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PubMed2003

Acetyl-L-carnitine cytoprotection against 1-methyl-4-phenylpyridinium toxicity in neuroblastoma cells.

Acetyl-L-carnitine (ALCAR) plays an integral role in the transport of long chain fatty acids across the inner mitochondrial membrane for oxidative phosphorylation. In non-human primates, administration of ALCAR was reported to prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurological injury to the substantia nigra. The present study investigates the effects of ALCAR against the toxicity of 1-methyl-4-phenylpyridinium (MPP(+)), the neurotoxic metabolite of MPTP, in murine brain neuroblastoma cells. MPP(+), a potent mitochondrial toxin, induced a dose-dependent reduction in mitochondrial oxygen consumption and cell viability, corresponding to an accelerated rate of cellular glucose utilization. Treatment with ALCAR, but not L-carnitine, prevented MPP(+) toxicity and partially restored intracellular ATP concentrations, but did not reverse the MPP(+)-induced loss of mitochondrial oxygen consumption. These data indicate that protective effects are independent of oxidative phosphorylation. ALCAR had a substantial glucose sparing effect in both controls and MPP(+)-treated groups, demonstrating a potential role in enhancing glucose utilization through glycolysis. Antagonizing the entry of fatty acids into the mitochondria, with either insulin or malonyl CoA, did not interfere with ALCAR protection against MPP(+). On the contrary, insulin potentiated the protective effects of ALCAR. In conclusion, these data indicate that ALCAR protects against MPP(+) toxicity, independent of mitochondrial oxidative capacity or beta-oxidation of fatty acids. In contrast, the protective effects of ALCAR appear to involve potentiation of energy derived from glucose through anaerobic glycolysis.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Gastric cytoprotective anti-ulcer effects of the leaf methanol extract of Ocimum suave (Lamiaceae) in rats.

The anti-ulcerogenic potential of the leaf methanol extract of Ocimum suave (Lamiaceae) was investigated using four methods of gastric lesion induction in experimental Wistar rats (150-200 g): (1) HCl/ethanol-induced gastric lesions, (2) Absolute ethanol-induced gastric lesions, (3) Indomethacin-HCl/ethanol-induced gastric lesions, (4) Pylorus ligation-induced gastric lesions. Administration of the extract of O. suave to the rats by oral route (75-500 mg/kg) dose-dependently prevented the formation of acute gastric lesions induced using the four experimental techniques. The dose-dependent reduction of lesion formation was in all cases accompanied by significant increases in gastric mucus production. At the dose of 250 mg/kg there was complete inhibition of gastric lesions induced using the HCl/ethanol solution. Pre-treatment, by intraperitoneal route, with indomethacin significantly reduced the ability of the extract to inhibit the formation of HCl/ethanol-induced lesions. When the rats were subjected to pylorus ligation, the dose of 500 mg/kg completely inhibited lesion formation but did not have any effect on gastric acid secretion compared with the controls. The mucus secretion promoting effect of the extract was most significant when the gastric environment was highly acidic. These results suggest that a new anti-ulcer therapy regimen may be formulated which does not require the use of antacids and anti-secretory agents.

Animals↗
PubMed2001

Enhanced antioxidant and cytoprotective abilities of vitamin E succinate is associated with a rapid uptake advantage in rat hepatocytes and mitochondria.

Numerous in vitro studies attest to the enhanced ability of vitamin E succinate (TS), as compared with conventional vitamin E compounds such as unesterified d-alpha-tocopherol (T) and d-alpha-tocopheryl acetate (TA), to protect hepatocytes from toxic oxidative stress. In the present study we tested the hypothesis that this unique protective ability is related to an enhanced cellular accumulation of TS. The results of this study indicate, using both in vitro and in vivo model systems, that acute TS administration results in a rapid increase in T and TS content and antioxidant protection of hepatocytes and mitochondria. In contrast, conventional vitamin E compounds such as T and TA lack these same protective properties. We suggest that TS acts as a unique delivery system for T, rapidly accumulating in cellular and mitochondrial membranes and gradually releasing active T to prevent membrane oxidative damage. We propose that TS administration may prove useful for the prevention and treatment of oxidative stress-mediated diseases, especially those of mitochondrial origin.

Animals↗
PubMed2003

Dietary flavonoid iron complexes as cytoprotective superoxide radical scavengers.

Superoxide radicals have been implicated in the pathogenesis of ischemia/reperfusion, aging, and inflammatory diseases. In the present work, we have shown that the Fe(3+) complexes of flavonoids (polyphenols) were much more effective than the uncomplexed flavonoids in protecting isolated rat hepatocytes against hypoxia-reoxygenation injury. The 2:1 flavonoid-metal complexes of Cu(2+), Fe(2+), or Fe(3+) were more effective than the parent compounds in scavenging superoxide radicals generated by xanthine oxidase/hypoxanthine (an enzymatic superoxide-generating system). The 2:1 [flavonoid:Fe(3+)] complexes but not the [deferoxamine:Fe(3+)] complex readily scavenged superoxide radicals. These results suggest that the initial step in superoxide radical scavenging (SRS) activity involves a redox-active flavonoid:Fe(3+) complex. Flavonoid:Fe(3+) complexes should, therefore, be tested as a therapy for the treatment of ischemia/reperfusion injury.

Animals↗
PubMed1998

Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide.

There has been confusion as to what role(s) nitric oxide (NO) has in different physiological and pathophysiological mechanisms. Some studies imply that NO has cytotoxic properties and is the genesis of numerous diseases and degenerative states, whereas other reports suggest that NO prevents injurious conditions from developing and promotes events which return tissue to homeostasis. The primary determinant(s) of how NO affects biological systems centers on its chemistry. The chemistry of NO in biological systems is extensive and complex. To simplify this discussion, we have formulated the "chemical biology of NO" to describe the pertinent chemical reactions under specific biological conditions. The chemical biology of NO is divided into two major categories, direct and indirect. Direct effects are defined as those reactions fast enough to occur between NO and specific biological molecules. Indirect effects do not involve NO, but rather are mediated by reactive nitrogen oxide species (RNOS) formed from the reaction of NO either with oxygen or superoxide. RNOS formed from NO can mediate either nitrosative or oxidative stress. This report discusses various aspects of the chemical biology of NO relating to biological molecules such as guanylate cyclase, cytochrome P450, nitric oxide synthase, catalase, and DNA and explores the potential roles of NO in different biological events. Also, the implications of different chemical reactions of NO with cellular processes such as mitochondrial respiration, metal homeostasis, and lipid metabolism are discussed. Finally, a discussion of the chemical biology of NO in different cytotoxic mechanisms is presented.

Animals↗
PubMed1998

Cytoprotective properties of melatonin: presumed association with oxidative damage and aging.

For years melatonin, a molecule widely produced in both the plant and animal kingdom, was thought to function exclusively as a synchronizer of seasonal reproduction, adjuster of the biological clock, sleep-inducing agent, and immune system stimulator. More recently melatonin has also been found to be a free-radical scavenger and antioxidant. Although pharmacologic levels (higher than those normally present endogenously) of melatonin possess substantial protective activity against molecular damage inflicted by free radicals, its role as a physiologic antioxidant is currently under active investigation. Toxic free radicals have been implicated in a variety of age-associated degenerative diseases, as well as in aging itself. Because melatonin production falls substantially during aging, the loss of this antioxidant is theorized to be instrumental in the degenerative processes associated with advanced age. The exogenous administration of melatonin has been found to be effective in reducing macromolecular damage that is normally seen in experimental models of age-related disease. How effective melatonin will be in terms of deferring aging, however, must await the outcome on subsequent studies.

Aging↗
PubMedDate not supplied

Chronic cytoprotection: pentadecapeptide BPC 157, ranitidine and propranolol prevent, attenuate and reverse the gastric lesions appearance in chronic alcohol drinking rats.

Unlike severe gastric damage acutely induced by ethanol administration in rat, the ulcerogenic effect of chronic alcohol administration (3.03 g/kg b.w. or 7.28 g/kg b.w.) given in drinking water, producing liver lesions and portal hypertension, is far less investigated. Therefore, focus was on the antiulcer effect of the gastric pentadecapeptide BPC 157, GEPPPGKPADDAGLV, M.W. 1419, known to have a beneficial effect in variety of gastrointestinal lesions models (10 microg or 10 ng/kg b.w. i.p. or i.g.), ranitidine (10 mg/kg b.w. i.g.) and propranol (10 mg/kg b.w. i.g.) or saline (5 ml/kg b.w. i.p./i.g.; control). They were given once daily (1) throughout 10 days preceding alcohol consumption, (2) since beginning of alcohol drinking till the end of the study, (3) throughout the last month of alcohol consumption, 2 months after alcohol drinking had been initiated. Gastric lesions were assessed, at the end of 3 months drinking [(1), (2)] or with respect to therapeutic effect of medication before medication or at the end of therapy. Pentadecapeptide BPC 157, ranitidine and propranolol may prevent gastric lesion development if given prophylactically, before alcohol drinking. Likewise, they attenuate the lesion appearance given once daily throughout the drinking period. Importantly, when given therapeutically, they may antagonize otherwise pertinent lesion presence in stomach mucosa of the drinking rats. Thus, these results demonstrate that pentadecapeptide BPC 157, ranitidine and propranol may prevent, attenuate or reverse the gastric lesions appearance in chronically alcohol drinking rats, and may be used for further therapy, while the other studies showed that their effect (except to ranitidine) is parallel with their beneficial effect on liver lesion and portal hypertension.

Alcohol Drinking↗
PubMed2006

Synthesis of thieno[2,3-b]pyridinones acting as cytoprotectants and as inhibitors of [3H]glycine binding to the N-methyl-D-aspartate (NMDA) receptor.

The standard glycine site antagonist of the N-methyl-D-aspartate (NMDA) receptor, 3-phenyl-4-hydroxyquinolin-2(1H)-one (21), was used as a template for bioisostere benzene/thiophene exchange. Phenylacetylation of aminothiophene carboxylic acid methyl esters and subsequent cyclization delivered the three possible thienopyridinone isomers. 4-Hydroxy-5-phenylthieno[2,3-b]pyridin-6(7H)-one (3a), with the shortest distance between the sulfur and the nitrogen atom, was the most potent isomer (K(i) against the binding of [(3)H]glycine to rat membranes 16 microM), comparable in potency to the model quinolinone (21, 12 microM). Replacement of the phenyl substituent of 21 by a 2-thienyl residue resulted in a 2-5-fold loss in potency and was abandoned. In the thieno part of the thienopyridinone nucleus, the most successful substituents were halogen (Cl or Br) close to the sulfur atom and short alkyl chains at the other position, resulting in 7h, 8h, 8i, and 8m, with K(i) values between 5.8 and 10.5 nM. Introduction of a 3'-phenoxy moiety yielded several compounds with still higher potencies (18h, 18i, 18l, and 18m; K(i) between 1.1 and 2.0 nM). Quantitative structure-activity relationship (QSAR) calculations resulted in a consistent interpretation of the potencies of most compounds. Several of these 3'-phenoxy derivatives protected mouse fibroblast cell lines with transfected NMDA receptors from glutamate-induced toxicity. In addition, we report in vivo results for four of these compounds.

Animals↗
PubMed1998

Selective cytoprotection with amifostine in concurrent radiochemotherapy for head and neck cancer.

BACKGROUND: Amifostine has reduced toxicities associated with radiation therapy and platinum-based chemotherapy. In a phase II randomized trial, we investigated the ability of amifostine to reduce the toxicity of carboplatin plus radiotherapy (RCT) in patients with head and neck cancer. PATIENTS AND METHODS: Thirty-nine patients with stage III or IV squamous cell carcinomas of the head and neck received RCT (following surgery or as primary treatment). Radiotherapy was given five days per week with daily fractions of 2 Gy, up to a total dose of 60 Gy in conjunction with carboplatin 70 mg/m2 on days 1 through 5 and days 21 through 26. Eligible patients were randomised to receive RCT alone or preceded by a rapid infusion of amifostine (500 mg) on the days when carboplatin was administered. RESULTS: Patients receiving amifostine + RCT (n = 25) had significantly reduced mucositis (P = 0.0001) and xerostomia (P = 0.0001) in comparison with patients receiving RCT alone (n = 14). Additionally, patients receiving amifostine + RCT had significantly less thrombocytopenia (P = 0.001) and leukopenia (P = 0.001). At 12 months following therapy, 79% of patients receiving amifostine + RCT had no evidence of disease compared with 64% of those receiving RCT alone. CONCLUSIONS: Amifostine reduces the RCT-induced toxicities in patients with head and neck cancer and has no negative impact on antitumour efficacy.

Adult↗
PubMed2003

Lack of cytoprotective effect of amifostine following HLA-identical sibling transplantation for advanced myelodysplastic syndrome (MDS): a pilot study.

The objective of this prospective study was to determine whether amifostine (Ethyol) reduced conditioning-related toxicity following a regimen of busulfan (7 mg/kg) and fractionated total body irradiation (6 x 200 cGy). In all, 12 patients with advanced myelodysplastic syndrome transplanted from HLA-identical siblings were enrolled. Patients received 340 mg/m(2) amifostine i.v. twice daily during conditioning (days -7 through -1). All patients developed oropharyngeal mucositis. Six patients had evidence of sinusoidal obstruction syndrome of the liver. Six patients experienced pulmonary toxicity of grades II-III. A total of 11 patients died, one with relapse and 10 with infectious complications or regimen-related toxicity. Nonrelapse causes of death included invasive aspergillosis in three, multiorgan failure in three, and idiopathic interstitial pneumonitis in two patients. One patient each died of organizing pneumonia and CMV pneumonia. One patient is alive in complete remission 31 months after transplantation. These results were not superior to those in patients conditioned with busulfan plus fractionated total body irradiation and not given amifostine, and suggest that amifostine, as administered here, has no protective effect against toxicity from this myeloablative regimen.

Adult↗
PubMed2005

Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation.

In this prospective multicentre trial, 90 patients undergoing autologous stem cell transplantation (ASCT) were randomised to receive (n=43) or not receive (n=47) amifostine 910 mg/m(2) prior to melphalan 200 mg/m(2). Patients were monitored for regimen-related toxicity, engraftment, supportive care, response and survival. Both groups underwent ASCT at a median of 8 months from diagnosis and were matched for disease characteristics, prior therapy and pre-ASCT disease responsiveness. Amifostine infusional side-effects were frequent, occurring in 65% of patients, but of mild severity. Amifostine use was associated with a reduction in the median grade of oral mucositis (1 vs 2, P=0.01) and the frequency of severe (WHO grades 3 or 4) mucositis (12 vs 33%, P=0.02), but no reduction in the requirement for parenteral nutrition or analgesic use. Conversion to complete remission post-ASCT occurred in 30 and 14% of the amifostine and control groups, respectively (P=0.09). With a median follow-up of 35 months, there was no statistically significant difference between the median progression-free or overall survival times for the two groups. We conclude that amifostine can be safely administered prior to high-dose melphalan and significantly reduces the frequency and severity of therapy-induced oral mucositis.

Adult↗
PubMed2003

Thioredoxin peroxidases can foster cytoprotection or cell death in response to different stressors: over- and under-expression of thioredoxin peroxidase in Drosophila cells.

Recently, we identified a set of five genes constituting the peroxiredoxin gene family in Drosophila melanogaster [Radyuk, Klichko, Spinola, Sohal and Orr (2001) Free Radical Biol. Med. 31, 1090-1100]. This set includes two abundant thioredoxin peroxidase (TPx) species, namely Drosophila peroxiredoxin DPx-4783, a cytosolic TPx and DPx-5037, a mitochondrial TPx. Overexpression of either one of them in Drosophila S2 cells conferred increased resistance to toxicity induced by hydrogen peroxide, paraquat or cadmium. To understand further the functional roles of these enzymes in vivo, we report in the present study the effects of decreased expression, using RNA interference, on the response of S2 cells to different stressors. When either of the TPxs was blocked, cells became relatively more susceptible to oxidative stress caused by exposure to hydrogen peroxide or paraquat, but were unaffected when challenged with copper and heat stress. In contrast, TPx overexpressing cells were more susceptible to copper and heat stress when compared with control cells and exhibited DNA fragmentation. Furthermore, when cells were supplemented with N -acetyl-L-cysteine together with copper, there was a clear negative effect on cell survival, which was exacerbated by TPx overexpression. Manipulations in the levels of TPxs demonstrated that, under different stress conditions, these enzymes might have both beneficial and detrimental effects on Drosophila cell viability.

Acetylcysteine↗
PubMed2002

Cytoprotective effects of nitrates in a cellular model of hydronephrosis.

BACKGROUND: The earliest insult to the kidney following the onset of ureteral obstruction is a marked elevation in collecting system pressure. This imparts a mechanical stress that is transmitted directly from the collecting system to the kidney substance. Renal tubular injury is the principal functional and histological change encountered, with glomerular changes being less marked and occurring later. Nitric oxide (NO) has been shown to protect against renal injury in UO, but its mode of action has not been clearly defined. METHODS: MDCK (canine) and HK-2 (human) renal tubular cells were grown under control conditions or subjected to mechanical strain for periods of 24 and 48 hours. Cells were studied treated with or without Fas-antibody, etoposide or diethyl maleate (DEM) alone or in combination with NG-monomethyl l-arginine (L-NMMA), sodium nitroprusside (SNP) or l-arginine. Cell proliferation and apoptosis was determined using propidium iodide DNA staining. NO production and inducible NO synthase (iNOS) expression were measured by the Griess reaction and Western blotting, respectively. RESULTS: Cells subjected to mechanical strain displayed a decrease in the proportion of cells undergoing cell division. They also showed an increased susceptibility to apoptosis. Associated with this was a decrease in Bcl-2 expression. An increase in iNOS expression was seen in cells subjected to mechanical strain, but no increase in NO production. The cellular effects of mechanical strain were reversed by SNP and l-arginine. CONCLUSIONS: Culture of renal tubule cells in an environment of mechanical strain results in an imbalance in homeostasis and a net cell loss. This can be reversed by the administration of an NO donor or precursor.

Animals↗
PubMed2004

Phase I study for poor-prognosis lymphoma: augmentation of the "BEAM" regimen with escalating dose melphalan using amifostine cytoprotection and autologous hematopoietic stem cell transplantation--a preliminary report.

We and others have previously shown that the use of amifostine (Ethyol; MedImmune Inc, Gaithersburg, MD) can ameliorate certain regimen-related toxicities of high-dose melphalan (HD-MEL) in the autologous hematopoietic stem cell transplant setting. Our recent experience indicated that the maximum tolerated dose of HD-MEL plus autologous hematopoietic stem cell transplant could be increased from approximately 200 mg/m2 to at least 280 mg/m2 with amifostine. Although a dose-limiting toxicity was not clearly identified, atrial fibrillation was noted in several patients. Phase II trials using this regimen have been reported in lymphoma and myeloma. Nonetheless, it is unlikely that single agent therapy, regardless of dose, will be highly curative in advanced hematologic malignancy. Thus, we used amifostine to permit dose escalation of HD-MEL within the BEAM (BCNU/etoposide/arabinosylcytosine/HD-MEL) combination chemotherapy regimen before autologous hematopoietic stem cell transplant in selected patients with lymphoma. Patient entry at the starting dose (ie, HD-MEL 140 mg/m2) has been completed without the development of severe regimen-related toxicities. This trial is ongoing.

Adult↗
PubMed1997

Cytoprotection by the osmolytes betaine and taurine in ischemia-reoxygenation injury in the perfused rat liver.

Medium osmolarity sensitively regulates Kupffer cell functions like phagocytosis and prostaglandin (PG) and cytokine production. Betaine and taurine, recently identified as osmolytes in liver cells, interfere with these effects. Because Kupffer cell activation is an important pathogenic mechanism in ischemia-reoxygenation injury, the influence of osmolarity and osmolytes was investigated in a rat liver perfusion model of warm ischemia. Livers were perfused with different medium osmolarities for 60 to 90 minutes in the absence of oxygen, followed by another 90 minutes of reoxygenation. Lactate dehydrogenase (LDH) leakage into the effluent perfusate during the hypoxic and the reoxygenation period was eight- to 10-fold higher with a medium osmolarity of 385 mosmol/L than in normo-osmolarity, and further decreased with hypo-osmolar perfusion buffer. Betaine and taurine addition to the perfusate in near physiological concentrations decreased hypoxia-reoxygenation-induced LDH leakage, aspartate transaminase (AST) leakage, and perfusion pressure increase in hyperosmolar and normo-osmolar perfusions. Stimulation of PGD2, PGE2, thromboxane B2 (TXB2), and tumor necrosis factor alpha (TNF-alpha) release, as well as induction of carbon uptake by the liver during reoxygenation, were suppressed by betaine and taurine, pointing to an interference of these osmolytes with Kupffer cell function. In contrast, endothelial cell function as assessed by hyaluronic acid (HA) uptake was not influenced. It is concluded that warm ischemia-reoxygenation injury in rat liver is aggravated by hyperosmolarity and attenuated by hypo-osmolarity. The osmolytes betaine and taurine have a protective effect, presumably by inhibition of Kupffer cell activation.

Animals↗