Glutathione and protein kinase C in peripheral nervous tissue.
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Animals↗
Biomedical subjects
J Romá
Publications and source records attributed to J Romá.
Phenytoin-induced glutathione depletion in rat peripheral nerve.
Administration of high doses (150-250 mg/kg body weight) of phenytoin (DPH) promote a 40% decrease in glutathione (GSH) content of rat sciatic nerve. This DPH-induced GSH depletion is accompanied with an electrophysiological impairment of peripheral neuromuscular function. H7 (20 mg/kg body weight IP, 30 min prior to DPH), a protein kinase C inhibitor, was able to prevent the DPH-induced GSH depletion only at the lower DPH dose used. This same inhibitor completely prevented the electrophysiological impairment at the lower DPH dose, and only partially at the higher DPH dose used. These results confirm the hypothesis of a DPH-dependent activation of PKC (that might be triggered by, or be the consequence of, the reduction of the intracellular antioxidant GSH), as one of the pathophysiological mechanisms involved in DPH-induced neurotoxicity.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Interferon decreases serum lipid peroxidation products of hepatitis C patients.
Thiobarbituric acid reactive substances (TBARS) concentration in serum has been determined in healthy subjects and in patients suffering acute hepatitis and chronic cases of hepatitis C. Treatment with interferon of the chronic active hepatitis C patients, 5 x 10(6) U three times a week during 2 months, led in those patients whose SGPT activity normalized in serum, to a concomitant decrease in serum TBARS content. The possible theoretical involvement of peroxidation and antioxidants in this beneficial effect of interferon in hepatitis C patients is discussed. The results presented confirm the value of TBARS as laboratory test in the management of liver diseases and as a useful tool for the study of pathogenic and/or therapeutic mechanisms of this viral infection.
Acute Disease↗
4-Hydroxynonenal, a lipid peroxidation product, induces relaxation of human cerebral arteries.
The relaxant effect of 4-hydroxynonenal (4-HNE), a lipid peroxidation product, on human cerebral arteries was studied. Addition of 4-HNE to artery rings promoted no contraction, and after stimulation with prostaglandin F2 alpha (PFG2 alpha; 10(-7)-3 x 10(-6) M), 100% relaxation was obtained with 3 x 10(-5) M 4-HNE. Inhibition of nitric oxide formation with NG-nitro-L-arginine methyl ester hydrochloride (L-NAME; (10(-4) M), as well as prostaglandin synthesis with indomethacin (3 x 10(-6) M), partially prevented 4-HNE-induced relaxation, but each of these substances separately failed to inhibit complete relaxation. Addition of both inhibitors together reduced 4-HNE-induced relaxation to approximately 50%, but relaxation could not be abolished. When the endothelium was removed, 4-HNE did not promote relaxation after PGF2 alpha stimulation. The possible roles of different intracellular signaling systems in the vascular effect of 4-HNE are discussed.
Aged↗
Decreased glutathione peroxidase activity in sciatic nerve of alloxan-induced diabetic mice and its correlation with blood glucose levels.
The effect of alloxan-induced diabetes on glutathione peroxidase (GSH-Px) activity in sciatic nerve of mice has been studied. We have found, 7 days after alloxan treatment, a significant decrease in this enzymatic activity in the cytosol of sciatic nerve of diabetic mice, and moreover, that these changes remained unaltered up to 21 days after alloxan injection. No modification in the glutathione content of sciatic nerve of diabetic mice was observed throughout the experiment when compared with controls. The decrease in GSH-Px activity in this tissue shows a good correlation with the increase of blood glucose levels throughout the experiment. It is hypothesized whether a combination of mechanisms could be involved in this decrease of GSH-Px activity and if oxygen radicals might be the common mediators of these processes.
Animals↗
Glutathione system of human retina: enzymatic conjugation of lipid peroxidation products.
The major aspects of the glutathione (GSH)-related antioxidant defense of human retina are presented. These include concentration of GSH and activities of some GSH-dependent enzymes: glutathione peroxidase, glutathione disulfide reductase, and glutathione S-transferase toward a broad spectrum substrate 1-chlor-2,4-dinitrobenzene and a toxic product of lipid peroxidation (4-hydroxynonenal). The presence of a relatively high GSH concentration, GSH peroxidase activity, and GSH S-transferase specific activity toward 4-hydroxynonenal in human retina might constitute a central defense mechanism in inflammation-promoted oxidative stress and subsequent lipid peroxidation. The use of different substrates for the determination of the GSH peroxidase activity showed no statistically significant difference, thus suggesting the lack of Se-independent GSH peroxidase in human retina. Large individual variations were obtained for GSH concentration and the different activities tested; the apparent correlation with age of these findings is currently under investigation.
Aldehydes↗
Alterations in the antioxidant defense of peripheral nervous tissue following acute ethanol administration.
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Animals↗
Prevention of the acute neurotoxic effects of phenytoin on rat peripheral nerve by H7, an inhibitor of protein kinase C.
The neurotoxic effects of a single dose of phenytoin (150 mg/kg body weight) alone or 30 min after H7 (a protein kinase C inhibitor) injection (20 mg/kg body weight) were investigated in terms of peripheral neuromuscular function and Na+,K(+)-ATPase activity of the sciatic nerve. This intraperitoneal injection of phenytoin induced complete blockade of muscle action potentials in the dorsal segmental muscles of the rat tail evoked by electric stimulation of the caudal nerve and a 40% decrease in the Na+,K(+)-ATPase activity of the rat sciatic nerve when compared with control values, measured as the difference between total and ouabain-insensitive ATPase activity. Prior administration of H7 resulted in the complete prevention of both effects. Implications of protein kinase C inhibition in phenytoin neurotoxicity are discussed.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
H7, a protein kinase C inhibitor, increases the glutathione content of neuroblastoma cells.
It is shown that the intracellular glutathione (GSH) concentration of neuroblastoma-2a cells in culture increases with a maximum at 24 h after starting treatment with 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), an inhibitor of protein kinase C (PKC). Other inhibitors of this and other protein kinases, e.g. sphingosine, staurosporine, and HA 1004, at the concentrations tested, had a less marked or negligible effect on intracellular GSH concentration. 12-O-Tetradecanoylphorbol-13-acetate (TPA) was also tested and showed no significant effect 24 h after addition.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Oxygen toxicity in the nervous tissue: comparison of the antioxidant defense of rat brain and sciatic nerve.
Nervous tissue, central and peripheral, is, as any other, subject to variations in oxygen tension, and to the attack of different xenobiotics; these situations may promote the generation of activated oxygen species of free radical character. Results are presented showing that the content of total glutathione (GSH) in brain is 10-fold that found in the sciatic nerve of the rat (2620 vs. 261 nmol/g wet weight, respectively). The existence of a relatively high superoxide dismutase activity in peripheral nervous tissue, when compared with brain or liver, in combination with the DT-diaphorase activity detected in the sciatic nerve might represent an effective defense mechanism against quinone toxicity, as is also discussed. Nervous tissue, both central and peripheral lack Se-independent GSH peroxidase activity. Finally, the activities of other glutathione-related enzymes studied in the sciatic nerve are very low, when compared with the central nervous tissue, thus suggesting a higher susceptibility of peripheral tissue to oxidative stress damage, since GSH concentration and/or any GSH-related enzymatic activities, e.g. GSH peroxidase or glutathione disulfide reductase, might become limiting.
Animals↗
Careful consideration of the effects induced by glutathione depletion in rat liver and heart. The involvement of cytosolic and mitochondrial glutathione pools.
One of the most widely used mechanisms by which the role of glutathione (GSH) in cellular functions has been withdrawn, is to deplete GSH intracellularly. The importance of the procedure and xenobiotic chosen to get it is discussed. Mitochondrial GSH plays certainly an important role in maintaining cellular homeostasis. This contribution varies depending on the tissue and the conclusions obtained about the functions of this GSH pool in one organ may not be applied to others. Original data on the subcellular distribution of GSH in myocardial tissue of the rat are presented, and the effect of phorone on both cardiac GSH pools is compared with the effect in liver. The mechanical failure of myocardium after ischemic or reperfusion damage might involve mitochondrial GSH, in view of the literature data referring to the role of thiol groups in energy transfer from mitochondria to cytosol.
Animals↗
Dependence of hepatic gluconeogenesis on PO2: inhibitory effects of halothane.
The dependence of gluconeogenesis and O2 uptake on PO2 in isolated rat hepatocytes is presented. Maintenance of steady-state PO2 was achieved with an oxystat system (Biochem. J. 236: 765-769, 1986). O2 uptake showed a half-maximal (K0.5) value of 0.5 Torr PO2, whereas the glucose synthesis rate was half-maximal at 1.2 Torr PO2. Halothane at concentrations greater than 1 mM exerted a parallel inhibition of O2 uptake and glucose synthesis at all PO2 levels studied. In contrast, at halothane concentrations less than 1 mM, inhibition of glucose synthesis occurred only at less than 20 Torr PO2. At these low concentrations, halothane was without significant effects on cellular O2 uptake. In isolated mitochondria, inhibition of O2 uptake was already half-maximal at a halothane concentration of 0.5 mM. In this subcellular system the inhibitory effect of halothane was independent of PO2. These results demonstrate that the critical PO2 at which cellular O2 utilization begins to decrease and the PO2 at which glucose synthesis begins to decrease are comparable; both PO2 levels are approximately 5 Torr. The metabolic zonation of the liver lobule is discussed in view of the results presented.
Animals↗
Isonicotinic acid hydrazide: early effects on peripheral nerve conduction velocity.
This report describes the effects of short treatments with isonicotinic acid hydrazide (isoniazid), 300 mg/kg/day, on conduction velocity in the rat tail dorsal nerve trunk. After 6 days of continuous treatment, conduction velocity falls significantly for measurements made at 35 degrees C. After 10 days it falls significantly at both 25 degrees C and 35 degrees C. This appears to be the first electrophysiological corroboration of the early neuropathological changes recently observed in isoniazid treated rats and seems to provide evidence that the temperature at which the experiments are made is important in determining conduction velocity changes.
Animals↗
Antioxidant and glutathione-related enzymatic activities in rat sciatic nerve.
The present work tries to establish the antioxidant capacity of the peripheral nervous tissue of the rat, in terms of the enzymatic activities present in this tissue that either prevent the formation of activated species as the semiquinone radical (DT-diaphorase), protect against activated oxygen species (superoxide dismutase, glutathione peroxidase), conjugate natural toxic products or xenobiotics (glutathione S-transferase, especially the activity conjugating 4-hydroxy-nonenal), or complete the glutathione system metabolism (glutathione disulfide reductase, gamma-glutamyl transpeptidase). All the activities studied are lower in this tissue than they are in liver, except for gamma-glutamyl transpeptidase. The relevance of the results obtained and its possible relationship with different neuropathies is discussed. It is concluded that the peripheral nervous tissue is by far less protected than the liver against oxidative damage.
Animals↗
Temperature dependence of the toxic effects of phenytoin on peripheral neuromuscular function of the rat tail.
We studied the acute effects of a single dose of phenytoin (250 mg/kg) on peripheral neuromuscular function. The evoked muscle action potentials of the dorsal segmental muscles in the rat tail, and the conduction velocity of the dorsal nerve trunk which innervates them, were measured before and after the intraperitoneal injection of phenytoin. The experiments were performed at different temperatures, 27 (physiological tail temperature), 36 and 37 degrees C (physiological central temperature) in different groups of animals. The amplitudes of the evoked muscle action potentials in the treated groups showed no significant modifications at 27 degrees C, at 36 degrees C a small nonsignificant decrease could be observed, and a complete block occurred at 37 degrees C. The mean blocking time was approximately one hour. No significant variations of conduction velocity were observed at 27 and 36 degrees C, whereas it decreased significantly after 30 minutes at 37 degrees C. The results presented confirm phenytoin toxicity. How far these results, especially the decrease of nerve conduction velocity observed at 37 degrees C, confirm a previous hypothesis which supported that peripheral and central nervous system are affected by phenytoin by similar mechanisms, is discussed.
Action Potentials↗
Nerve conduction velocity decrease and synaptic transmission alterations in caffeine-treated rats.
The action of caffeine on peripheral neuromuscular function was studied by means of in vivo determinations of electrophysiological parameters, i.e., amplitude of extracellularly recorded muscle action potentials and nerve conduction velocity in the dorsal skeletal muscle and caudal nerve of the rat tail, respectively. Repeated exposure of the rats was carried out by adding caffeine to the drinking water for 10 days. Here we report the novel finding that motor nerve conduction velocity showed a significant decrease in caffeine-treated animals, whereas no change was observed in the amplitude of indirectly evoked extracellular muscle action potentials. The physiological recovery of the amplitude of the compound muscle action potential observed in nonintoxicated rats after high-frequency stimulation (10 Hz) was not observed in intoxicated animals and is also discussed.
Action Potentials↗
A simple microassay for the determination of hydrazine in biological samples. Effect of hydrazine and isoniazid on liver and brain glutathione.
A simple microassay for the determination of hydrazine in laboratory samples is presented. The colored product of the reaction of p-dimethylaminobenzaldehyde with hydrazine was tested at 470 nm using double-beam mode in different samples. Internal standards and data on blood serum, liver, and brain of rats treated with hydrazine or isoniazid are presented. The tissue glutathione content of these rats was determined, and the possible implication of glutathione in the brain toxicity of hydrazine is discussed.
Animals↗
Treatment of perennial allergic rhinitis with cetirizine.
A study was made of 30 patients with perennial extrinsic rhinitis sensitized only to dust mites who were treated with cetirizine for 15 days, at a dose of 10 mg/24 hours. The following parameters were evaluated in each patient on day -1 before initiating treatment and on day 15: histamine 1/100 prick-test, Dermatohophagoides pteronyssinus prick-test, physical examination, assessment of nasal edema and rhinorrhea by anterior rhinoscopy, and of the degree of nasal obstruction by active anterior rhinomanometry. Each patient was given a form for daily clinical self-evaluation of the following subjective symptoms: sneezing, rhinorrhea, nasal obstruction, and nasal itchiness. The occurrence of side effects was evaluated. Cetirizine reduced significantly the area of the histamine and D. pteronyssinus papules elicited by prick-test. Clinical symptoms decreased significantly, with sneezing, nasal itchiness and rhinorrhea being greatly relieved, and nasal obstruction, evaluated by means of active anterior rhinomanometry performed before and after 15 days of treatment, being less alleviated. There was scant incidence of side effects in patients treated with cetirizine.
Adolescent↗