Potential role of oxidative stress on the prescription of rehabilitation interventions in spinal cord injury.

STUDY DESIGN: Review article. OBJECTIVES: To provide an overview of free radical biology, particularly with respect to muscle physiology, as well as the potential effects of muscle morphological changes, physical capacity and nutritional status on oxidative stress in people with chronic spinal cord injury (SCI). The potential implications of these factors for determining the optimal dosage of rehabilitation training interventions in people with chronic SCI will also be presented. SETTING: Vancouver, BC, Canada. METHODS: Literature review. RESULTS: Not applicable. CONCLUSION: There has been a great deal of focus on rehabilitation exercise interventions providing intensive practice of movements to enhance functional recovery and physical capacity following SCI. However, there is still much to be understood about the appropriate dosage of training parameters (e.g. frequency, duration). It has been known for several decades that exercise increases free radical production, leading to oxidative stress. To date, there has been little consideration of the potential interaction of oxidative stress with training parameters on functional outcomes in chronic SCI. Furthermore, individuals with chronic SCI face many secondary consequences of their injury, such as muscle atrophy, change in muscle fiber type, general deconditioning and nutritional status, that are known to influence free radical production and antioxidant capacity. Better understanding of the potential confounding effects of oxidative stress associated with exercise will improve our ability to determine the optimal 'dose' of rehabilitation training to maximize functional recovery following SCI.

Increased plasma endothelin-1 and cardiac nitric oxide during doxorubicin-induced cardiomyopathy.

The major limiting factor in long-term administration of doxorubicin is the development of cumulative dose-dependent cardiomyopathy and congestive heart failure. Although several mechanisms have been suggested to explain the exact cause of doxorubicin-induced cardiomyopathy, the role of the vascular endothelium-derived vasoactive mediators in the pathophysiology of this toxic effect is still unknown. Accordingly, the present study has been initiated to investigate whether the changes in plasma level of endothelin-1 and nitric oxide along with cardiac nitric oxide are associated with the development of doxorubicin-induced cardiomyopathy. Doxorubicin was injected with a single dose of 5 mg/kg and every other day with a dose of 5 mg/kg, intraperitoneally, to have four cumulative doses of, 10, 15, 20 and 25 mg/kg in five separate groups of male rats. An additional group receiving a single dose of 20 mg/kg and one receiving normal saline were also included in the study. Twenty-four hr after the last dose, the animals were sacrificed and the plasma levels of endothelin-1 and nitric oxide in addition to cardiac nitric oxide were determined. The results show that doxorubicin caused a statistically significant increase of 85%, 76% and 97% in plasma endothelin-1 at a cumulative dose levels of 10, 15 and 20 mg/kg, respectively. However, the level of plasma nitric oxide remained unchanged. Furthermore, doxorubicin treatment resulted in a significant dose-dependent increase in serum lactate dehydrogenase and creatine phosphokinase. In contrast, the increase in nitric oxide production in cardiac tissue by doxorubicin was not dose-dependent with the maximum increase (81%) at a cumulative dose of 10 mg/kg. It is worth mentioning that plasma endothelin-1 and cardiac nitric oxide were significantly increased at 24 hr after the single dose of 20 mg/kg doxorubicin. The increase of plasma endothelin-1 and cardiac nitric oxide with the cardiomyopathy enzymatic indices, may point to the conclusion that both endothelin-1 and cardiac nitric oxide are increased during the development of doxorubicin-induced cardiomyopathy.

L-carnitine prevents the progression of atherosclerotic lesions in hypercholesterolaemic rabbits.

This study has been initiated to investigate, in hypercholesterolaemic rabbits, whether L-carnitine deficiency could be an additional risk factor in atherosclerosis, and if so, whether L-carnitine supplementation could prevent the progression of atherosclerosis. Hypercholesterolaemia was induced by feeding rabbits 2% cholesterol-enriched diet for 28 days, whereas, carnitine deficiency was induced by daily i.p. administration of 250 mg kg(-1) of D-carnitine for 28 days. Histopathological examination of aorta and coronaries from hypercholesterolaemic rabbits revealed severe atherosclerotic lesions, intimal plaques and foam cell formation. Also, hypercholesterolaemic diet resulted in a significant 53 and 43% decrease in reduced glutathion (GSH) levels and a significant (1.87-fold) and (14.1-fold) increase in malonedialdhyde (MDA) levels in aorta and cardiac tissues, respectively. Daily administration of L-carnitine (250 mg kg(-1)) for 28 days, completely prevented the progression of atherosclerotic lesions induced by hpercholesterolaemia in both aorta and coronaries. Conversely, daily administration of D-carnitine (250 mg kg(-1)) for 28 days increased the progression of atherosclerotic lesions with the appearance of foam cells and apparent intimal plaques which are even larger than that seen in hypercholesterolaemic rabbits. Both L-carnitine and D-carnitine produced similar effects on the lipid profile, GSH and MDA which may point to the conclusion that: (1) L-carnitine prevents the progression of atherosclerotic lesions by another mechanism in addition to its antioxidant and lipid-lowering effects; (2) endogenous carnitine depletion and/or carnitine deficiency should be viewed as an additional risk factor in atherogenesis.

Propionyl-L-carnitine as protector against adriamycin-induced cardiomyopathy.

Propionyl- l -carnitine (PLC) is a naturally occurring compound that has been considered for the treatment of many forms of cardiomyopathies. In this study, the possible mechanisms whereby PLC could protect against adriamycin (ADR)-induced cardiomyopathy were carried out. Administration of ADR (3 mg kg(-1)i.p., every other day over a period of 2 weeks) resulted in a significant two-fold increase in serum levels of creatine phosphokinase, lactate dehydrogenase and glutamic oxaloacetic transaminase, whereas daily administration of PLC (250 mg kg(-1), i.p. for 2 weeks) induced non-significant change. Daily administration of PLC to ADR-treated rats resulted in complete reversal of ADR-induced increase in cardiac enzymes except lactate dehydrogenase which was only reversed by 66%. In cardiac tissue homogenate, ADR caused a significant 53% increase in malonedialdehyde (MDA) and a significant 50% decrease in reduced glutathione (GSH) levels, whereas PLC induced a significant 33% decrease in MDA and a significant 41% increase in GSH levels. Daily administration of PLC to ADR-treated rats completely reversed the increase in MDA and the decrease in GSH induced by ADR to the normal levels. In rat heart mitochondria isolated 24 h after the last dose, ADR induced a significant 48% and 42% decrease in(14)CO(2)released from the oxidation of [1-(14)C]palmitoyl-CoA and [1-(14)C]palmitoylcarnitine, respectively, whereas PLC resulted in a significant 66% and 54% increase in the oxidation of both substrates, respectively. Interestingly, administration of PLC to ADR-treated rats resulted in complete recovery of the ADR-induced decrease in the oxidation of both substrates. In addition, in rat heart mitochondria, the oxidation of [1-(14)C]pyruvate, [1-(14)C]pyruvate and [1-(14)C]octanoate were not affected by ADR and/or PLC treatment. Moreover, ADR caused severe histopathological lesions manifested as toxic myocarditis which is protected by PLC. Worth mentioning is that PLC had no effect on the antitumour activity of ADR in solid Ehrlich carcinoma. Results from this study suggest that: (1) in the heart, PLC therapy completely protects against ADR-induced inhibition of mitochondrial beta -oxidation of long-chain fatty acids; (2) PLC has and/or induces a powerful antioxidant defense mechanism against ADR-induced lipid peroxidation of cardiac membranes; and finally (3) PLC has no effect on the antitumour activity of ADR.

Modulation of radiation-induced organs toxicity by cremophor-el in experimental animals.

Pharmacological and cytogenetic evaluations of the protective effects of polyethoxylated castor oil cremophor-EL (cremophor) against hepato, renal and bone marrow toxicity induced by gamma irradiation in normal rats were carried out. A single dose of irradiation (6 Gy) caused hepatic and renal damage manifested biochemically as an elevation in levels of serum alanine and aspartate aminotransferase as well as an increase in blood urea. Cremophor administration at a dose level of 50 microl kg-1 intravenously 1 day before exposure to irradiation (6 Gy) protected the liver and kidney as indicated by the recovery of levels of hepatic aminotransferase, urea and lipid profiles to normal values. Gamma irradiation of male rats caused a decrease in reduced glutathione and an increase in the oxidized form in rat-liver homogenate. A highly significant increase in the incidence of micronucleated normochromatic erythrocytes and micronucleated polychromatic erythrocytes was observed after irradiation exposure. The induced genotoxicity in the bone marrow cells was corrected by pretreatment with cremophor. The findings of this study suggest that cremophor pretreatment can potentially be used clinically to prevent irradiation-induced hepato, renal and bone marrow toxicity without interference with its cytotoxic activity.

Propionyl-L-carnitine as potential protective agent against adriamycin-induced impairment of fatty acid beta-oxidation in isolated heart mitochondria.

Propionyl-L-carnitine (PLC), a natural short-chain derivative of L-carnitine, has been tested in this study as a potential protective agent against adriamycin (ADR)-induced cardiotoxicity in isolated rat heart myocytes and mitochondria. In cardiac myocytes, ADR (0.5 mM) caused a significant (70%) inhibition of palmitate oxidation, whereas, PLC (5 mM) induced a significant (49%) stimulation. Addition of PLC to ADR-incubated myocytes induced 79% reversal of ADR-induced inhibition of palmitate oxidation. In isolated rat heart mitochondria, ADR produced concentration-dependent inhibition of both palmitoyl-CoA and palmitoyl-carnitine oxidation, while PLC caused a more than 2.5-fold increase in both substrates. Preincubation of mitochondria with 5 mM PLC caused complete reversal of ADR-induced inhibition in the oxidation of both substrates. Also ADR induced concentration-dependent inhibition of CPT I which is parallel to the inhibition of its substrate palmitoyl-CoA. In rat heart slices, ADR induced a significant (65%) decrease in adenosine triphosphate (ATP) and this effect is reduced to 17% only by PLC. Results of this study revealed that ADR induced its cardiotoxicity by inhibition of CPT I and beta-oxidation of long-chain fatty acids with the consequent depletion of ATP in cardiac tissues, and that PLC can be used as a protective agent against ADR-induced cardiotoxicity.

Reversal of doxorubicin-induced cardiac metabolic damage by L-carnitine.

Biopharmacological evaluations of the protective effects of L-carnitine (a naturally occurring quaternary ammonium compound) against doxorubicin-induced metabolic damage were carried out in isolated cardiac myocytes and in isolated rat heart mitochondria. Perfusion of the heart with DOX (0.5 mM) caused a significant 70% inhibition of palmitate oxidation in cardiac myocytes, while L-carnitine (5 mM) perfusion caused stimulation which accounted for 37%. Perfusion of the heart with L-carnitine after 10-min perfusion with DOX (0.5 mM) caused 88% reversal of DOX-induced inhibition of palmitate oxidation in cardiac cells. In rat heart mitochondria, DOX has no effect on either palmitate oxidation or acyl-CoA synthetase activity, whereas Enoximone (c-AMP-dependent phosphodiesterase inhibitor), caused a significant inhibition of palmitate oxidation and acyl-CoA activity (40 and 27%, respectively). The oxidation of palmitoyl-CoA, an index of carnitine palmitoyltransferse reaction was significantly inhibited by DOX as a function of DOX concentration. Preincubation of mitochondria with L-carnitine caused reversal of DOX-induced inhibition of palmitoyl-CoA oxidation depending on the concentration of L-carnitine. Moreover, L-carnitine treatment did not interfere with the cytotoxic effect of doxorubicin against the growth of solid Ehrlich carcinoma. The findings of this study may suggest that inhibition of fatty acid oxidation in the heart is at least a part of doxorubicin cardiotoxicity and that L-carnitine can be used to prevent the doxorubcin-induced cardiac metabolic damage without interfering with its antitumour activities.