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PubMed1976

Changes of some enzymatic activities in iodoacetate-treated microconidiating cultures of Neurospora crassa.

In iodoacetate-treated microconidating cultures of Neurospora crassa, mycelial yield, sucrose consumption and ethanol production are reduced. The specific activity of glyceraldehyde-3-phosphate dehydrogenase is sharply decreased while the specific activities of glucose-6-phosphate dehydrogenase and of 6-phosphogluconate dehydrogenase are stimulated. A polyphenoloxidase is induced in the microconidiating cultures.

Catechol Oxidase↗
PubMed1975

Inhibition of thiamine transport in anaerobic baker's yeast by iodoacetate, 2,4-dinitrophenol N,N'-dicyclohexylcarbodiimide and fatty acids.

1. [14C]Thiamine uptake by baker's yeast (Saccharomyces cerevisiae) was strongly inhibited by 0.2 mM iodoacetate, 0.2 mM 2,4-dinitrophenol and 0.1 mM N,N'-dicyclohexylcarbodiimide under anaerobic conditions. 2. The inhibition of anaerobic [14C]thiamine uptake by these inhibitors was accompanied by almost parallel decreases in the ATP level of the yeast cells. 3. On the other hand, the short-chain fatty acids inhibited [14C]thiamine uptake to a large extent, without greatly affecting the intracellular ATP level. This suggests that the acids primarily block the use of energy from ATP for the transport rather than the fermentation process. 4. Caproate, which has a most pronounced inhibitory effect on [14C]thiamine uptake, significantly prevented the dissipation of an energized membrane state of yeast cells necessary for the active transport of thiamine. 5. Possible ways in which the inhibitors may affect thiamine uptake were discussed.

Adenosine Triphosphate↗
PubMed2004

The monosodium iodoacetate model of osteoarthritis: a model of chronic nociceptive pain in rats?

Osteoarthritis (OA) is a widespread condition affecting the elderly population. One of the most prominent features but least studied symptoms is chronic pain associated with OA. The study objective was to determine pain endpoints in rats with monosodium iodoacetate (MIA) induced OA, and to investigate the efficacy of common nociceptive agents. Sprague-Dawley rats received an intraarticular injection of either 25 microl 80 mg/ml MIA or 25 microl 0.9% sterile saline into the right knee joint. Changes in von Frey thresholds and latencies to stroking with a cotton bud (punctate and dynamic allodynia, respectively) were measured pre- and for up to 10 weeks post-intraarticular injection. Changes in hind paw weight distribution were also determined. Both punctate allodynia and a weight bearing deficit were observed in MIA-treated rats for up to 10 weeks. Interestingly, dynamic allodynia was not detected at any time point tested. Morphine (0.3-3 mg/kg, s.c.) and tramadol (3-100 mg/kg, p.o.) dose-dependently inhibited punctate allodynia and partially reversed weight bearing deficit. In conclusion, the MIA model of OA is reproducible and mimics OA pain in humans. Analgesic drug studies indicate this model may be useful for investigating chronic nociceptive pain.

Analysis of Variance↗
PubMed1978

Caffeine contracture and iodoacetate rigor in frog skeletal muscle. A comparison.

Frog sartorius muscle treated with 5.0 mM or greater caffeine exhibits stiffness similar to that obtained from muscle in iodoacetate rigor. The data provide quantitative evidence that suggests that caffeine at irreversible contracture-producing concentrations somehow induces a rigor or rigorlike state in skeletal muscle.

Animals↗
PubMed2003

Reactive oxygen species play an important role in iodoacetate-induced neurotoxicity in primary rat neuronal cultures and in differentiated PC12 cells.

The role of reactive oxygen species in the pathogenesis of the neurotoxicity associated with ischemia-reperfusion, was investigated in a model of primary rat neuronal cultures and of differentiated PC12 cells, subjected to chemical ischemia by iodoacetic acid (IAA, 2.5 h) followed by a short period of reperfusion (1 h). The injury to the cells was assessed by lactate dehydrogenase (LDH) release into the culture media. The PC12 cells exhibited relative resistance to IAA cytotoxicity. Therefore these cells were studied at a 4-fold higher IAA concentration (400 microM instead of 100 microM for the neurons). The injury to both cell types was significantly greater in the short post-insult reperfusion (PIR) period than during the insult period. The presence, during the combined insult and PIR periods, of alpha-tocopherol (100 microM), melatonin (1 mM) and LY231617 (5 microM), conferred to both cell types considerable protection against the injury occurring during the insult and during the PIR periods (assessed separately). Superoxide dismutase (SOD; 500 IU/ml) conferred protection to the neurons, but not to the PC12 cells. When exposure to the antioxidants was limited to the short (15 min) pre insult period, only LY231617 conferred protection. In the neurons the protection occurred only during the insult period, whereas in the PC12 cells during both the insult and PIR periods. When the exposure to the antioxidants was limited to the PIR period, only SOD conferred protection and only in the neuronal cultures. These findings suggest that neuronal damage caused during ischemia-reperfusion can be diminished markedly by co-presence of antioxidants during the insult period. Certain antioxidants may protect the neurons even when present only before or after the insult.

Animals↗
PubMed2000

Characterization of iodoacetate-mediated neurotoxicity in vitro using primary cultures of rat cerebellar granule cells.

The neuroprotective efficacy of antioxidant molecules against iodoacetate (IAA) neurotoxicity in rat cerebellar granule cell (CGC) cultures was investigated. Transient exposure to IAA caused a concentration-dependent decrease in cell viability (ED50 = 9.8 microM). Dizocilpine maleate (MK-801), and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo[f]quinoxaline-7-sulfonamide (NBQX), failed to prevent IAA toxicity. Certain antioxidant molecules were shown to be neuroprotective against IAA when combined with MK-801 but were ineffective when administered alone. (S)-(-)-Trolox, butylated hydroxytoluene (BHT), and U-83836E exhibited EC50 values of 78, 5.9, and 0.25 microM, respectively, in the presence of 10 microM MK-801. IAA also induced an increase in intracellular oxidative stress, which was quenched by the antioxidants (in the presence of MK-801) in cultures loaded with the oxidant sensitive dye 2'7'-dichlorodihydrofluorescein diacetate (DCFH-DA).

Animals↗
PubMed2003

Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis.

OBJECTIVE: To describe an in vivo model in the rat in which change in weight distribution is used as a measure of disease progression and efficacy of acetaminophen and two nonsteroidal anti-inflammatory drugs (NSAIDs) in a model of monosodium iodoacetate (MIA)-induced osteoarthritis (OA). METHODS: Intra-articular injections of MIA and saline were administered to male Wistar rats (175-200 g) into the right and left knee joints, respectively. Changes in hind paw weight distribution between the right (osteoarthritic) and left (contralateral control) limbs were utilized as an index of joint discomfort. Acetaminophen and two archetypal, orally administered NSAIDs, naproxen and rofecoxib, were examined for their ability to decrease MIA-induced change in weight distribution. RESULTS: A concentration-dependent increase in change in hind paw weight distribution was noted after intra-articular injection of MIA. Both naproxen and rofecoxib demonstrated the capacity to significantly (P<0.05) decrease hind paw weight distribution in a dose-dependent fashion, indicating that the change in weight distribution associated with MIA injection is susceptible to pharmacological intervention. CONCLUSION: The determination of differences in hind paw weight distribution in the rat MIA model of OA is a technically straightforward, reproducible method that is predictive of the effects of anti-inflammatory and analgesic agents. This system may be useful for the discovery of novel pharmacologic agents in human OA.

Acetaminophen↗
PubMed1978

Probe of beta-galactosidase structure with iodoacetate. Differential reactivity of thiol groups in wild-type and mutant forms of beta-galactosidase.

Carboxymethylation with 14 C-labeled iodoacetate of cysteine residues in wild-type beta-galactosidase from Escherichia coli and in a defective beta-galactosidase from deletion mutant strain M15 was investigated in order to determine accessible positions in the tetrameric wild-type form and the dimeric mutant M15 protein. The extent of carboxymethylation, the effects on biological activity, antibody activation, physical stability, and the labeling of particular residues were studied. The results distinguish three groups of spatial relationships for cysteine residues in the protein, define possible regions for subunit interactions, and confirm that no cysteine residue is specifically involved in catalysis. Residue 1019 and to a lesser extent 498 are accessible in the tetrameric protein and probably represent exposed areas. In the M15 protein, these two, and three additional residues, at 76,387 and 600, were found to react significantly with reagent. One or more of the latter are suggested to be in the dimer-dimer interface. Complementation and activation by antibody are inhibited by carboxymethylation of M15 protein.

Binding Sites, Antibody↗
PubMed1975

Essential and nonessential thiols of yeast hexokinase. Reactions with iodoacetate and iodoacetamide.

The reaction of yeast hexokinase with iodoacetate or iodoacetamide has been investigated in detail, using pure hexodinase B. Of the four thiols in each subunit of the molecule, two (the "apparently essential thiols") are alkylated rapidly at 35 degrees, and the enzymic activity is lost in parallel with their reaction. The other two thiols react subsequently to completion, but at a very much slower rate. In the conditions use, no other uptake of the reagent occurs elsewhere during these thiol alkylations. Electrophoretically homogeneous kialkylated and tetraalkylated protein species are formed, in the two stages of the reaction. The inactivating reaction at 35 degrees with the apparently essential thiols is second order. The rate constant increases with increasing pH, in the range pH 7.0-8.5, in a manner consistent with control of the reaction by a group with pKa of approximately 10. The absolute (pH independent) rate constant is of the same order as that for a normal thiol in model compounds. The availability of the apparently essential thiols appears to be associated with some conformational change in the molecule in the monomer form: it declines at high ionic strengths, is maximal at intermediate values where the dimer first dissociates, but is lowered in the dimer at very low ionic strengths. The reaction also shows a sharp temperature dependence: the dimer at 30 degrees (in constrast to 35 degrees) shows no availability of the apparently essential thiols. A similar transition to a state permitting fast inactivation is found with pH, above pH 8.5. The reaction of the two apparently essential thiols is strongly inhibited by glucose. ATP and ADP, and their Mg complexes, protect significantly, but less effectively than does glucose. The affinities of these substrates at the active site of the enzyme are measured in this protection system. These various reactions appear to be of value for identifying the cysteine-containing regions that are involved in the active center or in its maintenance in the structure.

Adenosine Diphosphate↗
PubMed2001

Glucose loading during primary culture has opposite effects on the viability of hepatocytes exposed to potassium cyanide and to iodoacetic acid.

Whether or not to apply nutritional pretreatment and how to do so are controversial issues with respect to the liver about to undergo aggressive intervention. We studied the effects of glucose loading on the viability of hepatocytes that were subsequently exposed to the inhibitors of carbohydrate metabolism, potassium cyanide (KCN) and iodoacetic acid (IAA). After rat hepatocytes were cultured for 24 hours in Leibovitz's L-15 medium containing 0, 10, 20, and 30 mmol/L glucose, the medium was replaced with modified Hanks-HEPES buffer with or without 2.5 mmol/L KCN or 0.5 mmol/L IAA. Lactate dehydrogenase (LDH) activity, lactate concentration, and pH of the supernatant were measured after 0, 2, 4, and 6 hours of exposure to KCN and after 0, 20, 40, and 60 minutes of exposure to IAA. Glycogen and adenosine triphosphate (ATP) contents in the hepatocytes were measured simultaneously. Hepatocytes cultured with various concentrations of glucose for 24 hours stored levels of glycogen in proportion to the glucose concentration in the culture medium without any significant difference in viability. The hepatocytes cultured with higher glucose concentrations maintained a higher ATP content and released less LDH and more lactate, and the pH decreased in the supernatant during exposure to KCN. Conversely, hepatocytes cultured with lower glucose concentrations maintained a higher ATP content and released less LDH during exposure to IAA. In conclusion, prior glucose loading appears to be beneficial for hepatocytes if oxidative phosphorylation is to be inhibited, whereas withholding glucose appears to be beneficial if glycolysis is to be inhibited.

Adenosine Triphosphate↗
PubMedDate not supplied

Mono-iodoacetate-induced histologic changes in subchondral bone and articular cartilage of rat femorotibial joints: an animal model of osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease characterized by joint pain and a progressive loss of articular cartilage. Studies to elucidate the pathophysiology of OA have been hampered by the lack of a rapid, reproducible animal model that mimics both the histopathology and symptoms associated with the disease. Injection of mono-iodoacetate (MIA), an inhibitor of glycolysis, into the femorotibial joint of rodents promotes loss of articular cartilage similar to that noted in human OA. Here, we describe the histopathology in the subchondral bone and cartilage of rat (Wistar) knee joints treated with a single intra articular injection of MIA (1 mg) and sacrificed at 1, 3, 5, 7, 14, 28, and 56 days postinjection. Histologically, the early time points (days 1-7) were characterized by areas of chondrocyte degeneration/necrosis sometimes involving the entire thickness of the articular cartilage in the tibial plateaus and femoral condyles. Changes to the subchondral bone, as evidenced by increased numbers of osteoclasts and osteoblasts, were noted at by day 7. By 28 days, there was focal fragmentation and collapse of bony trabeculae with fibrosis and increased osteoclastic activity. By 56 days there were large areas of bone remodeling evidenced by osteoclastic bone resorption and newly formed trabeculae with loss of marrow hematopoietic cells. Subchondral cysts and subchondral sclerosis were present in some rats. In conclusion, intra-articular injection of MIA induces loss of articular cartilage with progression of subchondral bone lesions that mimic those of OA. This model offers a rapid and minimally invasive method to reproduce OA-like lesions in a rodent species.

Animals↗
PubMed1976

Production and rejoining of single-strand breaks in DNA of Escherichia coli cells after exposure to gamma-rays in the presence of iodoacetic acid under oxic and anoxic conditions.

The presence of iodoacetic acid (IAA, 10(4) M) during exposure of Escherichia coli cells to 25 krad gamma-radiation under anoxia resulted in a greater number of radiation-induced single-strand scissions in DNA. The single-strand breaks produced under oxic conditions of irradiation, however, were only marginally increased when IAA was present during irradiation. Although cells irradiated under anoxic or oxic condition and those irradiated under anoxic condition in the presence of IAA were capable of rejoining single-strand breaks produced in DNA, those irradiated under oxic condition in the presence of IAA had lost this capacity.

DNA Repair↗
PubMed1999

Hydroxyl radical generation and lipid peroxidation in C2C12 myotube treated with iodoacetate and cyanide.

To mimic exercise-induced events such as energetic impairment, free radical generation, and lipid peroxidation in vitro, mouse-derived C2C12 myotubes were submitted to the inhibition of glycolytic and/or oxidative metabolism with 1 mM iodoacetate (IAA) and/or 2 mM sodium cyanide (CN), respectively, under 5% CO2/95% air up to 180 min. Electron spin resonance (ESR) analysis with a spin-trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) revealed time-course increases in spin adducts from hydroxyl radical (DMPO-OH) and carbon-centered radical (DMPO-R) in the supernatant of C2C12 myotubes treated with the combination of IAA + CN. In this condition, malondialdehyde (MDA) and lactate dehydrogenase (LDH) were released into the supernatant. By the addition of iron-chelating 1 mM deferoxamine to the C2C12 preparation with IAA + CN, both ESR signals of DMPO-OH and DMPO-R were completely abolished, and the release of MDA and LDH were significantly reduced, while cyanide-resistant manganese superoxide dismutase had negligible effects on these parameters. Hence, a part of the injury of C2C12 myotube under IAA + CN was considered to result from the lipid peroxidation, which was induced by hydroxyl radical generated from iron-catalyzed systems such as the Fenton-type reaction. This in vitro model would be a helpful tool for investigating the free radical-related muscle injury.

Animals↗
PubMed1955

The effect of iodoacetate and other inhibitors on phage production and lysis in three phage systems.

The minimal bacteriostatic concentration of iodoacetate, azide, or proflavine was added at intervals during the latent periods of virus in three different bacterium-bacteriophage systems (M. aureus, B. mycoides, E. coli). For each interval at which inhibitor was added, the occurrence of lysis and the final yield of phage were determined. In the B. mycoides and E. coli systems, when added during the first part of the latent period, inhibitor prevented lysis and no phage was released. Introduction of inhibitor during the last part of the latent period resulted in normal lysis and in a linear increase in phage that progressively approached the yield obtained in the absence of inhibitor (the later the introduction, the higher the yield). In the M. aureus system, phage production and lysis in the presence of inhibitor followed the same general pattern, except that release of phage and normal lysis occurred in infected cells to which inhibitor had been added quite early in the latent period. Our results, when compared with those of Foster (1948) with proflavine and Bozeman et al. (1954) with chloramphenicol, suggest that (1) the final phage yields represent the amount of mature intracellular virus present at the time of addition of inhibitor and (2) the reactions leading to lysis proceed independently of those leading to the formation of mature virus once phage infection has reached a critical point in time.

Azides↗
PubMed1959

Active state of muscle in iodoacetate rigor.

Frog sartorius muscles, equilibrated to 2 x 10(-4)M iodoacetic acid-Ringer's solution and activated by a series of twitches or a long tetanus, perform a rigor response consisting in general of a contractile change which plateaus and is then automatically reversed. Isotonic rigor shortening obeys a force-velocity relation which, with certain differences in value of the constants, accords with Hill's equation for this relation. Changes in rigidity during either isotonic or isometric rigor response show that the capacity of the rigor muscle to bear a load increases more abruptly than the corresponding onset of the ordinarily recorded response, briefly plateaus, and then decays. A quick release of about 1 mm. applied at any instant of isometric rigor output causes the tension to drop instantaneously to zero and then redevelop, the rate of redevelopment varying as does the intensity of the load-bearing capacity. These results demonstrate that rigor mechanical responses result from interaction of a passive, undamped series elastic component, and a contractile component with active state properties like those of normal contraction. Adenosinetriphosphate is known to break down in association with development of the rigor active state. This is discussed in relation to the apparent absence of ATP splitting in normal activation of the contractile component.

Adenosine Triphosphate↗
PubMed1975

Mechanical properties of frog skeletal muscles in iodoacetic acid rigor.

1. Methods have been developed for describing the length: tension characteristics of frog skeletal muscles which go into rigor at 4 degrees C following iodoacetic acid poisoning either in the presence of Ca2+ (Ca-rigor) or its absence (Ca-free-rigor). 2. Such rigor muscles showed less resistance to slow stretch (slow rigor resistance) that to fast stretch (fast rigor resistance). The slow and fast rigor resistances of Ca-free-rigor muscles were much lower than those of Ca-rigor muscles. 3. The slow rigor resistance of Ca-rigor muscles was proportional to the amount of overlap between the contractile filaments present when the muscles were put into rigor. 4. Withdrawing Ca2+ from Ca-rigor muscles (induced-Ca-free rigor) reduced their slow and fast rigor resistances. Readdition of Ca2+ (but not Mg2+, Mn2+ or Sr2+) reversed the effect. 5. The slow and fast rigor resistances of Ca-rigor muscles (but not of Ca-free-rigor muscles) decreased with time. 6. The sarcomere structure of Ca-rigor and induced-Ca-free rigor muscles stretched by 0.2lo was destroyed in proportion to the amount of stretch, but the lengths of the remaining intact sarcomeres were essentially unchanged. This suggests that there had been a successive yielding of the weakeast sarcomeres. 7. The difference between the slow and fast rigor resistance and the effect of calcium on these resistances are discussed in relation to possible variations in the strength of crossbridges between the thick and thin filaments.

Animals↗
PubMed1995

Iodoacetate-induced skeletal muscle contracture: changes in ADP, calcium, phosphate, and pH.

The effects of iodoacetic acid (IAA) and ischemic contraction were studied in rat extensor digitorum longus muscles. Ischemic stimulation of IAA-treated muscles produced contracture. We measured total muscle water content, distribution of water between intracellular and extracellular spaces, creatine concentration ([Cr]), creatine phosphate concentration ([PCr]), [ATP], [Pi], intracellular pH, and intracellular Ca2+ concentration ([Ca2+]i) at the onset of contracture. [ADP] was calculated from the equilibrium of the creatine kinase reaction using the measured values of [ATP], [PCr], [Cr], and pH. At the onset of contracture there was a 75% reduction of [PCr], a 12-fold increase in [ADP], and an 11-fold increase in [Ca2+]i compared with unstimulated IAA-treated muscles. [ATP] was not depleted at contracture compared with unstimulated IAA-treated muscles, and [Pi] increased less in muscles at contracture compared with stimulated control muscles. The persistent tension in contractures probably resulted from increased [Ca2+]i combined with increased myofibrillar Ca2+ sensitivity due to elevated [ADP] and relatively reduced intracellular acidification and [Pi].

Adenosine Diphosphate↗