Double-blind, placebo-controlled study of L-acetylcarnitine for the treatment of hyperactive behavior in fragile X syndrome.
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Acetylcarnitine↗
Biomedical subjects
M Calvani
Publications and source records attributed to M Calvani.
Carnitine increases glucose disposal in humans.
OBJECTIVE: The goal of this work is to assess the effect of L-carnitine on glucose disposal, particularly on insulin sensitivity, in healthy volunteers. METHODS: Fourteen healthy human volunteers were subjected to the intravenous glucose tolerance test (analyzed by means of the minimal model technique), together with indirect calorimetry and measurement of serum free fatty acids, after a bolus of glucose plus carnitine (C) or a bolus of glucose plus saline (P). RESULTS: The minimal model demonstrated a significant increase in glucose disposal from plasma with carnitine: Glucose effectiveness passed from 2.7%/min to 3.8%/min. No significant changes were observed in the Insulin Sensitivity Index or in Insulin/C-Peptide secretion. Calorimetry showed a significant increase in respiratory quotient, resulting from a significant increase in carbohydrate oxidation rate during carnitine administration by an average of 0.0176+/-0.0118 g/min (p=0.015). Energy expenditure was not modified by treatment. A smaller decrease in plasma fatty acid concentrations was noted with carnitine plus glucose than after glucose alone. CONCLUSIONS: From these data it appears that carnitine stimulates glucose disposal and oxidation in the healthy volunteer. Therefore, carnitine might be useful as an adjunct in the therapy of diabetes mellitus.
Adult↗
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↗
L-carnitine esters as "soft", broad-spectrum antimicrobial amphiphiles.
A new class of antimicrobial, "soft", quaternary ammonium l-carnitine esters, of the type (CH3)3N+-CH2-CHOCO(R1)-CH2-COO(R2) Cl-, has been designed, with R1 and R2 being in general long-chain alkyl substituents. The series shows good activity against a wide range of bacteria, yeasts, and fungi. Lipophilicity has been measured by RP-HPLC method to give the logarithm of the experimental capacity factor (log k'), and a quantitative relationship has been determined between log k' and the theoretical partition coefficient (CLOGP); also, bond-dipole descriptors have been introduced into calculations by accounting for polar moieties present within the apolar cores of the molecules, giving a more refined calculated capacity factor (log k'calcd). Finally the latter has been related to the antimicrobial activity (MIC values). The proposed models are predictive for the best broad-spectrum antimicrobial compound within the series.
Anti-Bacterial Agents↗
Tissue transglutaminase-catalyzed formation of high-molecular-weight aggregates in vitro is favored with long polyglutamine domains: a possible mechanism contributing to CAG-triplet diseases.
To investigate possible biochemical mechanisms underlying the "toxic gain of function" associated with polyglutamine expansions, the ability of guinea pig liver tissue transglutaminase to catalyze covalent attachments of various polyamines to polyglutamine peptides was examined. Of the polyamines tested, spermine is the most active substrate, followed by spermidine and putrescine. Formation of covalent cross links between polyglutamine peptides and polyamines yields high-M(r) aggregates--a process that is favored with longer polyglutamines. In the presence of tissue transglutaminase, purified glyceraldehyde-3-phosphate dehydrogenase (a key glycolytic enzyme that binds tightly to the polyglutamine domains of both huntingtin and dentatorubral-pallidoluysian atrophy proteins) is covalently attached to polyglutamine peptides in vitro, resulting in the formation of high-M(r) aggregates. In addition, endogenous glyceraldehyde-3-phosphate dehydrogenase of a Balb-c 3T3 fibroblast cell line overexpressing human tissue transglutaminase forms cross-links with a Q60 polypeptide added to the cell homogenate. Possibly, expansion of polyglutamine domains (thus far known to occur in the gene products associated with at least seven neurodegenerative diseases) leads to increased/aberrant tissue transglutaminase-catalyzed cross-linking reactions with both polyamines and susceptible proteins, such as glyceraldehyde-3-phosphate dehydrogenase. Formation of cross-linked heteropolymers may lead to deposition of high-M(r) protein aggregates, thereby contributing to cell death.
Animals↗
Anaphylaxis to sheep's milk cheese in a child unaffected by cow's milk protein allergy.
UNLABELLED: A 5-year-old atopic boy unaffected by cow's milk protein allergy experienced several anaphylactic reactions after eating food containing "pecorino" cheese made from sheep's milk. Prick-prick tests were strongly positive to sheep's buttermilk curd and 'pecorino' sheep's cheese. Skin prick tests to fresh sheep's milk and to goat's milk were also positive, whereas they were negative to all cow's milk proteins, to whole pasteurized cow's milk and to cheese made from cow's milk. Specific IgE antibodies were negative to all cow's milk proteins. CONCLUSION: Sheep's milk and cheese derived from sheep's milk may cause severe allergic reactions in children affected and, as we report, in children not affected by cow's milk protein allergy.
Animals↗
Role of acetyl-L-carnitine in rat brain lipogenesis: implications for polyunsaturated fatty acid biosynthesis.
This study was undertaken to explore the metabolic fate of acetyl-L-carnitine in rat brain. To measure the flux of carbon atoms into anabolic processes occurring at regional levels, we have injected [1-(14)C]acetyl-L-carnitine into the lateral brain ventricle of conscious rats. After injection of [1-(14)C]acetyl-L-carnitine, the majority of radioactivity was recovered as 14CO2 expired (60% of that injected). The percentage of radioactivity recovered in brain was 1.95, 1.60, 1.30, and 0.93% at 1, 3, 6, and 22 h, respectively. Radioactivity distribution in various lipid components indicated that the fatty acid moiety of phospholipid contained the majority of radioactivity. The radioactive profile of these fatty acids showed that the acetyl moiety of acetyl-L-carnitine was incorporated into saturated (60%), monounsaturated (15%), and polyunsaturated (25%) fatty acids [mainly present in 20:4 (5.2%) and 22:6 (7.8%)]. Injection in the brain ventricle of radioactive glucose, the major source of acetyl-CoA in the CNS, revealed that glucose was a precursor of saturated (85%) and monounsaturated (15%) but not of polyunsaturated fatty acids. Thus, this study demonstrated distinct fates of glucose and acetyl-L-carnitine following intracerebroventricular injection. In summary, these data implicate acetyl-L-carnitine as an important member of a complex acetate trafficking system in brain lipid metabolism.
Acetylcarnitine↗
The entry of [1-13C]glucose into biochemical pathways reveals a complex compartmentation and metabolite trafficking between glia and neurons: a study by 13C-NMR spectroscopy.
Glial-neuronal interactions were investigated in rats injected intraperitoneally with [1-13C]glucose and killed after 15, 30, 45, or 60 min. Brain extracts were analyzed by 13C-NMR spectroscopy and the fractional 13C-enrichment at individual carbon positions was measured for amino acids, lactate, and N-acetyl-aspartate. [1-13C]Glucose was shown to be metabolized by both neurons and glia, with the anaplerotic pathway through pyruvate carboxylase (PC) accounting for 10% of total cerebral glucose metabolism. The PC-mediated pathway accounted for 39% of the glutamine synthesis, and for 8, 6, 14% of glutamate, GABA, and aspartate synthesis, respectively. These results reflect a compartmentation of the cerebral amino acids synthesis within glial and neuronal cells. The appearance of the 13C-label in C5 of glutamate and glutamine, C1 of GABA and C2 of lactate, is suggestive of pyruvate, formation from TCA cycle intermediates and provides evidence of metabolite trafficking between astrocytes and neurons.
Animals↗
Carnitine palmitoyltransferase and acyl-coA binding protein: two more players in the membrane phospholipid fatty acid turnover of human red cells?
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1-Acylglycerophosphocholine O-Acyltransferase↗
In experimental diabetes the decrease in the eye of lens carnitine levels is an early important and selective event.
Carnitine is present in the eye tissues of the rabbit and the highest concentration is found in the lens. In streptozotocin-diabetic rats, the carnitine loss of the lens is an initial and important event. At 8 days after the induction of diabetes, the carnitine content in the rat lens was reduced by 63% compared to control. The loss of lens carnitine continued at 15 and 45 days after the induction. Total carnitine level in the serum was diminished by 15 days, and the reduction in percentage term was much lower in comparison to the loss of lens carnitine. In the rabbit after alloxan-diabetes induction, there is an extensive loss of carnitine in the lens: -85% after 4 months. The carnitine levels in the other eye tissues seem substantially unaffected. The loss of lens carnitine was present even with an inconsistent hyperglycaemia. No difference was found in serum carnitine levels between controls and alloxan-treated rabbits. The role of carnitine in lens is still unclear, but its loss may be related to the appearance of cataract. A derivative of carnitine, acetylcarnitine, might prevent the processes involved in the formation of cataracts by a pharmacological action, as has been shown for aspirin.
Alloxan↗
Acetyl-L-carnitine arginine amide prevents beta 25-35-induced neurotoxicity in cerebellar granule cells.
Cerebellar granule cells (CGC) at different stages of maturation in vitro (1 or 6 DIV), were treated with beta 25-35 and acetyl-L-carnitine arginine amide (ST857) in presence of 25 mM KCl in the culture medium, and neuronal viability was assessed. Three days of treatment slightly modified the survival of 1 DIV-treated cells, which degenerate and die five days later beta-amyloid matching. Similarly, a significative neurotoxic effect was observed on 6 DIV treated-cells after 5 days of exposure to the peptide, while the death occurred within 8 days. ST857 coincubated with beta 25-35 was able to rescue neurons from beta 25-35-induced neurotoxicity. We also studied the changes in Ca2+ homeostasis following glutamate stimulation, in control and beta-amyloid treated single cells, either in presence or in absence of ST857. beta 25-35 did not affect basal [Ca2+]i, while modified glutamate-induced [Ca2+]i increase, causing a sustained plateau phase of [Ca2+]i, that persisted after the removal of the agonist. ST857 pretreatment completely reverted this effect suggesting that, in CGC chronically treated with beta 25-35, ST857 could protect the cells by neurotoxic insults of the peptide likely interfering with the cellular mechanisms involved in the control of Ca2+ homeostasis.
Acetylcarnitine↗
Addition of L-carnitine to additive solution-suspended red cells stored at 4 degrees C reduces in vitro hemolysis and improves in vivo viability.
BACKGROUND: The role of L-carnitine (LC) as the requisite carrier of long-chain fatty acids into mitochondria is well established. Human red cells (RBCs), which lack mitochondria, possess a substantial amount of LC and its esters. In addition, carnitine palmitoyl transferase, an enzyme that catalyzes the reversible transfer of the acyl moiety from acyl-coenzyme A to LC is found in RBCs. It has recently been shown that LC and carnitine palmitoyl transferase play a major role in modulating the pathway for the turnover of membrane phospholipid fatty acids in intact human RBCs, and that LC improved the membrane stability of RBCs subjected to high shear stress. RBC membrane lesions occur during storage at 4 degrees C; this study investigated whether the addition of LC (5 mM) to a standard RBC preservative solution (AS-3) affected cellular integrity with 42 days' storage. STUDY DESIGN AND METHODS: A paired (n = 10) crossover design was used for RBCs stored in AS-3 with and without LC. Both in vitro RBC properties reflective of metabolic and membrane integrity and in vivo measures of cell viability (24-hour percentage of recovery and circulating lifespan) were measured at the end of the storage. In addition, the turnover of membrane phospholipid and long-chain acylcarnitine fatty acids and the carnitine content of control and LC-stored RBCs were measured. RESULTS: It was shown that LC was irreversibly taken up by RBCs during storage, with a fourfold increase at 42 days. Furthermore, as found by the use of radiolabeled palmitate, the stored RBCs were capable of generating long-chain acylcarnitine. The uptake of LC during storage was associated with less hemolysis and higher RBC ATP levels and by a significantly greater in vivo viability for LC-stored RBCs than for control-stored RBCs: a mean 24-hour percentage of recovery of 83.9 +/- 5.0 vs. 80.1 +/- 6.0 percent and a mean lifespan of 96 +/- 11 vs. 86 +/- 14 days, respectively (p < 0.05). CONCLUSION: A beneficial effect of the addition of LC to RBCs stored at 4 degrees C was evident. This effect may be related to both biophysical and metabolic actions on the cell membrane.
Adenine↗
Correlation between Epstein Barr virus antibodies, serum IgE and atopic disease.
It is currently accepted that viral infections may influence the development of atopy. In the present study we evaluated serum IgE levels as well as the prevalence of symptoms indicative of atopic disease and EBV antibodies in 353 children aged from 1 month to 19 years. Antibodies against EBV were detected by immunofluorescence. IgE levels in serum were measured by enzyme immunoassay. Dividing the study population according to EBV seropositivity and age, we noted that the prevalence of high IgE levels (> 2 s.d.) was, in total, more frequent in the EBV negative (32.9%) than in the positive subjects (27.6%). Interestingly, this higher prevalence was found only in the groups aged under six, especially in the 7 to 29 month group, where it was statistically significant (p=0.037), whereas in the 6-19 year group the situation was reversed. Furthermore, selecting only the atopic children younger than 3 years of age with high IgE levels and clinical symptoms of atopy (wheezing and/or dermatitis) it was possible to demonstrate lower EBV seropositivity compared with the normal IgE controls for each group, even though these differences were not statistically significant. In conclusion, the results of our study suggest that, in our selected population, EBV infection in the first years of life is associated with a lower prevalence of high IgE levels.
Adolescent↗
Acetyl-L-carnitine flux to lipids in cells estimated using isotopomer spectral analysis.
Acetyl-L-carnitine is known as a reservoir of activated acetyl units and as a modulator of metabolic function. The objective of this study was to quantify the fate of the acetyl moiety of acetyl-L-carnitine in lipogenic pathways. Lipogenesis was studied in an adipocyte model, differentiated 3T3-L1 cells, and a hepatoma cell, HepG2 cells. Lipogenesis and ketogenesis were examined in rat hepatocytes. Both de novo synthesis and elongation of fatty acids were investigated using gas chromatography/mass spectrometry and [1,2-(13)C]acetyl-L-carnitine. Comparisons were performed with [13C]glucose and [13C]acetate. Isotopomer Spectral Analysis, a stable isotope method for differentiating between the enrichment of the precursor and the amount of synthesis was used to analyze the data. Acetyl-L-carnitine was generally less effective than acetate as a precursor for de novo lipogenesis. The effects of acetyl-L-carnitine were not identical to those of acetate plus carnitine as expected if acetyl-L-carnitine flux to acetyl CoA is controlled by carnitine acetyl transferase. Acetyl-L-carnitine (2 mM) contributed approximately 10% of the lipogenic acetyl-CoA used for synthesis and elongation as well as 6% of the ketogenic acetyl-CoA. No differences were found between the precursor enrichment for de novo lipogenesis and for elongation of saturated fatty acids. Flux of acetyl-L-carnitine to lipid was increased, not decreased, by the ATP citrate lyase inhibitor, -hydroxycitrate. In contrast, flux of glucose to lipid was dramatically decreased by this inhibitor. These results indicate that flux of acetyl-L-carnitine to lipid can bypass citrate and utilize cytosolic acetyl-CoA synthesis.
3T3 Cells↗
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↗
Longitudinal assessment of symptoms of depression, agitation, and psychosis in 181 patients with Alzheimer's disease.
OBJECTIVE: The goal of this study was to define the recurrence or continuation of neuropsychiatric symptoms in patients with Alzheimer's disease who were observed serially for a 1-year period. METHOD: One hundred eighty-one patients with probable Alzheimer's disease were assessed five times at 3-month intervals with a standardized neuropsychiatric rating instrument. RESULTS: Recurrence rates of neuropsychiatric symptoms during the 1-year period were 85% for depression, 93% for agitation, and 95% for psychosis. Symptom frequency at any point in time underestimated the cumulative 1-year frequency. Recurrence rates were significantly greater among patients who had multiple symptoms. Women exhibited more symptoms than men. Patients in the oldest age group (76-87 years) had more psychosis, less depression and agitation, and slower cognitive decline. Psychosis was associated with more rapid cognitive decline, and agitation was associated with more rapid functional deterioration. CONCLUSIONS: These results indicate that once psychiatric symptoms are present in patients with Alzheimer's disease, they frequently recur. These symptoms vary with age, sex, and rate of illness progression.
Age Factors↗
Abnormality of nerve conduction in diabetic neuropathy: Is there a functional relationship with the carnitine system?
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Animals↗