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E Arrigoni-Martelli

Publications and source records attributed to E Arrigoni-Martelli.

At least 19 recordsLinked to original sources
PubMed2001

Carnitine protects mitochondria and removes toxic acyls from xenobiotics.

The carnitine system is altered by several xenobiotics (drugs and chemicals). These alterations are responsible for most toxic effects, which can be reverted or minimized by L-carnitine administration. Formation of nonmetabolizable acyl coenzyme A (CoA) is a typical step in the biotransformation of pivaloyl antibiotics, valproate and ifosfamide. The elevated levels of acylcarnitine occurring in human urine due to impaired metabolism of specific acyl CoA support the role of L-carnitine as an acceptor of specific, nonmetabolizable acyl CoA. The consequence of this process is a secondary carnitine deficiency. The formation of stable complexes with an essential component of mitochondrial membrane, cardiolipin, and the inhibition of myocardial specific isoform of carnitine-palmitoyl transferase are presumably the basis of adriamycin cardiotoxicity. L-carnitine interacts with cardiolipin, modifying membrane permeability and protecting the functions of the mitochondria. This mechanism can be proposed to explain the protective effects of L-carnitine against adriamycin cardiotoxicity, ammonium acetate and zidovudine-induced mitochondrial ultrastructural and functional alterations. Cisplatin, cephalosporin and carbapenem antibiotics inhibit carnitine reabsorption in renal tubules and cause proximal tubular damage. The study of peroxisomal producing agents belonging to largely different chemical classes showed that these agents caused carnitine system perturbations which may have the potential to be highly relevant biomarkers of exposure to the nongenotoxic peroxisomal proliferating agent class of hepatic tumorigens.

Acyl Coenzyme A↗
PubMed2000

Regulation by carnitine of myocardial fatty acid and carbohydrate metabolism under normal and pathological conditions.

This review focuses on the regulation of myocardial fatty acids and glucose metabolism in physiological and pathological conditions, and the role of L-carnitine and of its derivative, propionyl-L-carnitine. Fatty acids are the major oxidation fuel for the heart, while glucose and lactate provide the remaining need. Fatty acids in cytoplasm are transformed to long-chain acyl-CoA and transferred into the mitochondrial matrix by the action of three carnitine dependent enzymes to produce acetyl-CoA through the beta-oxidation pathway. Another source of mitochondrial acetyl-CoA is from the oxidation of carbohydrates. The pyruvate dehydrogenase (PDH) complex, the key irreversible rate limiting step in carbohydrate oxidation, is modulated by the intra-mitochondrial ratio acetyl-CoA/CoA. An increased ratio results in the inhibition of PDH activity. A decreased ratio can relieve the inhibition of PDH as shown by the transfer of acetyl groups from acetyl-CoA to carnitine, forming acetylcarnitine, a reaction catalyzed by carnitine acetyl-transferase. This activity of L-carnitine in the modulation of the intramitochondrial acetyl-CoA/CoA ratio affects glucose oxidation. Myocardial substrate metabolism during ischemia is dependent upon the severity of ischemia. A very severe reduction of blood flow causes a decrease of substrate flux through PDH. When perfusion is only partially reduced there is an increase in the rate of glycolysis and a switch from lactate uptake to lactate production. Tissue levels of acyl-CoA and long-chain acylcarnitine increase with important functional consequences on cell membranes. During reperfusion fatty acid oxidation quickly recovers as the prevailing source of energy, while pyruvate oxidation is inhibited. A considerable body of experimental evidence suggests that L-carnitine exert a protective effect in in vitro and in vivo models of heart ischemia and hypertrophy. Clinical trials confirm these beneficial effects although controversial results are observed. The actions of L-carnitine and propionyl-L-carnitine cannot be explained as exclusively dependent on the stimulation of fatty acid oxidation but rather on a marked increase in glucose oxidation, via a relief of PDH inhibition caused by the elevated acetyl-CoA/CoA ratio. Enhanced pyruvate flux through PDH is beneficial for the cardiac cells since less pyruvate is converted to lactate, a metabolic step resulting in the acidification of the intracellular compartment. In addition, L-carnitine decreases tissue levels of acyl moieties, a mechanism particularly important in the ischemic phase.

Animals↗
PubMed1999

Attenuation by acetyl-L-carnitine of neurological damage and biochemical derangement following brain ischemia and reperfusion.

Alterations in brain metabolism after ischemia and reperfusion are described herein. Several roles played by carnitine and acetylcarnitine can be of particular relevance in counteracting these brain metabolism alterations. The effects of acetylcarnitine in several experimental models of brain ischemia in rats are described. The data obtained show that acetylcarnitine can have significant clinical neuroprotective effects when administered shortly after the onset of focal or global cerebral ischemia. In the canine cardiac arrest model, acetylcarnitine improved the postischemic neurological outcome and tissue levels of lactate and pyruvate were normalized. A trend toward reversal of pyruvate dehydrogenase inhibition in acetylcarnitine-treated dogs was also observed. The immediate postischemic administration of acetylcarnitine prevents free radical-mediated protein oxidation in the frontal cortex of dogs submitted to cardiac arrest and resuscitation. The transfer of the acetyl group to coenzyme A (CoA) to form acetyl-CoA as the primary source of energy is a plausible mechanism of action of acetylcarnitine.

Acetylcarnitine↗
PubMed1996

Structural, metabolic and ionic requirements for the uptake of L-carnitine by primary rat cortical cells.

L-Carnitine (L-C) is involved in the transport of acyl groups into mitochondria for beta-oxidation, although its role in the adult brain is still uncertain. We have shown before that the uptake of L-carnitine into cultured rat cortical neurones was dependent on temperature as well as the Na gradient and is inhibited by compounds resembling its structure, like gamma-aminobutyric acid (GABA), but most potently by specific GABA uptake blockers. In this study we have characterised this uptake process further. We have shown that the uptake of L-carnitine may be dependent on Cl ions, in addition to Na ions, but non on Ca ions. The L-C uptake was inhibited by substituent anions in the order gluconate (83%) > isethionate (32%), with propionate being ineffective, whereas GABA uptake was inhibited most potently by propionate substitution (79%) and equally by isethionate and gluconate (67%). This L-C uptake process was not affected by the amino acids, glutamine or lysine, up to 1 mM concentration, although beta-alanine at 500 microM caused a 38% inhibition. The uptake of L-C was also significantly inhibited by structurally-related compounds, with a carbon chain length of three to six atoms, possessing an amine group and/or a carboxyl group. At a concentration of 500 microM, 3-aminopropane sulphonic acid (53%), gamma-butyrobetaine (31%), gamma-hydroxybutyric acid (34%) and 4 methylaminobutyric acid (33%). Other compounds were effective only at the lower concentration of 10 microM, such as butyric acid (25%), nicotinic acid (26%), isonicotinic acid (26%), hexanoic acid (23%) and at 100 microM, like 6-aminocapric acid (22%). Drugs suggested to affect membrane properties, such as chlorpromazine, was without effect at 1 or 10 microM, whereas flunarizine (FLU) at 1 microM inhibited both L-C (24%) and GABA uptake (17%). Other drugs like the cholinesterase inhibitors, tacrine and eserine, also had a small inhibitory effect on L-C uptake, reducing it at 1 microM by 22 and 21% respectively, although higher concentrations were toxic (> 100 microM). Pretreatment of the cells with neuraminidase (50 U ml-1, 10 min) reduced the subsequent uptake of both L-C (18%) and GABA (42%). Hypoxia (3 h) also significantly attenuated L-C uptake (42%), however part of these effects were related to the loss of cell viability. In summary, L-C uptake occurs by a complex mechanism which at least in part may occur by a Na/Cl cotransport mechanism, which could be similar, to that of GABA or may even in part occur via the GABA transporter.

Amino Acids↗
PubMed1995

Positive action of propionyl-L-carnitine on mechanical performance of papillary muscle from Syrian hamsters with hereditary dilated cardiomyopathy.

Propionyl-L-carnitine has been shown to exert a beneficial effect on cardiac function in different experimental models of cardiomyopathy in the rat, most likely by improving cardiac metabolism and energy production. We have previously shown that, in a strain of hamsters with hereditary dilated cardiomyopathy (BIO TO.2), the mechanical activity of papillary muscle (length-tension, velocity of shortening, shortening, work and power relationship) is significantly depressed when compared to the same parameter in normal hamsters (BIO F1.B). The repeated oral treatment with propionyl-L-carnitine (60 mg/kg per os for 7 weeks) to BIO TO.2 hamsters had a significant positive inotropic effect, as indicated by an increase in developed tension up to the levels observed in papillary muscles from normal hamsters. This action is most likely associated with metabolic effects similar to those observed in rats.

Administration, Oral↗
PubMed1995

Effect of propionyl-L-carnitine treatment on membrane phospholipid fatty acid turnover in diabetic rat erythrocytes.

In this work we have examined the effect of the oral administration of propionyl-L-carnitine (PLC) on the membrane phospholipid fatty acid turnover of erythrocytes from streptozotocin-induced diabetic rats. A statistically significant reduction in radioactive palmitate, oleate, and linoleate, but not arachidonate, incorporation into membrane phosphatidylcholine (PC) of diabetic rat erythrocytes with respect to control animals was found. Changes in radioactive fatty acid incorporation were also found in diabetic red cell phosphatidylethanolamine (PE), though they were not statistically significant. Oral propionyl-L-carnitine (PLC) treatment of diabetic rats partially restored the ability of intact red cells to reacylate membrane PC with palmitate and oleate, and reacylation with linoleate was fully restored. The analysis of the membrane phospholipid fatty acid composition revealed a consistent increase of linoleate levels in diabetic rat red cells, a modest decrease of palmitate, oleate and arachidonate. The phospholipid fatty acid composition of diabetic red blood cells was not affected by the PLC treatment. Lysophosphatidylcholine acyl-CoA transferase (LAT) specific activity measured with either palmitoyl-CoA or oleyl-CoA was significantly reduced in diabetic erythrocyte membranes in comparison to controls. In addition, LAT kinetic parameters of diabetic erythrocytes were altered. The reduced LAT activity could be partially corrected by PLC treatment of diabetic rats. Our data suggest that the impaired erythrocyte membrane physiological expression induced by the diabetic disease may be attenuated by the beneficial activity of PLC on the red cell membrane phospholipid fatty acid turnover.

Administration, Oral↗
PubMed1995

Uptake and release of carnitine by vascular endothelium in culture; effects of protons and oxygen free radicals.

The present paper shows that cultured bovine endothelial cells can be labeled with 3H-carnitine by incubation. This process is slow and is uphill, requiring Na+/K+ ATPase activity. After 3 days incubation isotopic equilibrium is reached, when the cells contain about 0.5 mM (total) carnitine at a medium concentration of about 3 microM. The plasmamembrane barrier is rather resistant to acidosis and oxygen free radicals (OFR). The rate of carnitine release increases significantly only at pH below 5.8. At pH 6.0 the release of stored carnitine can be initiated by the addition of D- or L-lactate. OFR, generated by the addition of xanthine and xanthine oxidase, did not affect carnitine release. Both mild acidosis and OFR left plasmamembranes of endothelial cells intact as judged by the absence of lactate dehydrogenase loss from the cells. Therefore, the known increase of capillary permeability during ischemia and reperfusion may not be due to plasmalemmal disruption of individual endothelial cells, but to increase of inter-endothelial spaces.

Acidosis↗
PubMed1995

Protective actions of L-carnitine and acetyl-L-carnitine on the neurotoxicity evoked by mitochondrial uncoupling or inhibitors.

The mechanism for the pathological increase in cell death in various disease states e.g. HIV immunodefficiency or even ageing or Alzheimer's disease, occurs by complex and as yet undefined mechanism(s) related to immunological, virological or biochemical disturbances (i.e. energy depletion, oxidative stress, increased protein degradation). We have studied mitochondrial uncoupling or inhibitor toxicity on neurones at the cellular level and at the mitochondrial level using rhodamine (Rh123) and 10-nonylacridine orange (NAO) fluorescence with confocal microscopy. Blockade of the mitochondrial chain complexes at various points was studied. The possible protective effects of the compound L-carnitine, which plays a central role in mitochondrial function, was tested in this form of neurotoxicity. It appears that L-carnitine and its acetylated form, acetyl-L-carnitine, can attenuate the cell damage, as assessed by lactate dehydrogenase (LDH) release, evoked by the uncoupler, p-(trifluoromethoxy)phenylhdyrazone (FCCP), or by the inhibitors, 3-nitropropionic acid (3-NPA) or rotenone. Further, the FCCP-induced inhibition of Rh123 uptake was antagonized by the preincubation of cells with L-carnitine. Since such neurotoxic mechanisms may be operating in the various pathological forms of myotoxicity and neurotoxicity, these observations suggest potential for a therapeutic approach.

Acetylcarnitine↗
PubMed1994

L-carnitine uptake into primary rat cortical cultures: interaction with GABA.

The ability of the primary rat cortical cells to take up L-carnitine increased with the age of the cultures and plateaued at around day 11 up to 25 days in vitro (DIV) when a slight decline was evident and by 32 DIV there was a major decrease in L-carnitine uptake. The uptake of L-carnitine displayed complex components. Elimination of mitochondrial energy supply by NaCN (1 mM), rotenone (1.25 microM) and DNP (50 microM), caused a small but significant decrease in the uptake (21, 11 and 16%, respectively). The uptake was highly dependent on the Na gradient, since ouabain (0.5 mM) and Na free buffer (replaced by 250 mM sucrose), reduced uptake by 54 and 63%, respectively. There was competition of L-carnitine uptake by molecules resembling its structure, e.g. gamma-aminobutyric acid (GABA), acetyl-L-carnitine (ALC), D-carnitine, L-aminocarnitine and L-choline, with GABA being the most potent inhibitor (57% at 50 microM) and L-choline not being significantly active. The Na-dependent uptake of L-carnitine was saturable with a high Km (692 microM) and Vmax (839 pmol/min/mg). This Na-dependent component was not further additive with the GABA (500 microM) or the DNP (50 microM) inhibitable component, suggesting that it represented the same phenomenon, probably the Na gradient dependent transport of L-carnitine. The results indicate that the uptake of L-carnitine occurs by Na-dependent saturable process as well as non-saturable, Na-independent processes. At least the former uptake mechanism is potently inhibited by GABA.

Animals↗
PubMed1994

Evidence for the involvement of carnitine-dependent long-chain acyltransferases in neuronal triglyceride and phospholipid fatty acid turnover.

This study focuses on the potential involvement of carnitine palmitoyltransferase (CPT) on the phospholipid and triglyceride fatty acid turnover in neurons. This category of enzymes, which has been identified in several rat brain tissues, is well known for its role in modulating cellular fatty acid oxidation. Neuronal cell cultures from rat brain cortex incorporated radioactive palmitate or oleate into phospholipids and triglycerides. The largest fraction of radioactive fatty acids was recovered in phosphatidylcholine followed by triglycerides and, to a lesser extent, phosphatidylethanolamine. CPT activity measured in neuronal lysates obtained from neurons treated with 40 microM 2-tetradecylglycidic acid (TDGA) was almost completely abolished. Furthermore, between 2 and 10 microM TDGA CPT activity dropped more rapidly than between 10 and 40 microM. When the cells were pretreated with TDGA, the incorporation process of either radioactive fatty acid into triglycerides was dose-dependently suppressed. Radioactive fatty acid incorporation into phosphatidylcholine was significantly decreased in cells treated with TDGA. In contrast, phosphatidylethanolamine reacylation was essentially not affected by the CPT inhibitor. Similar results on the fatty acid incorporation into triglycerides and phospholipids were observed with neurons treated with palmitoyl-DL-aminocarnitine (PAC), a reversible CPT inhibitor, which does not consume free CoA. These effects do not seem to be the result of an inhibitory activity toward one of the steps involved in the acylation-deacylation process of triglycerides or phospholipids, as cellular lysates from TDGA-treated cells or lysates containing PAC incorporated radioactive fatty acids at rates comparable to controls. Our results suggest that CPT may be an important partner in the pathway of phospholipid and triglyceride fatty acid turnover in neurons.

Animals↗
PubMed1994

The presence of L-carnitine in ocular tissues of the rabbit.

Carnitine plays an important role in the metabolism of fatty acids. Its presence is considerable in tissues that use fatty acids as an important source of energy, such as the heart and skeletal muscle. Free carnitine and acid soluble acylcarnitines are present in various tissues of the rabbit eye. The lowest concentration of carnitine was observed in the vitreous humor and the highest in the lens. The ratio, acid soluble acylcarnitine/free carnitine, was lower in the cornea, aqueous humor, vitreous humor and lens, than in iris, ciliary body and choroid-retina. The topical administration of carnitine increased both free carnitine and acetylcarnitine in cornea, and only free carnitine in aqueous humor and choroid retina. Only after intravenous administration, did the levels of free and acyl-carnitine increase in the iris and ciliary body. Neither of the two carnitine species was changed in vitreous humor. The determination of the activity of carnitine acetyltransferase in the eye showed that in the ciliary body the values of activity were three times higher than those in the iris and choroid-retina. The elevated ratio of acid soluble acylcarnitines with respect to free carnitine in iris, ciliary body, choroid-retina as well as the higher activity of carnitine acetyltransferase in the ciliary body, suggest that carnitine plays an important role in those tissues of the eye where cells of a muscular nature are present and may represent, after esterification, an important energy reserve.

Administration, Topical↗
PubMed1994

Neural dysfunction and metabolic imbalances in diabetic rats. Prevention by acetyl-L-carnitine.

The rationale for these experiments is that administration of L-carnitine and/or short-chain acylcarnitines attenuates myocardial dysfunction 1) in hearts from diabetic animals (in which L-carnitine levels are decreased); 2) induced by ischemia-reperfusion in hearts from nondiabetic animals; and 3) in nondiabetic humans with ischemic heart disease. The objective of these studies was to investigate whether imbalances in carnitine metabolism play a role in the pathogenesis of diabetic peripheral neuropathy. The major findings in rats with streptozotocin-induced diabetes of 4-6 weeks duration were that 24-h urinary carnitine excretion was increased approximately twofold and L-carnitine levels were decreased in plasma (46%) and sciatic nerve endoneurium (31%). These changes in carnitine levels/excretion were associated with decreased caudal nerve conduction velocity (10-15%) and sciatic nerve changes in Na(+)-K(+)-ATPase activity (decreased 50%), Mg(2+)-ATPase (decreased 65%), 1,2-diacyl-sn-glycerol (DAG) (decreased 40%), vascular albumin permeation (increased 60%), and blood flow (increased 65%). Treatment with acetyl-L-carnitine normalized plasma and endoneurial L-carnitine levels and prevented all of these metabolic and functional changes except the increased blood flow, which was unaffected, and the reduction in DAG, which decreased another 40%. In conclusion, these observations 1) demonstrate a link between imbalances in carnitine metabolism and several metabolic and functional abnormalities associated with diabetic polyneuropathy and 2) indicate that decreased sciatic nerve endoneurial ATPase activity (ouabain-sensitive and insensitive) in this model of diabetes is associated with decreased DAG.

Acetylcarnitine↗
PubMed1994

Carnitine and cardiac interstitium.

An important part of (acyl)carnitine may be stored in interstitial spaces and the external surface of adjacent cells. A high concentration of carnitine in the direct vicinity of cells may enhance the synthesis and export of long-chain acylcarnitine. Long-chain acylcoenzyme A, from which long-chain acyl carnitine is formed, cannot penetrate intact cell membranes. During hypoperfusion or ischemia, when long-chain acylcoenzyme A accumulates due to hampered fatty acid oxidation, there is an increased formation of long-chain acyl carnitine which diffuses into the interstitium and adjacent vascular endothelial cells. Due to its lipophilic nature and net positive charge (limitation of carboxyl-group dissociation in ischemic acidosis), long-chain acyl carnitine may decrease the affinity of Ca2+ to the cell surface and prevent Ca2+ overload of cells. The advantage of carnitine over many other cationic amphiphiles in the protection of areas of ischemia is that long-chain acyl carnitine is formed and stored only in ischemic areas.

Animals↗
PubMed1994

Fatty acid-induced Ca(2+)-dependent uncoupling and activation of external pathway of NADH oxidation are coupled to cyclosporin A-sensitive mitochondrial permeability transition.

Permeabilization of inner mitochondrial membrane by palmitic acid in the presence of Ca2+ (cyclosporin A-sensitive stimulation of respiration, decrease of delta psi and high amplitude swelling) is accompanied by activation of the external pathway of NADH oxidation in liver mitochondria. The "pore"-sealing agents (cyclosporin A, Mg2+ with ADP, and L-carnitine with ATP) are equally effective in preventing the induction of external pathway of NADH oxidation by Ca2+ with palmitate. However, activities of these agents are different in respect to recoupling of permeabilized mitochondria. Participation of cyclosporin A-sensitive "pore" in the fatty acid- and Ca(2+)-dependent induction of external pathway of NADH oxidation and in Ca(2+)-dependent uncoupling is discussed.

Adenosine Diphosphate↗
PubMed1993

Effects of L-carnitine and its acetate and propionate esters on the molecular dynamics of human erythrocyte membrane.

EPR and fluorescence probes were used in this study to define the effects of L-carnitine and its short-chain esters, acetyl-L-carnitine and propionyl-L-carnitine, on the natural fluidity gradient and molecular packing of phospholipid headgroups of erythrocyte membrane in intact cells. Purified erythrocyte suspensions, labeled with different stearic acid derivatives containing a stable doxyl radical ring at the C-5, C-7, C-12 and C-16, were incubated with 0.5-5 mM L-carnitine and its esters for 60 min at 37 degrees C and washed twice with an isosmotic buffer. A decrease in the order parameter, calculated from the EPR spectra of the 5-doxylstearic acid derivative, was observed at all the concentrations of propionyl-L-carnitine and the extent of the decrease was dose and temperature dependent. An increase of the chain length between the doxyl ring and the carboxylic group of the spin label, resulted in a much lower efficacy of propionyl-L-carnitine in decreasing the order parameter. Acetyl-L-carnitine also showed a significant effect of decreasing the molecular order but only at the lower temperatures of red cells labeled with 5-doxyl and treated with the highest concentration of the drug. L-Carnitine did not modify the molecular dynamics at all the temperatures and concentrations used in this study. L-Carnitine and its short-chain derivatives did not alter significantly membrane fluidity of deeper regions of the erythrocyte membrane, measured by means of the excimer/monomer fluorescence intensity ratio of pyrene incorporated into the membrane of intact erythrocytes. However, these compounds were all capable of loosening the molecular packing of the polar head of erythrocyte membrane phospholipids evaluated by the membrane binding fluorescence properties of merocyanine-540. The binding of the fluorescent probe decreased in the order propionyl-L-carnitine > acetyl-L-carnitine > L-carnitine. Our findings suggest that this category of compounds affect the molecular dynamics of a membrane bilayer region close to the glycerol backbone of phospholipids, which might be relevant for the expression of membrane functions.

Acetylcarnitine↗