 exchange activities in cell-free extracts were found to increase significantly. The glycine-CO2 exchange system was purified and shown to consist of a heat-labile component and a heat-stable component. By gel filtration, heat-labile component had an estimated native Mr = 230,000 and contained two subunits of Mr = 65,000 and 58,000 on sodium dodecyl sulfate-polyacrylamide gels, indicating an alpha 2 beta 2 tetramer. Heat-stable component had an estimated Mr = 20,000 and could not be replaced by lipoic acid in reaction mixtures. Pyridoxal phosphate was not bound to either of the purified components but was essential for glycine-CO2 exchange. By spectral analysis, heat-labile component was shown to interact with pyridoxal phosphate and that reductant influenced this interaction.

Amino Acid Oxidoreductases↗
PubMedDate not supplied

[Effect of a number of preparations on the function of the immune system in experimental influenza in mice].

(CBA X C57B1) X F1 mice were sensitized intraperitoneally with sheep erythrocytes and infected with influenza A viruses: nonpathogenic Leningrad-77 (H1N1) or pathogenic PR8 (HON1), before or five days after administration into the oesophagus of sodium succinate, levamisole, complexes I (panangin, sodium succinate, sodium glutamate) and 2 (lipoic acid, phosphothyamine, riboflavin, sodium pantothenate). The number of rosette-forming cells (RFC) in the spleen at 7 and 14 days postinfection, antibody titres, interferon level in the blood, the amount of virus in the lungs, spleen and lung morphology were studied. All the preparations used were found to increase the number of RFC in the spleen. Most effective were levamisole before infection, sodium succinate after infection, combination thereof, complex I after infection.

Adjuvants, Immunologic↗
PubMed1983

Mechanism of the glycine cleavage reaction. Steady state kinetic studies of the P-protein-catalyzed reaction.

Chicken liver P-protein of the multienzyme glycine cleavage system catalyzes the first partial reaction of glycine cleavage. In the partial reaction, glycine and H-protein serve as substrates and the products are CO2 (not bicarbonate) and the decarboxylated portion of glycine attached to H-protein. The reaction exhibited Michaelis-Menten kinetics with respect to both substrates. The optimum pH for the reaction is 7.1, with 6.5 for the reverse reaction. Km values for glycine and H-protein are independent of the concentration of the the co-substrate, and calculated values are 5.8 mM for glycine and 3.4 microM for H-protein. Initial velocity experiments gave intersecting double reciprocal plots that conform to a sequential mechanism. Product inhibition studies revealed that both products inhibited competitively with respect to the varied substrate. Glycine methyl ester was found to be a competitive inhibitor of glycine and noncompetitive inhibitor of H-protein. H-protein whose lipoic acid prosthetic group and cysteinyl residues were modified with N-ethylmaleimide was a noncompetitive inhibitor of glycine and a competitive inhibitor of H-protein. These results are most consistent with a sequential random Bi Bi mechanism in which no abortive dead end complex is formed. This was supported by an isotope exchange experiment.

Amino Acid Oxidoreductases↗
PubMed1980

The mitochondrial glycine cleavage system. Purification and properties of glycine decarboxylase from chicken liver mitochondria.

Glycine decarboxylase, tentatively called P-protein and considered a constituent of the glycine cleavage system, was purified to apparent homogeneity from chicken liver mitochondria. P-protein is a homodimer having a Mr = approximately 200,000 and consisting of identical subunits with Mr = approximately 100,000. Each subunit appears to contain an equimolar pyridoxal 5'-phosphate which is bound to the protein, possibly through a protonated aldimine linkage. The isoelectric point of P-protein was 7.2. P-protein could bind glycine, showing a Kd of 33 mM for it, and could catalyze glycine decarboxylation even though the rate of decarboxylation catalyzed by P-protein alone was extremely low. The product of glycine decarboxylation was methylamine and the Km for glycine. Methylamine could bind to P-protein, giving a Kd value of 63 mM, and it inhibited the glycine decarboxylation. P-protein alone could also slightly catalyze the exchange of carboxyl carbon of glycine with CO2 and the exchange appeared to obey a ping-pong mechanism. Both glycine decarboxylation and the glycine-CO2 exchange catalyzed by P-protein were stimulated 100-fold or more by the addition of lipoic acid, which is a functional group of H-protein. We may define P-protein as glycine decarboxylase although P-protein alone exhibits only very low catalytic activities.

Amino Acid Oxidoreductases↗