Antioxidants in peripheral nerve

Oxidative stress and antioxidants have been related in a wide variety of ways with nervous tissue. This review attempts to gather the most relevant information related to a) the antioxidant status in non pathologic nervous tissue; b) the hypothesis and evidence for oxidative stress (considered as the disequilibrium between prooxidants and antioxidants in the cell) as the responsible mechanism of diverse neurological diseases; and c) the correlation between antioxidant alterations and neural function, in different experimental neuropathies. Decreased antioxidant availability has been observed in different neurological disorders in the central nervous system, for example, Parkinson's disease, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, cerebral ischaemia, etc. Moreover, the experimental manipulation of the antioxidant defense has led in some cases to interesting experimental models in which electrophysiological alterations are associated with the metabolic modifications induced. In view of the electrophysiological and biochemical effects of some protein kinase C inhibitors on different neural experimental models, special attention is dedicated to the role of this kinase in peripheral nervous tissue. The nervous tissue, central as well as peripheral, has two main special features that are certainly related to its antioxidant metabolism: the lipid-enriched membrane and myelin sheaths, and cellular excitability. The former explains the importance of the glutathione (GSH)-conjugating activity towards 4-hydroxy-nonenal, a biologically active product of lipid peroxidation, present in nervous tissue and in charge of its inactivation. The impairment of the latter by oxidative damage or experimental manipulation of antioxidant metabolism is discussed. Work on different experimental neuropathies from author's laboratory has been primarily used to provide information about the involvement of free radical damage and antioxidants in peripheral nerve metabolic and functional impairment.     

Antioxidants in the respiratory system

BACKGROUND: Reactive oxygen species can participate in the airways reactivity changes after oxidants. The authors have observed an increase in airways reactivity after an exposure to toluene in guinea-pigs and cats in previous experiments. There literature data provide information on the prevention or the delay of free radical damage by antioxidants. MAIN PURPOSE: The aim of our study was to evaluate the effect of nonenzymatic antioxidants--vitamin C and vitamin E on the airways reactivity changes after the exposure to toluene vapours. METHODS: After a one-month-lasting pretreatment with 500 mg/kg/day vitamin C and 50 mg/kg/day vitamin E the guinea-pigs were exposed to toluene for 3 days 2 hours. Then the reactivity of trachea and lung strip smooth muscle to histamine was evaluated. RESULTS: The pretreatment with vitamin C did not evoke statistical significant changes of trachea and lung strip smooth muscles reactivity when compared with the control group. The pretreatment with vitamin E produced a statistically non-significant decrease in trachea smooth muscle reactivity, but an increase in contraction amplitude of lung strip smooth muscle. Trachea was without expressive histological changes. The lung showed granulomatous inflammation with lymphocytes and eosinophils. SUMMARY: Antioxidants in used doses did not prevent the reactivity changes evoked by toluene exposure. (Fig. 2, Tab. 4, Ref. 14.)     

Antioxidants, prostaglandins and prematurity

Preterm labor could have very bad consequences for the new-born. Every method which maintain pregnancy till term deserves to be analyzed. Such an analysis could throw a light on the process of parturition and open therapeutic possibilities against prematurity. Once a food-stuff antioxidant, Diphenyl-p-Phenylene-Diamine (DPPD) given to pregnant rats, delays or prevents parturition. We confirm the results of Oser. The daily dose of 20 mg from the 17th day of pregnancy upsets parturition. If injected from the 14th day, the parturition never occurs on time. Under the same circumstances (from the 14th day) the daily dose of 40 mg, more effective than 20 or 30 mg prolongs the pregnancy duration, causes fetal resorptions and often prevents birth of living fetuses. 200 micrograms of prostaglandin F2 alpha given on the 21st day almost totally cancel the very toxic action of 40 mg of DPPD which has been injected daily from the 14th day. When an antioxidant lengthens the pregnancy duration of rats, prostaglandin F2 alpha reestablish parturition. Thus the parturition delaying action of an antioxidant may be stymied by prostaglandin F2 alpha. This delaying action might be due to an inhibition of the synthesis of prostaglandin. If applied against the threat of preterm birth, it will be necessary to test the innocuity, at the doses used, of the selected antioxidant and the absence of side effects for the mother and fetus.     

Antioxidants and atherosclerotic heart disease

Epidemiologic studies have provided evidence of an inverse relation between coronary artery disease and antioxidant intake, and vitamin E supplementation in particular. The oxidative-modification hypothesis implies that reduced atherosclerosis is a result of the production of LDL that is resistant to oxidation, but linking the reduced oxidation of LDL to a reduction in atherosclerosis has been problematic. Several important additional mechanisms may underlie the role of antioxidants in preventing the clinical manifestations of coronary artery disease (Fig. 2). Specifically, there is evidence that plaque stability, vasomotor function, and the tendency to thrombosis are subject to modification by specific antioxidants. For example, cellular antioxidants inhibit monocyte adhesion, protect against the cytotoxic effects of oxidized LDL, and inhibit platelet activation. Furthermore, cellular antioxidants protect against the endothelial dysfunction associated with atherosclerosis by preserving endothelium-derived nitric oxide activity. We speculate that these mechanisms have an important role in the benefits of antioxidants.     

Antioxidants for prevention of methionine oxidation in recombinant monoclonal antibody HER2

Recombinant humanized monoclonal antibody HER2, rhuMAb HER2, in liquid formulations undergoes oxidation when exposed to intense light and elevated temperatures (30 & 40 degrees C). Met-255 in the heavy chain of the Fc region of the antibody is the primary site of oxidation. Met-431 of the Fc fragment can also be oxidized under extreme conditions. The amount of oxidation was determined by cleaving the Fab and Fc fragments by papain digestion, and the oxidized Fc fragment was detected by hydrophobic interaction chromatography. Oxidation of rhuMAb HER2 was also formulation dependent. The presence of NaCl in the rhuMAb HER2 formulation caused an increase in oxidation at higher temperatures after contact with stainless steel containers or stainless steel components in the filling process. The corrosion of stainless steel by chloride ions at the low pH of the formulation buffer generated iron ions that catalyzed methionine oxidation in rhuMAb HER2. Temperature-induced oxidation of rhuMAb HER2 occurred by the formation of free radicals, and light-induced oxidation of rhuMAb HER2 occurred via single oxygen pathway. Antioxidants, such as methionine, sodium thiosulfate, catalase, or platinum, prevented Met oxidation in rhuMAb HER2, presumably as free radicals or oxygen scavengers. The minimum effective levels (molar ratios of protein to antioxidant) required to inhibit temperature-induced oxidation were 1:5 and 1:25 for methionine and thiosulfate, respectively. A thiosulfate adduct of rhuMAb HER2 was observed by cation-exchange chromatography. These studies demonstrate that stoichiometric amounts of methionine and thiosulfate are sufficient to eliminate temperature-induced oxidation of rhuMAb HER2 caused by free radicals that were generated by the presence of metal ion and peroxide impurities in the formulation.     

Antioxidants and inflammatory cell response in preeclampsia

We have previously reported that gastrin induces a rapid and transient tyrosine phosphorylation of phospholipase C gamma 1 (PLC gamma 1) in association with inositol 1,4,5-trisphosphate (IP3) formation in rat colonic epithelial cells (34). In this study, we demonstrate that gastrin regulates IP3 formation mainly through PLC gamma 1 isozyme. Immunoblotting analysis revealed the expression of PLC beta 3 and -gamma 1, but not PLC beta 1, -beta 2, or -beta 4 in the rat colonic epitheliums. To explore what PLC isozyme(s) modulates gastrin effect on IP3, immunoneutralizing antibody to PLC beta 1, -beta 3, or -gamma 1 was introduced into the colonic cells using a lipid carrier. The gastrin-stimulated increase in IP3 concentration was specifically prevented by anti-PLC gamma 1 but not by anti-PLC beta 1 or -beta 3 antibody. Immunoprecipitation assays have also revealed that gastrin promoted an increase in tyrosine phosphorylation and co-precipitation of a 60 kDa src kinase with PLC gamma 1. Administration of antibody specific to pp60c-src into the colonic cells prevented the gastrin-stimulated increases in IP3. Tyrosine phosphorylation of PLC gamma 1 may be a major mechanism through which gastrin regulates IP3 level in the colonic cells. Pretreatment of cells with the tyrosine kinase inhibitor genistein abrogated gastrin's effect on IP3, while extended pretreatment with pertussis toxin, a G-protein inhibitor, did not affect the ability of gastrin to stimulate IP3 formation. Colonic cells expressed the G alpha i subunits1-3; however, immunoblotting analysis did not reveal any difference in G alpha i proteins' expression between control and gastrin treated cells. The results provide direct evidence that gastrin regulates IP3 level by a signaling mechanism that involves PLC gamma 1 and pp60c-src kinase.     

Antioxidants inhibit ATP-sensitive potassium channels in cerebral arterioles

BACKGROUND AND PURPOSE: Hydrogen peroxide and peroxynitrite are capable of generating hydroxyl radical and are commonly suspected as sources of this radical in tissues. It would be useful to distinguish the source of hydroxyl radical in pathophysiological conditions and to clarify the mechanisms by which antioxidants modify vascular actions of oxidants. METHODS: We investigated the effect of three antioxidants--dimethylsulfoxide (DMSO), salicylate, and L-cysteine--on the cerebral arteriolar dilation caused by topical application of hydrogen peroxide and peroxynitrite in anesthetized cats equipped with cranial windows. We also tested the effect of these antioxidants on the vasodilation caused by pinacidil and cromakalim, two known openers of ATP-sensitive potassium channels. RESULTS: DMSO was more effective in inhibiting dilation from hydrogen peroxide, whereas salicylate and L-cysteine were more effective in inhibiting dilation from peroxynitrite. All three antioxidants inhibited dilation in concentrations that were remarkably low (< 1 mmol/L). All three antioxidants inhibited vasodilation from two known potassium channel openers, pinacidil and cromakalim. Their effect was specific because they did not affect dilation from adenosine or nitroprusside. CONCLUSIONS: The findings show that antioxidants block ATP-sensitive potassium channels in cerebral arterioles. This appears to be the mechanism by which antioxidants inhibit the dilation from hydrogen peroxide and peroxynitrite and not through scavenging of a common intermediate, ie, hydroxyl radical. The differences between effectiveness in inhibiting dilation from hydrogen peroxide and peroxynitrite by various antioxidants suggest that hydrogen peroxide and peroxynitrite act at two different sites, one in a water-soluble environment and the other in a lipid-soluble environment.     

Antioxidants protect podocyte foot processes in puromycin aminonucleoside-treated rats

Whether a reduction in urinary protein excretion in rats coadministered puromycin aminonucleoside and antioxidants was associated with a reduction in alterations to glomerular epithelial cell (podocyte) ultrastructure was examined. Daily urinary protein excretion was measured in rats that received a single i.v. injection of saline or puromycin aminonucleoside with or without coadministration of antioxidants. The coadministration of alpha-tocopherol/ascorbic acid, dimethyl thiourea, or superoxide dismutase to puromycin aminonucleoside-treated rats reduced proteinuria by approximately 90, 40, and 60%, respectively, over the 18-day period studied. For a second group of rats, daily urinary protein excretion was measured and kidneys were processed for light microscopy and transmission and scanning electron microscopy 4, 5, and 10 days after injection. Transmission electron microscopic morphometric analysis of glomeruli from puromycin aminonucleoside-treated rats coadministered antioxidants revealed significantly reduced foot process effacement on Days, 4, 5, and 10 compared with rats that received puromycin aminonucleoside alone. Thus, at Day 10, puromycin aminonucleoside-treated rats coadministered alpha-tocopherol/ascorbic acid, dimethyl thiourea, or superoxide dismutase contained 90, 74, and 88% (P < 0.01 in all cases) more glomerular epithelial cell filtration slits per unit length of glomerular basement membrane than rats treated with puromycin aminonucleoside alone. In contrast, by scanning electron microscopy, the antioxidants were found to provide no protection against the changes occurring in glomerular epithelial cell bodies and major processes. These results provide further evidence of a role for reactive oxygen species in puromycin aminonucleoside nephrosis and indicate that the antioxidants provide protection against the changes occurring in glomerular epithelial cell foot processes.     

Essential hypertension: first reason for persistent hypertension after unilateral adrenalectomy for primary aldosteronism?

OBJECTIVE: To evaluate the performance of two pulse oximeters in the measurement of arterial hemoglobin saturation in hypoxemic children. DESIGN: Prospective, repeated-measures observational study. SETTING: A 16-bed pediatric intensive care unit in a children's tertiary hospital. PATIENTS: Sixty-six patients with arterial saturation of <90%. INTERVENTIONS: Three arterial blood samples were taken from each subject during a 48-hr period. Pulse oximeter measurements of arterial saturation were compared with arterial saturation determined by cooximetry. MEASUREMENTS AND MAIN RESULTS: Arterial saturation was measured using one or both pulse oximeters (SpO2) and compared with the arterial hemoglobin saturation determined by cooximetry (SaO2). Sixty-two subjects were studied, using the Ohmeda pulse oximeter giving 185 data points (78 with saturations <75% [defined by the average of pulse oximeter and cooximeter]); 53 subjects were studied, using the Hewlett-Packard pulse oximeter yielding 155 data points (60 with saturations <75%). SpO2 ranged from 24% to 94%. Bias and precision of the Ohmeda pulse oximeter were -2.8% and 4.8% >75% and -0.8% and 8.0% <75%. Bias and precision of the Hewlett-Packard pulse oximeter were -0.5% and 5.1% >75% and 0.4% and 4.6% <75%. Intrapatient regression coefficient (r) for the differences between pulse oximeter and cooximeter was 0.58 for the Ohmeda and 0.59 for the Hewlett-Packard. Regression coefficients for predicting change in cooximeter value given a change in the Ohmeda pulse oximeter were 0.59 and 0.71 <75% and >75%, respectively. Similar coefficients for the Hewlett-Packard pulse oximeter were 0.50 and 0.70, respectively. CONCLUSION: The performance of the Ohmeda pulse oximeter deteriorated below an SpO2 of 75%. The Hewlett-Packard pulse oximeter performed consistently above and below an SpO2 of 75%. The ability of both pulse oximeters to reliably predict change in SaO2 based on change in pulse oximetry was limited. We recommend measurement of PaO2 or SaO2 for important clinical decisions.     

Angiotensin converting enzyme inhibitors for hypertension

The review paper presents modern opinions upon angiotensin-converting enzyme (ACE) inhibitors for the treatment of hypertension. It describes their hypotensive properties and therapeutic efficacy. The review discusses also using of ACE inhibitors for disorders often coexisting with hypertension, likewise it presents ACE inhibitors in combination with other hypotensive drugs. The paper discusses also side effects of ACE inhibitors as well as diseases, in which ACE inhibitors are contraindicated.     

Therapeutic options for severe pulmonary hypertension

Pulmonary hypertension occurs as a consequence of numerous and varied conditions, all of which result in an elevation of pulmonary vascular resistance. Over the past decade, significant progress has been made in understanding the factors which contribute to the progressive nature of pulmonary vascular disease, and in identifying new treatments for pulmonary hypertension. The majority of these therapeutic options are pharmacologic, but for specific circumstances, surgical therapy may be a consideration. This article discusses nonspecific therapies for all patients with pulmonary hypertension, vasodilator therapy (including screening for vasodilator responsiveness, standard oral agents, and newer intravenous or inhalational therapies) and surgical options applicable to specific situations.     

Which calcium antagonists for hypertension?

Calcium antagonists have been used for treatment of cardiovascular diseases for more than 25 years. Several recent retrospective studies have suggested that chronic treatment with short-acting dihydropyridines increased the incidence of cardiac events, cancer and gastrointestinal bleedings. Randomized prospective studies have, however, never been able to confirm these observations. In addition, well-conducted studies using verapamil and diltiazem have suggested that these calcium antagonists may even improve cardiovascular mortality and morbidity of the hypertensive patient. There is therefore no reason to believe that the questionable results derived from retrospective studies of the effects of short-acting calcium antagonists on cardiac and noncardiac events may apply to the newer generation of long-acting calcium antagonists.     

Depletion of Antioxidants from a HDPE Geomembrane in a Composite Liner

The results of two series of accelerated aging tests are reported. Both series of tests were conducted at temperatures of 85, 70, 55, and 26°C over a period of about 3?years. In the simulated liner series, the top of the geomembrane was covered with a geotextile (protection) layer that was exposed to simulated municipal solid waste (MSW) landfill leachate while the bottom of the geomembrane was in contact with a hydrated geosynthetic clay liner. In the immersion series, the geomembrane was immersed in the simulated MSW leachate, and hence, both sides were exposed to leachate. The results from oxidative induction time tests indicate that the antioxidant depletion is about 2.2–4.8 times faster for the leachate immersed geomembrane than for geomembrane in a composite liner. The higher rates are attributed to the higher extraction of antioxidants from two sides of the geomembrane immersed in leachate. The measured antioxidant depletion rates are extrapolated to a range of temperatures (0–60°C) using Arrhenius modeling. At a liner temperature of 35°C, the calculated time for the depletion of antioxidants is about 40?years for a geomembrane in a composite liner compared to 10?years if it is simply immersed in leachate. These tests suggest that to obtain realistic estimates of geomembrane service life one needs data from tests that simulate the expected field conditions and that prediction based on immersion tests may underestimate the service life.