ArticleLiterature Review

The neurobiology of acetyl-L-carnitine

Authors:
To read the full-text of this research, you can request a copy directly from the author.

Abstract

A large body of evidence points to the positive effects of dietary supplementation of acetyl-L-carnitine (ALC). Its use has shown health benefits in neuroinflammation, which is a common denominator in a host of neurodegenerative diseases. ALC is the principal acetyl ester of L-Carnitine (LC), and it plays an essential role in intermediary metabolism, acting as a donor of acetyl groups and facilitating the transfer of fatty acids from cytosol to mitochondria during beta-oxidation. Dietary supplementation of ALC exerts neuroprotective, neurotrophic, antidepressive and analgesic effects in painful neuropathies. ALC also has antioxidant and anti-apoptotic activity. Moreover, ALC exhibits positive effects on mitochondrial metabolism, and shows promise in the treatment of aging and neurodegenerative pathologies by slowing the progression of mental deterioration. In addition, ALC plays neuromodulatory effects on both synaptic morphology and synaptic transmission. These effects are likely due to affects of ALC through modulation of gene expression on several targets in the central nervous system. Here, we review the current state of knowledge on effects of ALC in the nervous system.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the author.

... Neuronal carnitine showed several fold changes in response to SCFA treatment in both SH-SY5Y cell line and Long-Evans's rat brain (Fig. 2). Carnitine can be derived either from the diet or synthesized within the brain and consists of both free carnitine and acylated carnitine species [36][37][38] . Carnitine allows long-chain fatty acids to be transported across the inner mitochondrial membrane to be oxidized by beta-oxidation for energy or integrated into structural lipids. ...
... Carnitine has been shown to have potentially neuroprotective effects in ameliorating metabolic disturbances in the brain and nervous system during injury. However, abnormal AC concentrations have been associated with autism, specifically elevated levels of short chain AC and long chain fatty acids 36,38,39 , which were observed in both the cell line and rat brain analysis of this study (Fig. 2). Furthermore, within some molecular species of AC in rat brain, sex specific effects are observed. ...
... In our study, increased C0 was observed, along with alterations in other groups and individual AC species in both neuronal cells and rat brain samples (Fig. 2). Several studies suggest that alterations in carnitine can augment aging related mitochondria, lipid, and metabolic dysfunction by impairing energy production and metabolism [36][37][38][39] . This supports carnitine's ability to modulate brain energetics and its importance in maintaining overall brain health 37 . ...
Article
Full-text available
Communication between gut microbiota and the brain is an enigma. Alterations in the gut microbial community affects enteric metabolite levels, such as short chain fatty acids (SCFAs). SCFAs have been proposed as a possible mechanism through which the gut microbiome modulate brain health and function. This study analyzed for the first time the effects of SCFAs at levels reported in human systemic circulation on SH-SY5Y human neuronal cell energy metabolism, viability, survival, and the brain lipidome. Cell and rat brain lipidomics was done using high resolution mass spectrometry (HRMS). Neuronal cells viability, survival and energy metabolism were analyzed via flow cytometer, immunofluorescence, and SeahorseXF platform. Lipidomics analysis demonstrated that SCFAs significantly remodeled the brain lipidome in vivo and in vitro. The most notable remodulation was observed in the metabolism of phosphatidylethanolamine plasmalogens, and mitochondrial lipids carnitine and cardiolipin. Increased mitochondrial mass, fragmentation, and hyperfusion occurred concomitant with the altered mitochondrial lipid metabolism resulting in decreased neuronal cell respiration, adenosine triphosphate (ATP) production, and increased cell death. This suggests SCFAs at levels observed in human systemic circulation can adversely alter the brain lipidome and neuronal cell function potentially negatively impacting brain health outcomes.
... ALCAR improved peripheral nerve function by increasing nerve conduction velocity, reducing sensory neuronal loss, and promoting nerve regeneration (Chiechio et al., 2007;Karsidag et al., 2012). It has been also reported that ALCAR raises pain threshold, displayed an anti-hyperalgesic effect both under acute (Ghelardini et al., 2002;Galeotti et al., 2004) and chronic conditions as well as in clinical settings (diabetes, anticancer and antiretroviral treatment) (Ghirardi et al., 2005;Sima et al., 2005;Osio et al., 2006;Traina, 2016). ...
... Actually ALCAR is currently used for the treatment of neuropathic pain. Its long-term analgesic effects are dependent on epigenetic modifications, such as reversible modifications in gene activity (Traina, 2016). Thus ALCAR represents a consistent therapeutic option for peripheral neuropathies. ...
... Thus ALCAR represents a consistent therapeutic option for peripheral neuropathies. Its complex neurotrophic and analgesic effects open new strategies in the study of peripheral nerve disease management (Traina et al., 2016). ...
Article
Full-text available
Peripheral neuropathies are chronic painful syndromes characterized by allodynia, hyperalgesia and altered nerve functionality. Nerve tissue degeneration represents the microanatomical correlate of peripheral neuropathies. Aimed to improve the therapeutic possibilities, this study investigated the hypersensitivity and the neuromorphological alterations related to the loose ligation of the sciatic nerve in rats. Effects elicited by treatment with acetyl-L-carnitine (ALCAR) in comparison to gabapentin were assessed. Axonal injury, reduction of myelin deposition and accumulation of inflammatory cells were detected in damaged nerve. A decrease of phosphorylated 200-kDa neurofilament (NFP) immunoreactivity and a redistribution in small clusters of myelin basic like-protein (MBP) were observed in ipsilateral nerves. Treatment with ALCAR (100 mg/kg intraperitoneally - i.p.) and gabapentin (70 mg/kg i.p.) administered bis in die for 14 days induced a significant pain relieving effect. ALCAR, but not gabapentin, significantly countered neuromorphological changes and increased axonal NFP immunoreactivity. These findings indicate that both ALCAR and gabapentin significantly decreased the hypersensitivity related to neuropathic lesions. The observation of the positive ALCAR effect on axonal and myelin sheath alterations in damaged nerve supports its use as neurorestorative agent against neuropathies through mechanism(s) consistent to those focused in this study.
... As shown in previous studies, dietary L-carnitine supplementation has successfully been used as an essential quaternary ammonium compound nutrient that exerts favorable effects on cellular energy metabolism and the processes involved in skeletal muscle remodeling [14][15][16]. Additionally, L-carnitine supplementation results in an increase in serum L-carnitine levels [17], and a significant positive correlation between increased serum L-carnitine concentrations and an alleviation of hypoxia-induced biochemical disruption has been reported in many trials [15,18]. ...
... For example, as reported by Karlic and Lohninger [19], treatment with L-carnitine attenuates the deleterious effects of high-intensity training by reducing the extent of hypoxic damage and exerts a favorable effect by accelerating recovery from exercise stress. In addition, dietary supplementation with L-carnitine has also shown promise in enhancing neuronal functionality, since the principal acetyl ester of L-carnitine, acetyl-L-carnitine (ALC) [14,20], exerts a wide spectrum of neuroprotective and neurotrophic effects on the nervous system [14], and ALC serves as a potential ergogenic aid to optimize neurotrophin signaling by increasing the energy supply and neuronal responses [14]. In particular, ALC increases neuroprotective properties by facilitating neurotransmitter biosynthesis in the brain [21], since ALC-derived acetyl-CoA serves as a promising alternative substrate for the synthesis of cerebral acetylcholine [22]. ...
... For example, as reported by Karlic and Lohninger [19], treatment with L-carnitine attenuates the deleterious effects of high-intensity training by reducing the extent of hypoxic damage and exerts a favorable effect by accelerating recovery from exercise stress. In addition, dietary supplementation with L-carnitine has also shown promise in enhancing neuronal functionality, since the principal acetyl ester of L-carnitine, acetyl-L-carnitine (ALC) [14,20], exerts a wide spectrum of neuroprotective and neurotrophic effects on the nervous system [14], and ALC serves as a potential ergogenic aid to optimize neurotrophin signaling by increasing the energy supply and neuronal responses [14]. In particular, ALC increases neuroprotective properties by facilitating neurotransmitter biosynthesis in the brain [21], since ALC-derived acetyl-CoA serves as a promising alternative substrate for the synthesis of cerebral acetylcholine [22]. ...
Article
Full-text available
KAATSU training at greatly reduced intensities has been proven to result in substantial increases in both muscle hypertrophy and strength. Nevertheless, this revolutionary training method (combined with the restriction of venous blood flow from the working muscle) may cause underlying hypoxia and neurotransmitter dysfunction, which are linked to neuromuscular fatigue. Hence, an exploration of KAATSU training-induced hypoxic and neurodegenerative events is of utmost importance before promoting this training mode, although KAATSU has been shown to result in numerous positive training adaptations. Furthermore, based on substantial evidence, L-carnitine supplementation exerts neuroprotective effects by attenuating hypoxic stress and neurotransmitter dysfunction. However, studies directly examining the effects of KAATSU exercise on both hypoxia and neurotransmitter dysfunction, which would aggravate the detrimental effects of neuromuscular fatigue, are lacking. In addition, an expansion of the applications of L-carnitine to a smaller-molecule field for treating KAATSU training-evoked neuromuscular fatigue requires further clarification. Therefore, this review aims to present the current evidence for the effectiveness of exogenous L-carnitine at reducing the amount of hypoxic damage and its neuroprotective effects mediated by increasing cerebral acetylcholine levels. Simply, L-carnitine administration may be an important contributor to the mechanisms curtailing KAATSU training-induced neuromuscular fatigue.
... Several studies have demonstrated the antiinflammatory, anti-oxidant and free radical scavenging properties of ALCAR, as well as its stabilizing effects on mitochondrial membrane [22]. ALCAR has been shown to exert beneficial effects in disorders where the oxidative stress acts as a promoting factor [17,20,[23][24][25][26], such as diabetes, Alzheimer's [26,27]. Considering the pleiotropic beneficial actions, excellent safety and tolerability profile, ALCAR has been employed in clinical settings related to neurological disorders [26,28,29]. ...
... Several studies have demonstrated the antiinflammatory, anti-oxidant and free radical scavenging properties of ALCAR, as well as its stabilizing effects on mitochondrial membrane [22]. ALCAR has been shown to exert beneficial effects in disorders where the oxidative stress acts as a promoting factor [17,20,[23][24][25][26], such as diabetes, Alzheimer's [26,27]. Considering the pleiotropic beneficial actions, excellent safety and tolerability profile, ALCAR has been employed in clinical settings related to neurological disorders [26,28,29]. ...
... ALCAR has been shown to exert beneficial effects in disorders where the oxidative stress acts as a promoting factor [17,20,[23][24][25][26], such as diabetes, Alzheimer's [26,27]. Considering the pleiotropic beneficial actions, excellent safety and tolerability profile, ALCAR has been employed in clinical settings related to neurological disorders [26,28,29]. ...
Article
Full-text available
Background: Prostate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR. Methods: The chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts. Results: We found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo. Conclusions: Our results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible "repurposed agent' for cancer prevention and interception, similar to aspirin, metformin or beta-blockers.
... Acetyl-L-carnitine has essential roles in intermediary metabolism, where it acts as a donor of acetyl groups and is involved in the transport of fatty acids across the mitochondrial membrane during β-oxidation [88]. Dietary supplementation of acetyl-L-carnitine has been shown to have neuroprotective, neurotrophic, antidepressive, and analgesic effects in painful neuropathies [66]. ...
... The cumulative data gathered from in vitro and in vivo studies thus show that acetyl-Lcarnitine might prove to be an excellent drug for the treatment of AD and of other neurodegenerative diseases, especially as it is an endogenous substance. A comprehensive review of acetyl-L-carnitine and its induced neuroprotective and neurotrophic effects and their role in the brain has been published recently [88]. ...
Article
Full-text available
Neurodegenerative diseases, namely Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, Huntington’s disease, and multiple sclerosis are becoming one of the main health concerns due to the increasing aging of the world’s population. These diseases often share the same biological mechanisms, including neuroinflammation, oxidative stress, and/or protein fibrillation. Recently, there have been many studies published pointing out the possibilities to reduce and postpone the clinical manifestation of these deadly diseases through lifelong consumption of some crucial dietary substances, among which phytochemicals (e.g., polyphenols) and endogenous substances (e.g., acetyl-L-carnitine, coenzyme Q10, n-3 poysaturated fatty acids) showed the most promising results. Another important issue that has been pointed out recently is the availability of these substances to the central nervous system, where they have to be present in high enough concentrations in order to exhibit their neuroprotective properties. As so, such the aim of this review is to summarize the recent findings regarding neuroprotective substances, their mechanisms of action, as well as to point out therapeutic considerations, including their bioavailability and safety for humans.
... We also detected higher carnitine and 3hydroxybutyrate brain levels in SHR/NCrl rats vs controls. Carnitine plays a key role in energy metabolism by transporting long-chain fatty acids to the mitochondria for the production of acetyl-CoA via the beta-oxidation, and removes short and medium chain fatty acids formed by metabolic processes to prevent their accumulation in the mitochondria 43 . Thus, these higher brain carnitine levels could reflect modifications in the lipid metabolism in SHR/NCrl rats. ...
... Based on the lower thiamine levels we observed in SHR/NCrl rats, and on its role as cofactor of enzymes including the pyruvate dehydrogenase, we cannot exclude that the higher carnitine and 3-hydroxybutyrate levels we observed could reflect such a switch in energy substrates. Another explanation could rely in their antioxidant properties 43,[48][49][50] in response to the higher oxidative stress detected in this animal model of ADHD 34,35 . ...
Article
Full-text available
Attention-Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorder characterized by inattention, impulsivity, and hyperactivity. The neurobiological mechanisms underlying ADHD are still poorly understood, and its diagnosis remains difficult due to its heterogeneity. Metabolomics is a recent strategy for the holistic exploration of metabolism and is well suited for investigating the pathophysiology of diseases and finding molecular biomarkers. A few clinical metabolomic studies have been performed on peripheral samples from ADHD patients but are limited by their access to the brain. Here, we investigated the brain, blood, and urine metabolomes of SHR/NCrl vs WKY/NHsd rats to better understand the neurobiology and to find potential peripheral biomarkers underlying the ADHD-like phenotype of this animal model. We showed that SHR/NCrl rats can be differentiated from controls based on their brain, blood, and urine metabolomes. In the brain, SHR/NCrl rats displayed modifications in metabolic pathways related to energy metabolism and oxidative stress further supporting their importance in the pathophysiology of ADHD bringing news arguments in favor of the Neuroenergetic theory of ADHD. Besides, the peripheral metabolome of SHR/NCrl rats also shared more than half of these differences further supporting the importance of looking at multiple matrices to characterize a pathophysiological condition of an individual. This also stresses out the importance of investigating the peripheral energy and oxidative stress metabolic pathways in the search of biomarkers of ADHD.
... We hypothesized that calcium induced mitochondrial respiration would be hampered by inhibition of calcium-permeable NMDA receptors by ketamine, whereas ALCAR would increase mitochondrial respiration via activating the L-type calcium channels [33] and through fatty acid oxidation [34]. With mitochondrial respiration, ATP is generated along with ROS as a by-product [35]. ...
... Both prooxidative and antioxidative effects of L-carnitine have been reported in mammals [34,37,38]. We tested the effects of ALCAR on ROS generation in the zebrafish embryos. ...
Article
Ketamine, an anesthetic, is a non-competitive antagonist of the calcium-permeable N-methyl-d-aspartate (NMDA) receptor. High concentrations of ketamine have been implicated in cardiotoxicity and neurotoxicity. Often, these toxicities are thought to be mediated by reactive oxygen species (ROS). However, findings to the contrary showing ketamine reducing ROS in mammalian cells and neurons in vitro, are emerging. Here, we determined the effects of ketamine on ROS levels in zebrafish larvae in vivo. Based on our earlier studies demonstrating reduction in ATP levels by ketamine, we hypothesized that as a calcium antagonist, ketamine would also prevent ROS generation, which is a by-product of ATP synthesis. To confirm that the detected ROS in a whole organism, such as the zebrafish larva, is specific, we used diphenyleneiodonium (DPI) that blocks ROS production by inhibiting the NADPH Oxidases (NOX). Upon 20 h exposure, DPI (5 and 10 microM) and ketamine at 1 and 2 mM reduced ROS in the zebrafish larvae in vivo. Using acetyl l-carnitine (ALCAR), a dietary supplement, that induces mitochondrial ATP synthesis, we show elevated ROS generation with increasing ALCAR concentrations. Combined, ketamine and ALCAR counter-balanced ROS generation in the larvae suggesting that ketamine and ALCAR have opposing effects on mitochondrial metabolism, which may be key to maintaining ROS homeostasis in the larvae and affords ALCAR the ability to prevent ketamine toxicity. These results for the first time show ketamine’s antioxidative and ALCAR’s prooxidative effects in a live vertebrate.
... The results described above suggest that serum ALC and other acyl-L-carnitine levels decrease along a continuum from HS to SMC and MCI subjects, up to patients with AD [13,14,16]. It was demonstrated that ALC facilitates cholinergic neurotransmission directly or by providing an acetyl group that may be used for acetylcholine synthesis [17,18]. It was reported that ALC, by the stimulation of the synthesis of nerve growth factor receptors in the hippocampus and basal forebrain, prevents the loss of muscarinic receptors as well as nerve growth factor (NGF) and directly or indirectly modulates N-methyl-Daspartate receptor (NMDA). ...
... In animal experiments, it was found that ALC supplementation prevents the hyperphosphorylation of the protein τ induced by homocysteine (a new marker of AD) and inhibits the phosphorylation of β-amyloid [21]. It has been shown that ALC and L-carnitine reduce apoptosis through the mitochondrial pathway [18]. Suchy et al. [22] reported that carnitine supplementation reduces damage to the murine brain caused by free radicals and improves cognitive performance. ...
Article
Full-text available
The prevention or alleviation of neurodegenerative diseases, including Alzheimer’s disease (AD), is a challenge for contemporary health services. The aim of this study was to review the literature on the prevention or alleviation of AD by introducing an appropriate carnitine-rich diet, dietary carnitine supplements and the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, which contains elements of the Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet. L-carnitine (LC) plays a crucial role in the energetic metabolism of the cell. A properly balanced diet contains a substantial amount of LC as well as essential amino acids and microelements taking part in endogenous carnitine synthesis. In healthy people, carnitine biosynthesis is sufficient to prevent the symptoms of carnitine deficiency. In persons with dysfunction of mitochondria, e.g., with AD connected with extensive degeneration of the brain structures, there are often serious disturbances in the functioning of the whole organism. The Mediterranean diet is characterized by a high consumption of fruits and vegetables, cereals, nuts, olive oil, and seeds as the major source of fats, moderate consumption of fish and poultry, low to moderate consumption of dairy products and alcohol, and low intake of red and processed meat. The introduction of foodstuffs rich in carnitine and the MIND diet or carnitine supplementation of the AD patients may improve their functioning in everyday life.
... Many studies have proven that L-carnitine (LC), which should be supplied with the diet (red meat and dairy products) [16][17][18], or delivered as a dietary supplement, plays an important role in preventing AD [19,20]. L-carnitine acetylation increases its hydrophobicity that permits acetyl-L-carnitine (ALC) to cross the blood-brain barrier. ...
... L-carnitine acetylation increases its hydrophobicity that permits acetyl-L-carnitine (ALC) to cross the blood-brain barrier. The results of many studies suggest that ALC increases the level of the neurotransmitter acetylcholine (ACh) in the brain, being a donor of acetyl groups in its synthesis [19,21]. ALC treatment increases (~16%) the expression of the neurotrophin receptor p75-mRNA level. ...
Article
Full-text available
The ageing of the population is resulting in neurodegenerative diseases, including Alzheimer’s disease (AD), which are an increasing social, economic and medical problem. Diet and physical activity are now considered as important modifiable factors that help prevent or delay the development of AD and other dementia-related diseases. The pyramid of healthy nutrition and lifestyle is a way of presenting the principles, the implementation of which gives a chance for proper development and a long healthy life. The basis of the pyramid, in the first place, is physical activity. Our review of the literature in the PubMed database supports the hypothesis that complementary factors, such as proper diet, physical exercise and mental activity, have a positive impact on the prevention of neurodegenerative diseases. The nutritional recommendations for healthy adults primarily include the consumption of vegetables, fruits, cereals, legumes, vegetable oils and fishes. Therefore, the introduction of Mediterranean and Asian diets may reduce the risk of the neurodegenerative diseases associated with dementia, whereas dairy products and meat—the main sources of L-carnitine—should be consumed in moderate amounts. The aim of our work is to provide up-to-date knowledge about the appropriate dietary model and healthy lifestyle elements and their impact on good health and the long life of people.
... Recent studies reported that the microbiota-gut-brain axis plays a crucial role in several nervous conditions including stress, anxiety, addiction and depression as well as in neuroinflammation and neurodegeneration. Peripheral inflammation can lead inflammation to the CNS causing neurodegeneration and the inflammation resulting from the activation of innate immune system in periphery can influence behaviours of CNS, as cognitive performance [33,69,79,95]. ...
... Under stress, the brain can influence microbiota composition through the HPA axis, regulating cortisol secretion that, in turn, can alter the permeability and intestinal barrier function. CRH-induced activation of MCs resulted in selective release of VEGF [2,33,69,79,95]. The microbial intestinal ecosystem plays an important role, as it is the first effective barrier for the organism against pathogens. ...
Article
Mast cells (MCs) are mainly known for their involvement on allergic reactions through degranulation and release of vasoactive, inflammatory and nociceptive mediators. Upon encountering an allergen, MCs are first responders, true sensors of the environment, actually they respond to a wide range of "danger" signals both immunological and non-immunological in rapid and selective manner. They secrete both preformed and newly synthesized mediators acting as effectors in relationship between nervous, vascular and immune systems. For this peculiarity, MCs are "master regulators" and key players of the immune system as well as important source of essential and beneficial mediators with crucial roles in the regulation of various physiological processes. MCs are unique cells with multiple capabilities. It has well known that MCs are critical for the pathogenesis of inflammatory disease. MCs exert their effect through alteration of vascular permeability and recruitment of inflammatory cells. While a functional involvement of peripheral MCs in inflammatory conditions is well established, the role of Central Nervous System MCs is not well understood yet. Increasing evidence indicate that in the brain, the inflammation is strongly involved in the pathogenesis of neurodegenerative and neuropsychiatric diseases. In this review, we discuss some aspects of the current knowledge of MCs role in the brain and their potential role as therapeutic emerging target for neural diseases.
... Moreover, this molecule is widely consumed as a dietary supplement for physical exercise (Ribas, Vargas & Wajner, 2014;Nicassio et al., 2017). Recently, preclinical and clinical studies have demonstrated the effects of ALC on parameters relevant to anxiety, schizophrenia, and mood disorders; with onset of action faster than antidepressant drug and exert neuroprotective, neurotrophic, and analgesic effects (Levine et al., 2005;Wang et al., 2015;Traina, 2016;Singh et al., 2017;Nasca et al., 2017;Chiechio, Canonico & Grilli, 2017). ...
Article
Full-text available
Studies have suggested that oxidative stress may contribute to the pathogenesis of mental disorders. In this context, molecules with antioxidant activity may be promising agents in the treatment of these deleterious conditions. Acetyl-L-carnitine (ALC) is a multi-target molecule that modulates the uptake of acetyl-CoA into the mitochondria during fatty acid oxidation, acetylcholine production, protein, and membrane phospholipid synthesis, capable of promoting neurogenesis in case of neuronal death. Moreover, neurochemical effects of ALC include modulation of brain energy and synaptic transmission of multiple neurotransmitters, including expression of type 2 metabotropic glutamate (mGlu2) receptors. The aim of this study was to investigate the effects of ALC in zebrafish by examining behavioral and biochemical parameters relevant to anxiety and mood disorders in zebrafish. ALC presented anxiolytic effects in both novel tank and light/dark tests and prevented the anxiety-like behavior induced by an acute stressor (net chasing). Furthermore, ALC was able to prevent the lipid peroxidation induced by acute stress in the zebrafish brain. The data presented here warrant further investigation of ALC as a potential agent in the treatment of neuropsychiatric disorders. Its good tolerability also subsidizes the additional studies necessary to assess its therapeutic potential in clinical settings.
... Pyun et al. (2011) suggested that inhibition of ROS generation and preservation of mitochondrial integrity may be critical for the protection of auditory cells from the toxic effects of radiation. ALC, an antioxidant and antiapoptotic agent, has positive effects on mitochondrial metabolism and membrane stabilization (Traina 2016). It was mentioned that ALC had a protective effect against the cochlear damage caused by IR in the in vivo study (Altas et al. 2006). ...
Article
Full-text available
Purpose: The aim of the present study was to evaluate the effect of acetyl-L-carnitine (ALC) and N-acetyl cysteine (NAC) on ionizing radiation (IR)-induced cytotoxicity and change in DNA damage-related genes in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. Methods: HEI-OC1 cells were irradiated with 5 Gy radiation and treated by eight combinations of NAC and/or ALC: control, NAC, ALC, IR, NAC + IR, ALC + NAC, ALC + IR, and ALC + NAC + IR. Cell viability, apoptotic cell death and DNA damage were measured at the 72nd hour. Eighty-four IR-induced DNA-damage-related genes were determined by RT-PCR gene array and >10-fold changes were considered significant. Results: IR decreased cell viability by about 50% at 72 hours of incubation. In particular, the ALC and/or NAC combination before IR protected the HEI-OC1 cells (p < 0.05). Single and combination treatment prior to IR led to lower apoptotic cell death(p < 0.05). There was a significant lower DNA damage in ALC + NAC + IR group compared to IR group(p < 0.05). Expressions of Brca2, Xpc, Mlh3, Rad51, Xrcc2, Hus1, Rad9a, Cdkn1a, Gadd45a which are the DNA-repair genes were found to be significant higher in NAC + ALC + IR group than those in individual treatment of ALC or NAC. Conclusions: ALC and/or NAC treatment prior to IR led to higher cell viability and lower apoptotic cell damage compared to IR group. The results of the study show that the ALC + NAC combination treatment inhibits DNA damage and induces DNA-repair genes to repair radiation damage, and this combination treatment is more effective against radiation-induced DNA damage than NAC or ALC therapy individually.
... Acetyl-l-carnitine is a molecule derived from the acetylation of carnitine that is naturally produced by the body, but it can also be taken as a dietary supplement. This molecule has been demonstrated to possess multiple antioxidant properties in the nervous system, most of them related to its ability to act on mitochondrial metabolism [145,146]. In a double-blind study that enrolled 40 adults with DS between the ages of 18 and 30 years, acetyl-l-carnitine was administered in ascending doses: 10 mg/kg/day in the first month, 20 mg/kg/day in the second month, and 30 mg/kg/day for the rest of the study. ...
Article
Full-text available
There is currently no effective pharmacological therapy to improve the cognitive dysfunction of individuals with Down syndrome (DS). Due to the overexpression of several chromosome 21 genes, cellular and systemic oxidative stress (OS) is one of the most important neuropathological processes that contributes to the cognitive deficits and multiple neuronal alterations in DS. In this condition, OS is an early event that negatively affects brain development, which is also aggravated in later life stages, contributing to neurodegeneration, accelerated aging, and the development of Alzheimer’s disease neuropathology. Thus, therapeutic interventions that reduce OS have been proposed as a promising strategy to avoid neurodegeneration and to improve cognition in DS patients. Several antioxidant molecules have been proven to be effective in preclinical studies; however, clinical trials have failed to show evidence of the efficacy of different antioxidants to improve cognitive deficits in individuals with DS. In this review we summarize preclinical studies of cell cultures and mouse models, as well as clinical studies in which the effect of therapies which reduce oxidative stress and mitochondrial alterations on the cognitive dysfunction associated with DS have been assessed.
... The observed decrease in palmitic amide could be indicative of early-abrogated CNS signaling 2 weeks post-irradiation. Elevations in carnitine and sphinganine may reflect oxidative breakdown of lipid macromolecules from the irradiated CNS, possibly impacting neuroinflammation and mitochondrial energetics 44 . Lipids, myelin, and other fatty acids broken down intracellularly in the irradiated brain could be packaged into EVs and circulate to the periphery, contributing to the onset of radiation-induced neuroinflammation and degenerative pathways 45 . ...
Article
Full-text available
Ionizing radiation exposure to the brain is common for patients with a variety of CNS related malignancies. This exposure is known to induce structural and functional alterations to the brain, impacting dendritic complexity, spine density and inflammation. Over time, these changes are associated with cognitive decline. However, many of these impacts are only observable long after irradiation. Extracellular vesicles (EVs) are shed from cells in nearly all known tissues, with roles in many disease pathologies. EVs are becoming an important target for identifying circulating biomarkers. The aim of this study is to identify minimally invasive biomarkers of ionizing radiation damage to the CNS that are predictors of late responses that manifest as persistent cognitive impairments. Using a clinically relevant 9 Gy irradiation paradigm, we exposed mice to cranial (head only) irradiation. Using metabolomic and lipidomic profiling, we analyzed their plasma and plasma-derived EVs two days and two weeks post-exposure to detect systemic signs of damage. We identified significant changes associated with inflammation in EVs. Whole-plasma profiling provided further evidence of systemic injury. These studies are the first to demonstrate that profiling of plasma-derived EVs may be used to study clinically relevant markers of ionizing radiation toxicities to the brain.
... Two other mitochondrial antioxidants are currently under investigation: acetyl-L-carnitine (ALCAR) and R-α-lipoic acid (LA). These agents have been shown to weakly improve performance on memory tasks, attenuate oxidative stress and reduce mitochondrial abnormalities in rat hippocampus [133][134][135][136]. However, combination treatments have been found to be more effective [134]. ...
Article
Background: Neurodegeneration is a condition in which progressive loss of function and structure of neurons happen. Many lines of evidence suggest that oxidative stress have a central role in neurodegenerative diseases. Objective: To survey molecular mechanisms underlying the involvement of oxidative stress in developing different neurodegenerative diseases. Methods: Original and review articles were retrieved through a PubMed and Google scholar search (from 1989 to 2015) using the following key words: "oxidative stress", "nerve degeneration" and "neurodegenerative diseases". Results: A comprehensive analysis of the obtained articles confirmed the strong involvement of oxidative stress in pathophysiology of neurodegenerative diseases through a variety of mechanisms including oxidation of nucleic acids, proteins and lipids, formation of advanced glycation end products, mitochondrial dysfunction, glial cell activation, amyloid β deposition and plaque formation, activation of apoptosis, increased cytokine production and inflammatory responses and proteasomal dysfunction. Conclusion: Regarding the pivotal role of OS in neurodegeneration, modulation of free radical production or alleviating their harmful effects can be considered as potential therapeutic strategies for preventing and controlling NDs. Accordingly; boosting endogenous antioxidant capacity besides providing exogenous sources of antioxidants can be subjected to future research in order to discover new anti-NDs agents.
... The main role of acyl carnitines inside the cell is to facilitate transport of long-chain fatty acids across the mitochondrial membrane for subsequent beta-oxidation and energy production (Bieber and Choi 1977;Bender 2012;Longo et al. 2016;Traina 2016). In addition, acyl carnitines may also be formed in the catabolism of amino acids. ...
Article
Full-text available
Introduction Noise-induced hearing loss (NIHL) is an increasing problem in society and accounts for a third of all cases of acquired hearing loss. NIHL is caused by formation of reactive oxygen species (ROS) in the cochlea causing oxidative stress. Hydrogen gas (H2) can alleviate the damage caused by oxidative stress and can be easily administered through inhalation. Objectives To present a protocol for untargeted metabolomics of guinea pig perilymph and investigate the effect of H2 administration on the perilymph metabolome of noise exposed guinea pigs. Methods The left ear of guinea pigs were exposed to hazardous impulse noise only (Noise, n = 10), noise and H2 (Noise + H2, n = 10), only H2 (H2, n = 4), or untreated (Control, n = 2). Scala tympani perilymph was sampled from the cochlea of both ears. The polar component of the perilymph metabolome was analyzed using a HILIC-UHPLC-Q-TOF–MS-based untargeted metabolomics protocol. Multivariate data analysis (MVDA) was performed separately for the exposed- and unexposed ear. Results MVDA allowed separation of groups Noise and Noise + H2 in both the exposed and unexposed ear and yielded 15 metabolites with differentiating relative abundances. Seven were found in both exposed and unexposed ear data and included two osmoprotectants. Eight metabolites were unique to the unexposed ear and included a number of short-chain acylcarnitines. Conclusions A HILIC-UHPLC-Q-TOF–MS-based protocol for untargeted metabolomics of perilymph is presented and shown to be fit-for-purpose. We found a clear difference in the perilymph metabolome of noise exposed guinea pigs with and without H2 treatment.
... For example, anti-inflammatory treat- ment with ibuprofen has been shown previously to rescue age- related behavioral impairment ( Rogers et al., 2017). ALCAR has been shown to reduce neuroinflammation in aged animals and models of neurodegenerative disease (Afshin-Majd et al., 2017;Karalija et al., 2014;Kazak and Yarim, 2017;Traina, 2016). While it is not clear if the effect of ALCAR is due to improved glial or neuronal health, it is parsimonious to assume that increased mitochondrial function in the presynaptic terminal acts to enhance activity-dependent SV recycling. ...
... Furthermore, VD3 increases NF200 protein as a consequence of NEFH up-regulation. It is known that microtubules, microfilaments and neurofilaments play a crucial role in maintaining structure and function of neurites in mature neurons (Gentil et al., 2015;Traina, 2016). On the other hand we show that VDR is upregulated by VD3, confirming previous data (Marini et al., 2010). ...
Article
Full-text available
It has long been proven that neurogenesis continues in the adult brains of mammals in the dentatus gyrus of the hippocampus due to the presence of neural stem cells. Although a large number of studies have been carried out to highlight the localization of vitamin D receptor in hippocampus, the expression of vitamin D receptor in neurogenic dentatus gyrus of hippocampus in Parkinson’s disease (PD) and the molecular mechanisms triggered by vitamin D underlying the production of differentiated neurons from embryonic cells remain unknown. Thus, we performed a preclinical in vivo study by inducing PD in mice with MPTP and showed a reduction of glial fibrillary acidic protein (GFAP) and vitamin D receptor in the dentatus gyrus of hippocampus. Then, we performed an in vitro study by inducing embryonic hippocampal cell differentiation with vitamin D. Interestingly, vitamin D stimulates the expression of its receptor. Vitamin D receptor is a transcription factor that probably is responsible for the upregulation of microtubule associated protein 2 and neurofilament heavy polypeptide genes. The latter increases heavy neurofilament protein expression, essential for neurofilament growth. Notably N-cadherin, implicated in activity for dendritic outgrowth, is upregulated by vitamin D.
... Additionally, L-carnitine and ALC, through suppressing oxidative stress in mitochondria and then improving mitochondrial function, have shown antiapoptotic effects [43,44]. It has been reported that L-carnitine and its derivatives influence the expression of many genes that are implicated in the modulation of the production of free radicals, cellular antioxidant defenses, and restoration and stabilization of mitochondrial actions [45]. ...
Article
Full-text available
Background: This study was undertaken to evaluate the influence of oral Acetyl-L-carnitine (ALC) in patients with acute ischemic stroke. Methods: Sixty-nine cases with acute ischemic stroke with the onset of symptoms less than 24 hours not candidates for reperfusion therapy were randomly assigned to either the ALC group (1000 mg three times per day for three consecutive days) or the matching placebo group. The study outcomes based on intention-to-treat criteria included the change in the modified Rankin Scale (mRS) and National Institutes of Health Stroke Scale (NIHSS) score from baseline to day 90, as well as the change in serum levels of the inflammatory and oxidative stress biomarkers over the 3-day treatment protocol. Results: The NIHSS score and mRS score on day 90 were improved by 5.82 and 0.94 scores, respectively, in the ALC-treated group compared to 2.83 and 0.11 scores, respectively, in the placebo-treated group, which demonstrated the superiority of ALC relative to placebo. By using the multivariable analysis after adjusting for other variables in the model, compared to the group treated with placebo, patients in the ALC group had lower NIHSS score (β: -2.40, 95% CI: -0.69, -4.10 (p = 0.007)) and mRS score (β: -1.18, 95% CI: -0.52, -1.84 (p = 0.001)) 90 days after the intervention. The percentage of patients with a favourable functional outcome at day 90, defined as mRS scores of 0 or 1, was significantly higher in the ALC group in comparison to the placebo group (52.9% versus 28.6%). Further, over the 3-day treatment protocol, in the patients receiving ALC, the serum levels of proinflammatory biomarkers, including soluble intercellular adhesion molecule-1 (sICAM-1), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and neuron-specific enolase (NSE), showed a significant decrease, while the serum levels of antioxidant biomarkers, including glutathione peroxidase (GPx), superoxide dismutase (SOD), and total antioxidant capacity (TAC), as well as the total L-carnitine's level showed a significant increase compared to those in patients receiving placebo indicating significant alteration. Conclusions: Although preliminary, these results suggested that ALC administration during the acute phase of ischemic stroke might be helpful in improving functional and neurological outcomes that are probably linked to its anti-inflammatory and antioxidant properties. Trial Registration. This trial is registered with IRCT20150629022965N17 at Iranian Registry of Clinical Trials (registration date: 25/07/2018).
... This association facilitates their transport from the cytosol to the mitochondrial matrix, where fatty acids undergo β-oxidation. Both carnitine and acylcarnitines are involved in processes such as neurotransmission and apoptosis [168]. Decreased levels of carnitine and (long-chain) acylcarnitines have been detected in plasma from PD patients [149,169,170], while no changes in acylcarnitine levels have been found in either CSF or plasma from PD patients when compared to controls [171]. ...
Article
Full-text available
Parkinson’s disease (PD) is a neurodegenerative disease characterized by a progressive loss of dopaminergic neurons from the nigrostriatal pathway, formation of Lewy bodies, and microgliosis. During the past decades multiple cellular pathways have been associated with PD pathology (i.e., oxidative stress, endosomal-lysosomal dysfunction, endoplasmic reticulum stress, and immune response), yet disease-modifying treatments are not available. We have recently used genetic data from familial and sporadic cases in an unbiased approach to build a molecular landscape for PD, revealing lipids as central players in this disease. Here we extensively review the current knowledge concerning the involvement of various subclasses of fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterols, and lipoproteins in PD pathogenesis. Our review corroborates a central role for most lipid classes, but the available information is fragmented, not always reproducible, and sometimes differs by sex, age or PD etiology of the patients. This hinders drawing firm conclusions about causal or associative effects of dietary lipids or defects in specific steps of lipid metabolism in PD. Future technological advances in lipidomics and additional systematic studies on lipid species from PD patient material may improve this situation and lead to a better appreciation of the significance of lipids for this devastating disease.
... Some researchers attribute the cholinergic effects of ALC to the blocking of post-synaptic inhibition potentials, whereas others suggest a direct synaptic stimulation [22,23]. Based on the enhanced cellular energetics in the mitochondria, human studies show that ALC has the property to stabilize the cell membrane fluidity through the regulation of sphingomyelin levels, and to provide a substrate reservoir for cellular energy production, thereby preventing excessive neuronal degeneration [24]. ALC has also been shown to increase the hippocampal binding of glucocorticoids and nerve growth factor [25], to reduce the oxidative stress, and to inhibit the excitotoxicity in brain tissue and CSF, thus preventing cell death and ischemia-induced neuronal damage [26,27]. ...
Article
Full-text available
Several studies explored the effects of acetyl-L-carnitine (ALC) in dementia, suggesting a role in slowing down cognitive decline. Nevertheless, in 2003 a systematic review concluded there was insufficient evidence to recommend a clinical use, although a meta-analysis in the same year showed a significant advantage for ALC for clinical scales and psychometric tests. Since then, other studies have been published; however, a critical review is still lacking. We provide an update of the studies on ALC in primary and secondary dementia, highlighting the current limitations and translational implications. Overall, the role of ALC in dementia is still under debate. The underlying mechanisms may include restoring of cell membranes and synaptic functioning, enhancing cholinergic activity, promoting mitochondrial energy metabolism, protecting against toxins, and exerting neurotrophic effects. The effects of ALC on the gut–liver–brain axis seem to identify the category of patients in which the new insights contribute most to the mechanisms of action of ALC, likely being the liver metabolism and the improvement of hepatic detoxifying mechanisms the primary targets. In this framework, our research group has dealt with this topic, focusing on the ALC-related cross-talk mechanisms. Further studies with homogeneous sample and longitudinal assessment are needed before a systematic clinical application.
... Acetyl-L-carnitine (ALCAR) is an acetylated form of L-carnitine, a molecule naturally produced by the body. ALCAR is also administered as a dietary supplement for its ability to maintain and/or restore mitochondrial homeostasis during aging (reviewed in Rosca et al., 2009) and in conditions characterized by neurodegeneration (reviewed in Traina, 2016). Back in 1990, we reported that a single intraperitoneal injection (IJ) of ALCAR reverted the age-related decrease of mitochondrial transcription and translation in different tissues of old (Gadaleta et al., 1990a) as well as hypothyroid rats (Gadaleta et al., 1990b). ...
Article
We previously reported the ability of dietary supplementation with acetyl-l-carnitine (ALCAR) to prevent age-related decreases of mitochondrial biogenesis in skeletal muscle and liver of old rats. Here, we investigate the effects of ALCAR supplementation in cerebral hemispheres and cerebellum of old rats by analyzing several parameters linked to mitochondrial biogenesis, mitochondrial dynamics and antioxidant defenses. We measured the level of the coactivators PGC-1α and PGC-1β and of the factors regulating mitochondrial biogenesis, finding an age-related decrease of PGC-1β, whereas PGC-1α level was unvaried. Twenty eight-month old rats supplemented with ALCAR for one and two months showed increased levels of both factors. Accordingly, the expression of the two transcription factors NRF-1 and TFAM followed the same trend of PGC-1β. The level of mtDNA, ND1 and the activity of citrate synthase, were decreased with aging and increased following ALCAR treatment. Furthermore, ALCAR counteracted the age-related increase of deleted mtDNA. We also analyzed the content of proteins involved in mitochondrial dynamics (Drp1, Fis1, OPA1 and MNF2) and found an age-dependent increase of MFN2 and of the long form of OPA1. ALCAR treatment restored the content of the two proteins to the level of the young rats. No changes with aging and ALCAR were observed for Drp1 and Fis1. ALCAR reduced total cellular levels of oxidized PRXs and counteracted the age-related decrease of PRX3 and SOD2. Overall, our findings indicate a systemic positive effect of ALCAR dietary treatment and a tissue specific regulation of mitochondrial homeostasis in brain of old rats. Moreover, it appears that ALCAR acts as a nutrient since in most cases its effects were almost completely abolished one month after treatment suspension. Dietary supplementation of old rats with this compound seems a valuable approach to prevent age-related mitochondrial dysfunction and might ultimately represent a strategy to delay age-associated negative consequences in mitochondrial homeostasis.
... Although little work has been done with seizures directly [66], this molecule is thought to be neuroprotective, neurotrophic, and antioxidant. Notably, acetyl-carnitine is well-tolerated as a dietary supplement [67]. ...
Article
Full-text available
Background The low carbohydrate, high fat ketogenic diet can be an effective anticonvulsant treatment in some pediatric patients with pharmacoresistant epilepsy. Its mechanism(s) of action, however, remain uncertain. Direct sampling of cerebrospinal fluid before and during metabolic therapy may reveal key changes associated with differential clinical outcomes. We characterized the relationship between seizure responsiveness and changes in lipid and carbohydrate metabolites. Methods We performed metabolomic analysis of cerebrospinal fluid samples taken before and during ketogenic diet treatment in patients with optimal response (100% seizure remission) and patients with no response (no seizure improvement) to search for differential diet effects in hallmark metabolic compounds in these two groups. Optimal responders and non-responders were similar in age range and included males and females. Seizure types and the etiologies or syndromes of epilepsy varied but did not appear to differ systematically between responders and non-responders. Results Analysis showed a strong effect of ketogenic diet treatment on the cerebrospinal fluid metabolome. Longitudinal and between-subjects analyses revealed that many lipids and carbohydrates were changed significantly by ketogenic diet, with changes typically being of larger magnitude in responders. Notably, responders had more robust changes in glucose and the ketone bodies β-hydroxybutyrate and acetoacetate than non-responders; conversely, non-responders had significant increases in fructose and sorbose, which did not occur in responders. Conclusions The data suggest that a differential and stronger metabolic response to the ketogenic diet may predict a better anticonvulsant response, and such variability is likely due to inherent biological factors of individual patients. Strategies to boost the metabolic response may be beneficial.
... L-car has neuroprotective, neurotrophic, antidepressant, and analgesic effects in various neuropathies. It was shown that the use of L-car as a dietary supplement had health benefits in neuroinflammation (Traina 2016). Our data confirm that the use of L-car improve the long-term memory under LPS-induced inflammation (Fig. 1). ...
Article
Full-text available
Mildronate (MD) is a cardioprotective drug used for the treatment of cardiovascular diseases by switching metabolism from the fatty acids to glucose oxidation. This effect is achieved via inhibition of synthesis of L-carnitine (L-car), a common supplement, which is used for improving of fatty acid metabolism. Both MD and L-car have similar neuroprotective effect. Our goal was to investigate the effect of two drugs on the cognitive parameters of mice under different conditions (aging and lipopolysaccharide (LPS)-induced inflammation). We showed that L-car partly improved the memory and decreased the extent of mtDNA damage in the hippocampus of mice with the LPS-induced inflammation. L-car induced mitochondrial biogenesis and mitophagy in the Nrf2-dependent manner. Both MD and L-car upregulated expression of genes involved in the mitochondrial quality control. In 15-month-old mice, MD improved long-term and short-term memory, reduced the extent of mtDNA damage, and decreased the concentration of diene conjugates in the hippocampus in the Nrf2-independent manner. L-car as a Nrf2 activator had a better neuroprotective effect by normalizing mitochondrial quality control in the reversible cognitive impairment caused by the LPS-induced inflammation, while MD had a better neuroprotective effect in the irreversible cognitive impairment in aged mice, possibly due to a deeper restructuring of metabolism and reduction of oxidative stress.
... Carnitine (3-hydroxy-4-N-trimethylaminobutyrate, C 7 H 15 NO 3 ) is an essential dietary amino acid obtained from animal products such as meat, fish and milk, or is biosynthesized from l-lysine and l-methionine (Flanagan et al., 2010). It has various physiological and biochemical functions in the central nervous system, such as anti-inflammatory, antioxidant, anti-apoptosis and enhancement of autophagy (Moghaddas & Dashti-Khavidaki, 2016;Traina, 2016). Studies reported that l-carnitine supplementation can promote the early recovery of cerebral infarction through its antioxidant and anti-inflammatory functions (Wang et al., 2017). ...
Article
Full-text available
Introduction: Olanzapine (OLA) is one of the most commonly used second-generation antipsychotics for the treatment of schizophrenia. However, the heterogeneity of therapeutic response to OLA among schizophrenia patients deserves further exploration. The role of carnitine in the clinical response to OLA monotherapy remains unclear. Objectives: The current study was designed to investigate whether carnitine and its derivatives are linked to the response to OLA treatment. Drug-naïve first-episode patients with schizophrenia were recruited and treated with OLA for 4 weeks. Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) in pre and post treatment. Results: After treatment, we found a significant decrease in 2-Octenoylcarnitine levels and a significant increase in linoelaidyl carnitine, 11Z-Octadecenylcarnitine and 9-Decenoylcarnitine levels. Furthermore, baseline linoelaidyl carnitine levels were correlated with the reduction of PANSS positive symptom subscore. Linear regression and logistic regression analyses found that the baseline linoelaidyl carnitine level was a predictive marker for the therapeutic response to OLA monotherapy for 4 weeks. Conclusion: Our pilot study suggests that linoelaidyl carnitine levels at baseline may have a predictive role for the improvement of positive symptoms after OLA monotherapy in the patients with schizophrenia.
... Another important area that is emerging is the use of acylcarnitines as biomarkers for low-grade inflammation. Inflammation is increasingly considered to be an underlying cause not only of metabolic disorders, cardiovascular diseases, and many cancers but also of several CNS disorders, including depression and autism spectrum disorder (Traina, 2016;Kepka et al., 2021). The need for new biomarkers for psychiatric disorders is great, and this could be a field that will attract significant attention in the future. ...
Article
Acylcarnitines are fatty acid metabolites that play important roles in many cellular energy metabolism pathways. They have historically been used as important diagnostic markers for inborn errors of fatty acid oxidation and are being intensively studied as markers of energy metabolism, deficits in mitochondrial and peroxisomal β -oxidation activity, insulin resistance, and physical activity. Acylcarnitines are increasingly being identified as important indicators in metabolic studies of many diseases, including metabolic disorders, cardiovascular diseases, diabetes, depression, neurologic disorders, and certain cancers. The US Food and Drug Administration-approved drug L-carnitine, along with short-chain acylcarnitines (acetylcarnitine and propionylcarnitine), is now widely used as a dietary supplement. In light of their growing importance, we have undertaken an extensive review of acylcarnitines and provided a detailed description of their identity, nomenclature, classification, biochemistry, pathophysiology, supplementary use, potential drug targets, and clinical trials. We also summarize these updates in the Human Metabolome Database, which now includes information on the structures, chemical formulae, chemical/spectral properties, descriptions, and pathways for 1240 acylcarnitines. This work lays a solid foundation for identifying, characterizing, and understanding acylcarnitines in human biosamples. We also discuss the emerging opportunities for using acylcarnitines as biomarkers and as dietary interventions or supplements for many wide-ranging indications. The opportunity to identify new drug targets involved in controlling acylcarnitine levels is also discussed. SIGNIFICANCE STATEMENT: This review provides a comprehensive overview of acylcarnitines, including their nomenclature, structure and biochemistry, and use as disease biomarkers and pharmaceutical agents. We present updated information contained in the Human Metabolome Database website as well as substantial mapping of the known biochemical pathways associated with acylcarnitines, thereby providing a strong foundation for further clarification of their physiological roles.
... 2,3 One view is that ALCAR provides acetyl groups for the synthesis of acetylcholine, which exerts cholinergic effects and optimizes the balance of energy processes. 4 In addition, other neuromodulation effects of ALCAR include enhancing dopamine release and increasing gamma-aminobutyric acid, as well as correcting glutamatergic neurotransmission dysfunction. [5][6][7] ALCAR has also been shown to play a therapeutic role in peripheral neuropathy. ...
Article
Background: Neurogenic erectile dysfunction (NED) caused by cavernous nerve (CN) injury is a typical complication after pelvic surgery, which lacks efficient treatments. Acetyl-L-carnitine (ALCAR) has been proven to promote nerve repair. Objectives: To investigate the effect and potential mechanism of ALCAR in the treatment of NED. Materials and methods: Thirty-two rats were randomly divided into bilateral cavernous nerve injury (BCNI) group, BCNI + lower-dose ALCAR (50 mg/kg/day) group, BCNI + higher-dose (100 mg/kg/day) group and sham-operated group. Erectile function was assessed 14 days after daily intraperitoneal injection of ALCAR or placebo. The penile tissues were gathered for subsequent histological and molecular biological analysis. Rat Schwann cell (SC) line S16 was used to verify the mechanism of ALCAR in vitro. Results: We found that the erectile function of the rats in BCNI group was severely impaired, which was improved considerably in both BCNI+ALCAR-LD and BCNI+ALCAR-HD groups. Also, we observed decreased smooth muscle and increased collagen content in corpus cavernosum in BCNI group. The expressions of fibrosis markers TGF-β, CTGF, and Smad 2/3 were significantly up-regulated in the BCNI group. The above changes were alleviated after the administration of lower and higher-dose ALCAR. Meanwhile, the NO/cGMP pathway was promoted and the RhoA/ROCK pathway was inhibited in the corpus cavernosum of BCNI rats after ALCAR treatment, accompanied by increased nNOS and down-regulated Tyrosine Hydroxylase. In vitro, ALCAR promoted the migration and proliferation of SC, and increased the expression of Pmp22 and NGF. Further, rats treated with ALCAR had high expression of ATF3 and S100 in the distal nerve tissues of the CN extrusion site. Discussion and conclusion: ALCAR could promote nerve repair and regeneration, inhibit penile fibrosis and improve penile erection by promoting the proliferation and migration of SC and the secretion of NGF. Our study confirms that ALCAR may be a potential treatment strategy for NED. This article is protected by copyright. All rights reserved.
... ALC is naturally produced by ALC-transferase (CAT), an enzyme located in the mitochondrial matrix of a host of cellular types, and stimulates the catabolism of long fatty acids (β-oxidation) by facilitating the transport of fatty acids in mitochondria. 22,23 ALC is known to induce neuroprotective, neurotrophic, and analgesic effects in experimental animal models of neuropathic pain, including the chronic constriction injury (CCI) model in mice, and, therefore represents a valuable therapeutic option for painful peripheral neuropathies, such as diabetic neuropathy. [24][25][26][27] ALC-induced analgesia is mediated by epigenetic mechanisms based on acetylation of histones and transcription factors. ...
Article
Full-text available
Fabry disease (FD) is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3). A hallmark symptom of FD patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. Previous studies have shown that Acetyl-L-carnitine (ALC) has neuroprotective, neurotrophic, and analgesic activity in animal models of neuropathic pain. To study the action of ALC on neuropathic pain associated with FD, we treated α-GalA gene null mice (α-GalA(-/0)) with ALC for 30 days. In α-Gal KO mice ALC treatment induced acute and long-lasting analgesia, which persisted 1 month after drug withdrawal. This effect was antagonized by single administration of LY341495, an orthosteric antagonist of mGlu2/3 metabotropic glutamate receptors. We also found an up-regulation of mGlu2 receptors in cultured DRG neurons isolated from 30-day ALC treated α-GalA KO mice. However, the up-regulation of mGlu2 receptors was no longer present in DRG neurons isolated 30 days after the end of treatment. Taken together, these findings suggest that ALC induces analgesia in an animal model of FD by up-regulating mGlu2 receptors, and that analgesia is maintained by additional mechanisms after ALC withdrawal. ALC might represent a valuable pharmacological strategy to reduce pain in FD patients.
... L-carnitine (4-N-trimethylamino-3-hydroxybutyric acid, LC) is a naturally occurring compound whose primary function within the cell is to facilitate the transport of activated long-chain fatty acids into the mitochondrial matrix (the "carnitine shuttle") before they undergo β-oxidation, resulting in ATP formation [16]. In neuronal cells, the translocation of the acetyl moiety from the mitochondria into the cytosol through the carnitine shuttle promotes the synthesis of acetylcholine and acetylcarnitine (ALC) [16,17], which, in turn, may contribute to the modulation of brain energy metabolism, synaptic morphology and synaptic transmission [16,18,19]. Interestingly, disturbances in the biosynthesis and metabolism of LC have been documented in AD patients [20,21], suggesting that the perturbed transport of fatty acids into the mitochondria for β-oxidation may contribute to the impairment of energy metabolism observed in this neuropathological setting. ...
Article
Full-text available
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive regression and memory loss. Dysfunctions of both glucose metabolism and mitochondrial dynamics have been recognized as the main upstream events of the degenerative processes leading to AD. It has been recently found that correcting cell metabolism by providing alternative substrates can prevent neuronal injury by retaining mitochondrial function and reducing AD marker levels. Here, we induced an AD-like phenotype by using the glycolysis inhibitor glyceraldehyde (GA) and explored whether L-carnitine (4-N-trimethylamino-3-hydroxybutyric acid, LC) could mitigate neuronal damage, both in SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. We have already reported that GA significantly modified AD marker levels; here we demonstrated that GA dramatically compromised cellular bioenergetic status, as revealed by glycolysis and oxygen consumption rate (OCR) evaluation. We found that LC ameliorated cell survival, improved OCR and ATP synthesis, prevented the loss of the mitochondrial membrane potential (Δψm) and reduced the formation of reactive oxygen species (ROS). Of note, the beneficial effect of LC did not rely on the glycolytic pathway rescue. Finally, we noticed that LC significantly reduced the increase in pTau levels induced by GA. Overall, these findings suggest that the use of LC can promote cell survival in the setting of the metabolic impairments commonly observed in AD. Our data suggest that LC may act by maintaining mitochondrial function and by reducing the pTau level.
... Acetyl-L-carnitine is important for mitochondrial energy production (65). It also provides neuroprotection in hypoxic stress and improves cognitive impairment (66,67). ...
Article
Full-text available
Low levels of nutrient intake are common in industrialized countries. This has negative implications on health and is associated with chronic diseases. Supplementation of vitamins, minerals, and key nutrients to optimal levels may, therefore, be beneficial for individual health and for the health economy. Although the use of supplements has become very common, due to a lack of monitoring, there is very limited data on the efficacy of supplementation with different formulas. In this study, we present the results of a randomized controlled study on the efficacy of a novel formulated nutraceutical, N247, in 250 healthy volunteers aged 26–75 years and a placebo control group ( n = 35). The broad-spectrum formulation of N247 includes essential vitamins, minerals, and trace elements that are adequately balanced in regard to synergies and related metabolic functions. Moreover, tolerance, safety, and nutrient availability is an important aspect of daily, long-term use of N247. After 3 months of regular N247 use, levels of vitamins and minerals in serum were significantly increased in the N247 group compared with the control group and a placebo group, with excellent compliance rates. Coupled with additional natural ingredients that aim to increase the potency of the nutrients, N247 may represent a novel and beneficial supplement for individuals with nutritional deficiencies. Clinical Trial Registration: https://clinicaltrials.gov/ , identifier: NCT04054505.
... Although little work has been done with seizures directly [66], this molecule is thought to be neuroprotective, neurotrophic, and antioxidant. Notably, acetyl-carnitine is well-tolerated as a dietary supplement [67]. ...
Preprint
Full-text available
Background: The low carbohydrate, high fat ketogenic diet can be an effective anticonvulsant treatment in some pediatric patients with pharmacoresistant epilepsy. Its mechanism(s) of action, however, remain uncertain. Direct sampling of cerebrospinal fluid before and during metabolic therapy may reveal key changes associated with differential clinical outcomes. We characterized the relationship between seizure responsiveness and changes in lipid and carbohydrate metabolites. Methods: We performed metabolomic analysis of cerebrospinal fluid samples taken before and during ketogenic diet treatment in patients with optimal response (100% seizure remission) and patients with no response (no seizure improvement) to search for differential diet effects in hallmark metabolic compounds in these two groups. Optimal responders and non-responders were similar in age range and included males and females. Seizure types and the etiologies or syndromes of epilepsy varied but did not appear to differ systematically between responders and non-responders. Results: Analysis showed a strong effect of ketogenic diet treatment on the cerebrospinal fluid metabolome. Longitudinal and between-subjects analyses revealed that many lipids and carbohydrates were changed significantly by ketogenic diet, with changes typically being of larger magnitude in responders. Notably, responders had more robust changes in glucose and the ketone bodies b-hydroxybutyrate and acetoacetate than non-responders; conversely, non-responders had significant increases in fructose and sorbose, which did not occur in responders. Conclusions: The data suggest that a differential and stronger metabolic response to the ketogenic diet may predict a better anticonvulsant response, and such variability is likely due to inherent biological factors of individual patients. Strategies to boost the metabolic response may be beneficial.
Chapter
People with bipolar disorder (BD) all too often have suboptimal long-term outcomes with existing treatment options. They experience relapsing episodes of depression and mania and also have interepisodic mood and anxiety symptoms. We need to have a better understanding of the pathophysiology of BD if we are to make progress in improving these outcomes. This chapter will focus on the critical role of mitochondria in human functioning, oxidative stress, and the biological mechanisms of mitochondria in BD. Additionally, this chapter will present the evidence that, at least for some people, BD is a product of mitochondrial dysregulation. We review the modulators of mitochondria, the connection between current BD medication treatments and mitochondria, and additional medications that have theoretical potential to treat BD.
Article
Functional magnetic resonance imaging (fMRI) based on the blood oxygenation level‐dependent (BOLD) signal has been used to infer sites of neuronal activation in the brain. A recent study demonstrated, however, unexpected BOLD signal generation without neuronal excitation, which led us to hypothesize the presence of another cellular source for BOLD signal generation. Collective assessment of optogenetic activation of astrocytes or neurons, fMRI in awake mice, electrophysiological measurements, and histochemical detection of neuronal activation, coherently suggested astrocytes as another cellular source. Unexpectedly, astrocyte‐evoked BOLD signal accompanied oxygen consumption without modulation of neuronal activity. Imaging mass spectrometry of brain sections identified synthesis of acetyl‐carnitine via oxidative glucose metabolism at the site of astrocyte‐, but not neuron‐evoked BOLD signal. Our data provide causal evidence that astrocytic activation alone is able to evoke BOLD signal response, which may lead to reconsideration of current interpretation of BOLD signal as a marker of neuronal activation.
Article
The motor deficits which characterise the sporadic form of Parkinson's disease arise from age-related loss of a subset of dopamine neurons in the substantia nigra. Although motor symptoms respond to dopamine replacement therapies, the underlying disease process remains. This review details some features of the progressive molecular pathology and proposes deployment of a combination of nutrients: R-lipoic acid, acetyl-L-carnitine, ubiquinol, melatonin (or receptor agonists) and vitamin D3, with the collective potential to slow progression of these features. The main nutrient targets include impaired mitochondria and the associated oxidative/nitrosative stress, calcium stress and impaired gene transcription induced by pathogenic forms of alpha- synuclein. Benefits may be achieved via nutrient influence on epigenetic signaling pathways governing transcription factors for mitochondrial biogenesis, antioxidant defences and the autophagy-lysosomal pathway, via regulation of the metabolic energy sensor AMP activated protein kinase (AMPK) and the mammalian target of rapamycin mTOR. Nutrients also benefit expression of the transcription factor for neuronal survival (NR4A2), trophic factors GDNF and BDNF, and age-related calcium signals. In addition a number of non-motor related dysfunctions in circadian control, clock genes and associated metabolic, endocrine and sleep-wake activity are briefly addressed, as are late-stage complications in respect of cognitive decline and osteoporosis. Analysis of the network of nutrient effects reveals how beneficial synergies may counter the accumulation and promote clearance of pathogenic alpha-synuclein.
Conference Paper
Full-text available
Nutrition is still a health problem that needs attention in Indonesia. Based on the data of Basic Health Research (Riskesdas) (2010), the 12.2 % prevalence of toddlers’ obesity in 2007 increased to 14.0 % in 2010; whereas, in national scale, the 18.4 % prevalence of malnutrition in 2007 increased to 19.6% in 2013 (Riskesdas, 2013). Recent nutrition management programs have not shown maximum improvement. One of the programs to improve the nutritional status in the community is Posyandu, Pos Pelayanan Terpadu (United Service Post). In order to optimize the role of Posyandu, cadre leadership is needed. The purpose of this study is to analyz e how effective the transformation of Posyandu cadre leadership is in the effort to improve nutritional status. This study used a qualitative research method with snowball sampling technique. A head of Posyandu cadre became the main informant in this study; in addition, a Public Health Center (Public Health Center) nutritional officer and a mother who had a toddler during the head’s leadership period became the triangulation informants. The Data collection of this study used in-depth interviews. The result of the research indicates that the head of cadre had too much burden in her job; she assumed that her cadres cannot do the given tasks, while the cadres said that she did not give clear instruction and she always took over the tasks by herself. In conclusion, the leadership transformation did not go well because the head of cadre did not delegate tasks optimally to her cadres.
Article
PURPOSE. Abnormalities in lipid metabolism are implicated in age-related macular degeneration (AMD), but the pathways involved remain unclear. We assessed whether acylcarnitine concentrations, a marker of lipid and mitochondrial metabolism, differed between patients with AMD and controls. METHODS. In this cross-sectional case-control study, cases (n = 81) had neovascular AMD and controls (n = 79) had cataract with no other ocular pathology. Participants were recruited from eye clinics in Western Sydney, Australia, between 2016 and 2018. Plasma blood samples were collected and liquid chromatography mass spectrometry analyses performed to identify acylcarnitine concentrations. Acylcarnitine levels were adjusted for age, gender and smoking in multivariable models. Confirmation of key acylcarnitine identities was conducted using high mass accuracy liquid chromatography-tandem mass spectrometry. RESULTS. After multivariable adjustment, C2-carnitine (acetylcarnitine) levels were significantly lower in patients with neovascular AMD compared to controls (0.810 ± 0.053 (standard error) compared to 1.060 ± 0.053), p = 0.002). C18:2-DC carnitine (a dicarboxylic acylcarnitine with a 18 carbon side chain and 2 double bonds), levels were significantly higher in patients with neovascular AMD compared to controls (1.244 ± 0.046 compared to 1.013 ± 0.046), p = 0.001). Other acylcarnitines examined were not significantly different between cases and controls. CONCLUSIONS. Reduced plasma levels of C2-carnitine (acetylcarnitine) and increased plasma levels of C18:2-DC carnitine were observed in patients with neovascular AMD compared to controls. These findings suggest mitochondrial dysfunction could be involved in the pathogenesis of neovascular AMD.
Preprint
Full-text available
Background: The low carbohydrate, high fat ketogenic diet can be an effective anticonvulsant treatment in some pediatric patients with pharmacoresistant epilepsy. Its mechanism(s) of action, however, remain uncertain. Direct sampling of cerebrospinal fluid before and after metabolic therapy may reveal key changes associated with differential clinical outcomes. Methods: We performed metabolomic analysis of cerebrospinal fluid samples taken before and during ketogenic diet treatment in patients with optimal response (100% seizure remission) and patients with no response (no seizure improvement) to search for differential diet effects in hallmark metabolic compounds in these two groups. Optimal responders and non-responders were similar in age range and included males and females. Seizure types and the etiologies or syndromes of epilepsy varied but did not appear to differ systematically between responders and non-responders. Results: Principal component analysis showed a strong effect of ketogenic diet treatment on the cerebrospinal fluid metabolome. Longitudinal and between-subjects analyses revealed that many lipids and carbohydrates were changed significantly by ketogenic diet, with changes typically being of larger magnitude in responders. Notably, responders had more robust changes in glucose and the ketone bodies b-hydroxybutyrate and acetoacetate than non-responders; conversely, non-responders had significant increases in fructose and sorbose, which did not occur in responders. Conclusions: The data suggest that a differential and stronger metabolic response to the ketogenic diet may predict a better anticonvulsant response, and such variability is likely due to inherent biological factors of individual patients. Strategies to boost the metabolic response may be beneficial.
Article
Full-text available
Astrocytes play a major role in brain function and alterations in astrocyte function that contribute to the pathogenesis of many brain disorders. The astrocytes are attractive cellular targets for neuroprotection and brain tissue regeneration. Development of novel approaches to monitor and to control astroglial function is of great importance for further progress in basic neurobiology and in clinical neurology, as well as psychiatry. Recently developed advanced optogenetic and chemogenetic techniques enable precise stimulation of astrocytes in vitro and in vivo , which can be achieved by the expression of light-sensitive channels and receptors, or by expression of receptors exclusively activated by designer drugs. Optogenetic stimulation of astrocytes leads to dramatic changes in intracellular calcium concentrations and causes the release of gliotransmitters. Optogenetic and chemogenetic protocols for astrocyte activation aid in extracting novel information regarding the function of brain’s neurovascular unit. This review summarizes current data obtained by this approach and discusses a potential mechanistic connection between astrocyte stimulation and changes in brain physiology.
Article
Vascular dementia (VD) is the second largest type of dementia after Alzheimer's disease. At present, the pathogenesis is complex and there is no effective treatment. Floralozone has been shown to reduce atherosclerosis in rats caused by a high-fat diet. However, whether it plays a role in VD remains elusive. In the present study, the protective activities and relevant mechanisms of Floralozone were evaluated in rats with cognitive impairment, which were induced by bilateral occlusion of the common carotid arteries (BCCAO) in rats. Cognitive function, pathological changes and oxidative stress condition in the brains of VD rats were assessed using Neurobehavioral tests, Morris water maze tests, hematoxylin-eosin staining, Neu N staining, TUNEL staining, Golgi staining, Western blot assay and antioxidant assays (MDA, SOD, GSH), respectively. The results indicated that VD model was established successfully and BCCAO caused a decline in spatial learning and memory and hippocampal histopathological abnormalities of rats. Floralozone (50, 100, 150 mg/kg) dose-dependently alleviated the pathological changes, decreased oxidative stress injury, which eventually reduced cognitive impairment in BCCAO rats. The same results were shown in further experiments with neurobehavioral tests. At the molecular biological level, Floralozone decreased the protein level of transient receptor potential melastatin-related 2 (TRPM2) in VD and normal rats, and increased the protein level of NR2B in hippocampus of N-methyl-D-aspartate receptor (NMDAR). Notably, Floralozone could markedly improved learning and memory function of BCCAO rats in Morris water maze (MWM) and improved neuronal cell loss, synaptic structural plasticity. In conclusion, Floralozone has therapeutic potential for VD, increased synaptic structural plasticity and alleviating neuronal cell apoptosis, which may be related to the TRPM2/NMDAR pathway.
Article
Carnitine is an essential metabolite that is absorbed from the diet and synthesized in the kidney, liver, and brain. It ferries fatty acids across the mitochondrial membrane to undergo β-oxidation. Carnitine has been studied as a therapy or protective agent for many neurological diseases and neurotoxicity (e.g., prolonged anesthetic exposure-induced developmental neurotoxicity in preclinical models). Preclinical and clinical data support the notion that carnitine or acetyl carnitine may improve a patient's quality of life through increased mitochondrial respiration, release of neurotransmitters, and global gene expression changes, showing the potential of carnitine beyond its approved use to treat primary and secondary carnitine deficiency. In this review, we summarize the beneficial effects of carnitine or acetyl carnitine on the central nervous system, highlighting protective effects against neurotoxicity-induced damage caused by various chemicals and encouraging a thorough evaluation of carnitine use as a therapy for patients suffering from neurotoxicant exposure.
Article
On samples of the mitochondria and synaptic membranes isolated from rat brains using differential centrifugation, we tried to evaluate the neuroprotective efficacy of a combination of mitochondriaspecific antioxidants, acetyl-L-carnitine (ALC) and α-lipoic acid (LA), with nicotinamide (NAm), against diabetes-induced disorders in the CNS. Three groups of adult male Wistar rats were examined; these were control intact rats (group C), animals with experimental streptozotocin (STZ)-induced diabetes (group D; 6 weeks after STZ injections), and diabetic rats treated during the two final weeks of the above period by a combination of ALC, LA, and NAm (separate daily injections; doses 100, 50, and 100 mg/kg body mass, respectively; group D+T). At the day of preparation of the organelle samples, the mean blood glucose levels in groups C, D, and D+T were 4.8, 20.3, and 15.4 mM, respectively. The intensity of reactive oxygen species (ROS) production in the brain mitochondria from rats of group D measured by fluorescent analyses using 2’,7’-dichlorofluorescein diacetate was, on average, 37.2% greater than that in group C. Co-treatment provided a significant decrease in the above index in group D+T (27.8% in comparison with group D). Diabetes led to dramatic intensification of the CYP2E1 protein level in the liver of group D animals (242% vs. group C). In group D+T, this index was 33.1% lower than that in group D.
Article
Background: Post-traumatic stress disorder (PTSD) is a genuine obstructing mental disorder. As indicated by the name, it is related to the patients' stress augmented by life-threatening conditions or accidents. The PTSD has linked to oxidative stress that can result in neurodegeneration. L-carnitine (L-CAR) is known for its antioxidant properties, which can protect against neuronal damage. Objective: In the current study, we investigated the beneficial effects of L-CAR on the memory impairment induced by PTSD using a rat model. Methods: A model of single-prolonged stress (a cycle of restraining, forced swimming, rest, and finally diethyl ether exposure for 2 h, 20 min, 15 min, and 1-2 min, respectively) was used to induce PTSD-like behavior. Intraperitoneal L-CAR treatment (300 mg/kg/day) was introduced for four weeks. Both memory and special learning were evaluated utilizing the radial arm water maze (RAWM). Moreover, the levels of glutathione peroxidase (GPx), glutathione reduced (GSH), and glutathione oxidized (GSSG) were assessed as biomarkers oxidative stress in the hippocampus. Results: The results demonstrated that both the short and long-term memories were impaired by PTSD/SPS model (P < 0.05), while L-CAR treatment prevented this memory impairment in PTSD rats. Besides, L-CAR prevented the reduction in GPx activity and increase in GSSG, which were altered in the hippocampus of the PTSD/SPS rats (P < 0.05). Levels of GSH were not changed in PTSD and/or L-CAR rats. Conclusions: L-CAR administration prevented short- and long-term memories' impairments induced in the PTSD/SPS rat model. This is probably related to its antioxidant effects in the hippocampus.
Article
Aim The study was aimed at exploring the role of Acetyl L-Carnitine supplementation attenuating dementia and degradation of cognitive abilities in Hyperhomocysteinemia induced AD manifestations in the mouse model. Background Alzheimer’s disease (AD) is a neurological disorder that is marked by dementia, and degradation of cognitive abilities. There is great popularity gained by natural supplements as the treatment for AD, due to the higher toxicities of synthetic drugs. Hyperhomocysteinemia causes excitotoxicity to the cortical neurons, which brought us to the point that amino acids possibly have a role in causing cholinergic deformities, which are an important etiological parameter in AD. Acetyl L-Carnitine a methyl donor with the presence of three chemically reactive methyl groups linked to a nitrogen atom was found to possess neuroprotective activity against experimental models of AD. Objective The objective of the present investigation was to investigate and evaluate the pharmacological effect of Acetyl L-Carnitine against hyperhomocysteinemia induced Alzheimer’s disease (AD) in the mouse model. Material and Method The animals were divided into normal control (vehicle-treated), HHcy (dl-Homocysteine thiolactone treated) negative control, test group i.e., low dose (50mg/kg, p.o) of acetyl L-carnitine (L-ALC), high dose (100mg/kg,p.o) of acetyl L-carnitine (H-ALC), L-ALC+SOV (Sodium orthovanadate) and H-ALC+SOV. HHcy was induced by administration of dl-Homocysteine thiolactone (dl-HCT; 1 g/kg, p.o.) on day-1 to day-15 of experimental schedule to all animals except normal control. The changes in the behaviour pattern of the animals due to neuroinflammation, and cholinergic dysfunction were examined in rotarod, novel objective recognition, passive avoidance, elevated plus maze, and morris water maze analysis. Biochemical investigation includes the estimation of total homocysteine (tHcy), Creatinine Kinase (CK), Acetylcholinesterase (AChE), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and IL-6 and TNF-α. Result Supplementation of ALC in mouse considerably lowered the HHcy-induced AD manifestations in the experimental animals. It was found that ALC and SOV successfully diminished the behaviour abnormalities and lessened the Hcy-induced alteration in systemic Hcy levels, CK activity, and cholinergic dysfunction with improved bioenergetics in the Prefrontal cortex of the mice. Conclusion ALC was found to improve the HHcy-induced cognitive disabilities which was found to be associated with the decreased systemic levels of Hcy, CK, and cholinergic abnormalities. It also combats the oxidative stress-induced neuroinflammation with diminished pro-inflammatory markers in the pre frontal cortex. The outcomes collectively indicate ALC's potential to be used as a supplementation in the pharmacotherapy of AD.
Article
Objective: The aim of this study was to evaluate the effect of the co-administration of carnitine and chromium on mental health, hormonal, inflammatory and genetic parameters in women with PCOS. Methods: This randomized, double-blinded, placebo-controlled clinical trial was conducted on 54 subjects, aged 18–40 years old. Subjects were randomly allocated to take either 1000 mg/d carnitine plus 200 µg/d chromium as chromium picolinate (n = 26) or placebo (n = 27) for 12 weeks. Results: Carnitine and chromium co-supplementation, compared with the placebo, significantly improved beck depression inventory (β − 0.84; 95% CI, −1.51, −0.17; p = 0.01), general health questionnaire scores (β − 1.13; 95% CI, −2.13, −0.14; p = 0.02) and depression anxiety and stress scale scores (β − 0.96; 95% CI, −0.78, −0.14; p = 0.02). Participants who received carnitine plus chromium supplements had significantly lower total testosterone (β − 0.15 ng/mL; 95% CI, −0.24, −0.06; p = 0.002), hirsutism (β − 0.48; 95% CI, −0.91, −0.06; p = 0.02), high-sensitivity C-reactive protein (hs-CRP) (β − 1.02 mg/L; 95% CI, −1.79, −0.25; p = 0.01), and malondialdehyde (MDA) levels (β − 0.38 µmol/L; 95% CI, −0.56, −0.20; p < 0.001), and higher total antioxidant capacity (TAC) levels (β 107.18 mmol/L; 95% CI, 44.24, 170.12; p = 0.001) compared with the placebo. Moreover, carnitine and chromium co-supplementation upregulated gene expression of interleukin-6 (IL-6) (p = 0.02) and tumor necrosis factor alpha (TNF-α) (p = 0.02) compared with the placebo. Conclusion: Overall, the co-administration of carnitine and chromium for 12 weeks to women with PCOS had beneficial effects on mental health parameters, serum total testosterone, mF-G scores, hs-CRP, TAC and MDA levels, and gene expression of IL-6 and TNF-α.
Article
Opioid use disorder (OUD) is a mounting public health problem with substantial morbidity and mortality. Stress involvement in the course of OUD is generally accepted, but little is understood about the underlying neurobiological mechanisms in part due to a lack of laboratory-based models for chronic stress exposure. Post-traumatic stress disorder (PTSD) may be construed as a psychopathological prototype of chronic stress owing to the essential diagnostic criteria of experiencing and reliving a stressful event(s). Literature search on OUD and PTSD neurobiology was undertaken and the relevant data were integrated within four key areas: (1) OUD and PTSD comorbidity; (2) neurobiological overlap between OUD and PTSD; (3) chronic opioids- and stress-induced alterations of the reward-, stress- (i.e., "anti-reward") and related circuits and (4) mechanistically informed treatments of OUD and/or PTSD. Our findings suggest that even in the absence of prior opioid exposure PTSD patients may be susceptible for the development of OUD by the reason of similar (to those induced by opioids) reward alterations that may be targeted for therapeutic interventions.
Article
Full-text available
Diet and dietary habits of an individual are considered to be an essential factor based on biologically active compounds extracted or modified from either known or unknown natural sources, contributing to completing the dietary and nutritional needs beyond the traditional supplements. Moreover, the latest research information about their supportive and therapeutic utility suggests that they play a potential role in promoting the overall sensory and motor synergies in the brain, reducing cognitive decline and activating neuronal receptors. Many of the functional food items are reported to have many effective bioactive compounds such as-polyphenols, flavonoids, stilbenes, terpenoids, carotenoids, alkaloids, omega 3, PUFA, etc. Also, various phyto-compounds (ginseng, vitamin B12, alpha-lipoic acid, berry anthocyanins, trans-resveratrol, Ginkgo biloba, Bacopa monniera, Huperzine A, Centenella asiatica, vinpocetine, tocotrienols and palm oil, selenium) are noted globally for incrementing the cerebral health and its upkeep, listed as functional foods. This review study focuses on the direct co-relation and various effects of functional foods in reducing or preventing the neurodegeneration process. Authors have also summarized details of functional foods in supplementing the diet using the neuroprotective pathway and many newly discovered natural substances as functional foods along with their mechanism related to the expression of disease-promoting genes.
Conference Paper
Full-text available
Int roduzione L’idrosadenite suppurativa (IS) è una patologia infiammatoria cronica cutanea, multifattoriale, ricorrente e debilitante, che colpisce l’unità pilo-sebacea. Si manifesta con la comparsa di noduli, cisti, ascessi e fistole multiple, dolenti, nelle regioni corporee ricche di ghiandole apocrine quali le pieghe ascellari, inguinali, in regione ano-genitale e/o sotto o inter-mammaria 1. Tali manifestazioni, spesso maleodoranti e accompagnate dal drenaggio di materiale sieroso, sangue e pus, comportano una notevole sintomatologia dolorosa e compromettono in maniera evidente la qualità di visita del paziente. Nelle forme lievi-moderate di IS la terapia prevede l’utilizzo di farmaci topici (antibiotici) o sistemici (antibiotici e retinoidi) e la terapia laser mentre per le forme moderate-severe esiste l’indicazione per la terapia biologica con inibitori del TNF-alpha 2. Le forme avanzate richiedono l’approccio chirurgico con ampie escissioni di tessuto cutaneo lesionale. Riis et al hanno riportato 33 casi di IS in cui le lesioni nodulari e ascessuali sono state trattate con infiltrazioni intralesionali di triamcinolone con una significativa riduzione dell’eritema, edema, suppurazione e dimensione delle suddette lesioni 3. Il triamcinolone ha una potente azione antinfiammatoria poiché favorisce l’attivazione del recettore glucocorticoide che provoca il blocco della sintesi dei leucotrieni, la riduzione della produzione di citochine pro-infiammatorie e l’inibizione dell’attivazione dei linfociti T.
Conference Paper
Full-text available
Rat ionale De Quervain syndrome (dQT) is a degenerative tendinopathy of the first extensor compartment and a highly prevalent cause of reduction of quality of life (0.5-1.2% of population) 1. Inflammation is thought to be consequence of microtrauma due to synovial sheath degeneration and it may be involved in dQT pain flare- ups 2. Corticosteroid injections are effective for a conservative management with a number-needed-to-treat of 1-23–5. Considering the shallowness of the target structures, topical corticosteroids may represent a feasible and safer alternative to injections, that require expertise and may cause procedural pain, atrophic soft tissues changes, corticosteroid flares, vascular/nervous injuries 6. Methods Inclusion criteria were: clinical diagnosis of dQT, as demonstrated by spontaneous pain, swelling, erythema at the radial styloid; a positive Finkelstein test; ultrasonographic signs and an altered termographic pattern suggesting an active inflammatory tenosynovitis. The intervention was betamethasone valerate 2.250 mg (BMVP) as medicated plaster (Betesil, IBSA Farmaceutici, Italy) applied on the wrist radial aspect according to this scheme: one plaster daily for 8 days, one plaster q.a.d. for 8 days. The following outcomes were evaluated at baseline (T0) and at the one-month follow-up examination (T1): Patient-Rated Wrist/Hand Evaluation questionnaire (PRWHE, Italian version), ongoing pain intensity with 11-points Numeric Rating Scale (NRS), Patient Global Impression of Change (PGIC)7,8. Results The authors enrolled ten consecutive patients (mean age 50.7±13.45 years; male/female ratio 1:9). An improvement in PRWHE and NRS score was observed in 9/10 patients: PRWHE decreased from a median of 74 (interquartile range, IQR 3.75) to 8 (IQR 1.25, Wilcoxon-signed- rank-test p-value= 0.002); NRS decreased from a median of 8 (IQR 1.75) to 1.5 (IQR 1, Wilcoxon-signed-rank-test p-value= 0.008). Only one patient didn't show a clinically significant change in PRWHE(from 77,5 to 75,5) and NRS(from 9 to 9) scores. Overall patients’ satisfaction was high with a median PGIC score of 3 (“great improvement”). Conc lusions In our case series BMVP was safe and ameliorated clinically significant outcomes, such as quality of life and hand function. This administration route could be particularly useful in the primary care setting, where BMVP could reduce the systemic burden of medication and the risk of adverse effects. Furthermore, BMVP may be a cost-effective treatment through the reduction of secondary care referral for conservative management. The limitations of our study are related to the single center design with a short follow-up, so larger clinical studies are needed to confirm these results. References 1. Cavaleri, R. et al. J. Hand Ther. 29, 3–11 (2016) 2 . Ashe, M. C. et al. J. Hand Ther. 17, 329–334 (2004) 3. Kuo, Y.-L. et al. Ann. Plast. Surg. 74 Suppl 2, S146-151 (2015) 4. Ashraf, M. O. et al. Eur. J. Orthop. Surg. Traumatol. 24, 149–157 (2014) 5. Peters-Veluthamaningal, C. et al. Cochrane Database Syst. Rev. CD005616 (2009) 6. Brinks, A. et al. BMC Musculoskelet. Disord. 11, 206 (2010) 7. Fairplay, T. et al. J. Hand Surg. Eur. Vol. 37, 863–870 (2012) 8. Dworkin, R. H. et al. Pain 113, 9–19 (2005)
Conference Paper
Full-text available
Paziente di sesso femminile di anni 79, affetta da neoplasia polmonae, già trattata con lobectomia sinistra e già sottoposta a trattamento chemioterapico. A distanza di un anno dall’intervento comparsa di lesione secondaria in sede radiale distale al polso destro con dolore di forte intensità (VRS 8,), continuo di tipo misto e scarsamente controllato dalla terapia con oppiacei e neurolettici . La paziente esegue un ciclo di radioterapia mirata in sede della lesione, nel periodo di trattamento viene posizionato un catetere periferico a livello del nervo mediano dx con infusione continua di Naropina 0,3% alla velocità di 5ml/h. Durante questo periodo la paziente presenta una parziale remissione della sintomatologia dolorosa con VRS 2/3 . A distanza di circa un mese dall’ultima seduta di radioterapia la tumefazione risulta palpabile e aumentata di volume con interessamento anche dei tessuti molli e incremento della sintomatologia dolorosa (VRS 10) non controllata dalla terapia farmacologica assunta per via transdermica ed orale (Fentanil cerotto 75 mcg/h e Pregabalin 150 mg/die). Al controllo Tac e scintigrafia non si evidenziano al momento altre lesioni anche in altre sedi. Collegialmente insieme all’oncologo, il radioterapista ,il radiologo interventista ed il chirurgo della mano si decide di procedere a trattamento di termoablazione in radiofrequenza della lesione ossea, escludendo la escissione chirurgica altamente invasiva e invalidante. Pertanto la paziente veniva sottoposta a una seduta di Termoablazione in Radiofrequenza continua alla temperatura di 80° C per 300 secondi, con ago 14 G con punta esposta ½ cm in sede della lesione sotto guida fluoroscopica, in anestesia locale più sedazione profonda. Al risveglio la paziente riferisce dolore leggermente attenuato ma presente . Al controllo eseguito a cinque giorni dal trattamento la paziente riferisce la scomparsa della sintomatologia dolorosa, con riferita dolenzia della parte interessata con NRS 2. Si è proceduto quindi alla riduzione fino alla sospensione della terapia con oppioidi, la terapia con pregabalin 75 mg due volte al giorno è stata continuata insieme a Paracetemolo 1000 mg 3 volte/die. Conc lusioni La termoablazione con radiofrequenza si è dimostrata una tecnica di particolare utilità per il trattamento del dolore nella paziente affetta nel nostro caso da metastasi ossea. La scarsa invasività della tecnica rispetto al trattamento chirurgico ne fanno la tecnica di scelta laddove, come nel nostro caso, l’asportazione completa della patologia non era praticabile e la riduzione della sintomatologia era l’obiettivo terapeutico
Article
Based on the currently available scientific literature, indices of cellular energy status, in particular the ability of elevated levels of carnitine in muscle tissue, may be associated with a protective effect on neuromuscular fatigue. The aim of the study is to investigate the relationship between cellular energy exchange and endurance in young athletes. Materials and methods. The study included children and adolescents aged 12 to 18 years. The main research group (94 young athletes) consisted of two subgroups depending on the nature of the training load - cyclic (46) and game (48) sports. The control group - 37 children engaged in physical education only at school. Special research methods: tandem chromatography-mass spectrometry and cardiorespiratory stress testing. Results. The indices of free carnitine in young athletes, depending on the type of sports load, have significant differences. The use of the Tukey criterion revealed that the content of free carnitine in athletes with cyclic loads is significantly higher than in athletes of game types and the control group. Differences in absolute and relative maximum oxygen consumption (MIC) in the study groups were significant. Evaluation of the absolute index of the IPC showed that in boys - athletes of cyclic sports, the level of IPC is higher than that of athletes of game types and control groups. Relative indices of the IPC show similar trends. Conclusion. It was found that the indices of cellular energy and IPC in young athletes of cyclic sports are significantly higher in comparison with playing sports. With a comprehensive study of the energy status of young athletes, it is possible to predict the level of physical performance. The contribution of the level of free carnitine to the variance of the absolute MIC index is 20.9% (p < 0.01).
Article
Full-text available
Giovanna TrainaDepartment of Economics and Food Sciences, University of Perugia, Perugia, ItalyAbstract: L-carnitine (LC) is part of the carnitine shuttle system at the mitochondrial inner membrane (MIM) and transports long chain fatty acids over the MIM route. Acetyl-L -carnitine (ALC), the acetyl ester of LC, plays an essential role in intermediary metabolism. To ALC are ascribed neurotrophic actions, antioxidant and antiapoptotic activity, positive effects on mitochondrial metabolism, and stabilization of intracellular membranes. Acylcarnitine and LC supplementation have shown beneficial effects in the treatment of aging, chronic degenerative pathologies and the slowing of the progression of mental deterioration in neurodegenerative diseases, and painful neuropathies. ALC is reported to affect brain energy and phospholipid metabolism and to interact with cell membranes, proteins, and enzymes. It also shows a neuromodulatory effect on synaptic morphology and neurotransmitter synaptic transmission, including that of acetylcholine and dopamine. All these data suggest that ALC can affect several targets in the central nervous system. The roles and effects of LC and ALC have led researchers to investigate carnitine's involvement in a variety of neuropathological states and treatments, including autism, Parkinson's disease, Alzheimer's disease, Down's syndrome, Huntington's disease, cerebellar ataxia, age-associated mental decline, hepatic encephalopathy, and ammonia neurotoxicity. This review summarizes evidence that carnitine analogs play many roles in serious neurological pathologies.Keywords: L-carnitine, acetyl-L-carnitine, brain, neural disorders
Article
Full-text available
Acute kidney injury (AKI) is a public health concern with an annual mortality rate that exceeds those of breast and prostate cancer, heart failure, and diabetes combined. Oxidative stress and mitochondrial damage are drivers of AKI-associated pathology; however, the pathways that mediate these events are poorly defined. Here, using a murine cisplatin-induced AKI model, we determined that both oxidative stress and mitochondrial damage are associated with reduced levels of renal sirtuin 3 (SIRT3). Treatment with the AMPK agonist AICAR or the antioxidant agent acetyl-l-carnitine (ALCAR) restored SIRT3 expression and activity, improved renal function, and decreased tubular injury in WT animals, but had no effect in Sirt3-/- mice. Moreover, Sirt3-deficient mice given cisplatin experienced more severe AKI than WT animals and died, and neither AICAR nor ALCAR treatment prevented death in Sirt3-/- AKI mice. In cultured human tubular cells, cisplatin reduced SIRT3, resulting in mitochondrial fragmentation, while restoration of SIRT3 with AICAR and ALCAR improved cisplatin-induced mitochondrial dysfunction. Together, our results indicate that SIRT3 is protective against AKI and suggest that enhancing SIRT3 to improve mitochondrial dynamics has potential as a strategy for improving outcomes of renal injury.
Article
Full-text available
Cisplatin is an anti-neoplastic agent treatment with which causes many side effects including ototoxicity. The aim of this study was to investigate whether acetyl-l-carnitine would have protective effects on cisplatin-induced ototoxicity in vitro, and if present, to reveal roles of apoptotic gene expressions and pro-inflammatory cytokines. House Ear Institute-Organ of Corti 1 cell line was used for this study. Apoptotic genes were evaluated with an apoptosis PCR array and pro-inflammatory cytokine levels were measured using ELISA. Apoptotic cell death reduced by around 22% with acetyl-l-carnitine-cisplatin treatment compared to cisplatin alone. Genes displaying increase in expression of apoptosis, related to cisplatin treatment, were Casp8, Bcl10, Bcl2, Bcl2l1, Bcl2l2, Bid, Naip1, Bnip3l, Card6, Pak7, Cd40, Trp 53inp1, Cideb and Cd70. The acetyl-l-carnitine-cisplatin combination caused reduced expression of genes Casp8, Fas, Casp1, Tnfrsf11b, Tnfrsf10b induced by cisplatin. Acetyl-l-carnitine-cisplatin also caused reduced levels of IL-6, IL-1β and TNF-α, pro-inflammatory cytokines, induced by cisplatin. Protective mechanisms of aceytl-l-carnitine against cisplatin induced apoptosis, mainly due to activation of anti-apoptotic Bcl family members' genes, and in an Akt-related gene expression dependent manner. This is the first study to indicate that acetyl-L-carnitine can be an effective agent against cisplatin ototoxicity in auditory cells, with induction of anti-apoptotic gene expression and attenuating levels of pro-inflammatory cytokines.
Article
Full-text available
Diet in human health is no longer simple nutrition, but in light of recent research, especially nutrigenomics, it is linked via evolution and genetics to cell health status capable of modulating apoptosis, detoxification, and appropriate gene response. Nutritional deficiency and disease especially lack of vitamins and minerals is well known, but more recently, epidemiological studies suggest a role of fruits and vegetables, as well as essential fatty acids and even red wine (French paradox), in protection against disease. In the early 1990s, various research groups started considering the use of antioxidants (e.g., melatonin, resveratrol, green tea, lipoic acid) and metabolic compounds (e.g., nicotinamide, acetyl-L-carnitine, creatine, coenzyme Q10) as possible candidates in neuroprotection. They were of course considered on par with snake oil salesman (women) at the time. The positive actions of nutritional supplements, minerals, and plant extracts in disease prevention are now mainstream and commercial health claims being made are subject to regulation in most countries. Apart from efficacy and finding, the right dosages, the safety, and especially the level of purification and lack of contamination are all issues that are important as their use becomes widespread. From the mechanistic point of view, most of the time these substances replenish the body's deficiency and restore normal function. However, they also exert actions that are not sensu stricto nutritive and could be considered pharmacological especially that, at times, higher intake than recommended (RDA) is needed to see these effects. Free radicals and neuroinflammation processes underlie many neurodegenerative conditions, even Parkinson's disease and Alzheimer's disease. Curcumin, carotenoids, acetyl-L-carnitine, coenzyme Q10, vitamin D, and polyphenols and other nutraceuticals have the potential to target multiple pathways in these conditions. In summary, augmenting neuroprotective pathways using diet and finding new natural substances that can be more efficacious, i.e., induction of health-promoting genes and reduction of the expression of disease-promoting genes, could be incorporated into neuroprotective strategies of the future.
Article
Full-text available
Mitochondrial function and ambulatory activity were monitored after feeding old rats acetyl-l-carnitine (ALCAR). Young (3–5 mo) and old (22–28 mo) rats were given a 1.5% (wt/vol) solution of ALCAR in their drinking water for 1 mo, were sacrificed, and their liver parenchymal cells were isolated. ALCAR supplementation significantly reverses the age-associated decline of mitochondrial membrane potential, as assessed by rhodamine 123 staining. Cardiolipin, which declines significantly with age, is also restored. ALCAR increases cellular oxygen consumption, which declines with age, to the level of young rats. However, the oxidant production per oxygen consumed, as measured by 2′,7′-dichlorofluorescin fluorescence levels, is ≈30% higher than in untreated old rats. Cellular glutathione and ascorbate levels were nearly 30% and 50% lower, respectively, in cells from ALCAR-supplemented old rats than in untreated old rats, further indicating that ALCAR supplementation might increase oxidative stress. Ambulatory activity in young and old rats was quantified as a general measure of metabolic activity. Ambulatory activity, defined as mean total distance traveled, in old rats is almost 3-fold lower than in young animals. ALCAR supplementation increases ambulatory activity significantly in both young and old rats, with the increase being larger in old rats. Thus, ALCAR supplementation to old rats markedly reverses the age-associated decline in many indices of mitochondrial function and general metabolic activity, but may increase oxidative stress.
Article
Full-text available
Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a well-tolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-ĸB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-ĸB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.
Article
Full-text available
Acetyl-l-carnitine (ALC) is a naturally occurring substance that, when administered at supra-physiological concentration, is neuroprotective. It is involved in membrane stabilization and in enhancement of mitochondrial functions. It is a molecule of considerable interest for its clinical application in various neural disorders, including Alzheimer's disease and painful neuropathies. ALC is known to improve the cognitive capability of aged animals chronically treated with the drug and, recently, it has been reported that it impairs forms of non-associative learning in the leech. In the present study the effects of ALC on gene expression have been analyzed in the leech Hirudo medicinalis. The suppression subtractive hybridisation methodology was used for the generation of subtracted cDNA libraries and the subsequent identification of differentially expressed transcripts in the leech nervous system after ALC treatment. The method detects differentially but also little expressed transcripts of genes whose sequence or identity is still unknown. We report that a single administration of ALC is able to modulate positively the expression of genes coding for functions that reveal a lasting effect of ALC on the invertebrate, and confirm the neuroprotective and neuromodulative role of the substance. In addition an important finding is the modulation of genes of vegetal origin. This might be considered an instance of ectosymbiotic mutualism.
Article
Full-text available
The behavior of the peroxisome proliferator-activated receptor-γ coactivators PGC-1α/PGC-β-dependent mitochondrial biogenesis signaling pathway, as well as the level of some antioxidant enzymes and proteins involved in mitochondrial dynamics in the liver of old rats before and after 2 months of acetyl-L-carnitine (ALCAR) supplementation, was tested. The results reveal that ALCAR treatment is able to reverse the age-associated decline of PGC-1α, PGC-1β, nuclear respiratory factor 1 (NRF-1), mitochondrial transcription factor A (TFAM), nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 1 (ND1), and cytochrome c oxidase subunit IV (COX IV) protein levels, of mitochondrial DNA (mtDNA) content, and of citrate synthase activity. Moreover, it partially reverses the mitochondrial superoxide dismutase 2 (SOD2) decline and reduces the cellular content of oxidized peroxiredoxins. These data demonstrate that ALCAR treatment is able to promote in the old rat liver a new mitochondrial population that can contribute to the cellular oxidative stress reduction. Furthermore, a remarkable decline of Drp1 and of Mfn2 proteins is reported here for the first time, suggesting a reduced mitochondrial dynamics in aging liver with no effect of ALCAR treatment.
Article
Full-text available
The predominant molecular symptom of aging is the accumulation of altered gene products. Moreover, several conditions including protein, lipid or glucose oxidation disrupt redox homeostasis and lead to accumulation of unfolded or misfolded proteins in the aging brain. Alzheimer's and Parkinson's diseases or Friedreich ataxia are neurological diseases sharing, as a common denominator, production of abnormal proteins, mitochondrial dysfunction and oxidative stress, which contribute to the pathogenesis of these so called "protein conformational diseases". The central nervous system has evolved the conserved mechanism of unfolded protein response to cope with the accumulation of misfolded proteins. As one of the main intracellular redox systems involved in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins. Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Thus, the impact of dietary factors on health and longevity is an increasingly appreciated area of research. Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against disease. Genetics has revealed that ageing may be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin, a group of proteins linked to aging, metabolism and stress tolerance in several organisms. Recent findings suggest that several phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of vitagenes encoding survival proteins, as in the case of the Keap1/Nrf2/ARE pathway activated by curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Consistently, the neuroprotective roles of dietary antioxidants including curcumin, acetyl-L-carnitine and carnosine have been demonstrated through the activation of these redox-sensitive intracellular pathways. Although the notion that stress proteins are neuroprotective is broadly accepted, still much work needs to be done in order to associate neuroprotection with specific pattern of stress responses. In this review the importance of vitagenes in the cellular stress response and the potential use of dietary antioxidants in the prevention and treatment of neurodegenerative disorders is discussed.
Article
Full-text available
The most widely used platinum-derived drug is cisplatin in neuroblastoma (NB) chemotherapy, which is severely neurotoxic. Acetyl-L-Carnitine (ALC) is a natural occurring compound with a neuroprotective activity in several experimental paradigms. The aim of this study was to determine the effects of ALC on cisplatin induced cytotoxicity and oxidative stress in NB cells. SH-SY5Y (N-Myc negative) and KELLY (N-Myc positive) human NB cell lines were used. Cisplatin induced apoptosis was assessed by using a Cell Death Detection ELISA(PLUS) kit. Lipid peroxidation levels were determined by HPLC analysis. Glutathione levels were determined spectrophotometrically. ALC was used prophylactic or after cisplatin application. The level of cisplatin doses were determined in both type of NB cells at which 50% cell death occurred along with synchronized apoptosis induced. Prophylactic 10 and 50 micromol of ALC concentrations were decreased cisplatin induced lipid peroxidation compared to controls that normally exhibited apoptosis especially in SH-SY5Y cells. Cisplatin caused oxidative stress through decreasing glutathione levels in both cell types. ALC were effectively inhibited the increase in cisplatin induced oxidized glutathione and lipid peroxidation formation in NB cells. We suggested that prophylactic ALC would be a useful agent for cisplatin induced toxicity in NB cells.
Article
Full-text available
To investigate the mitochondrial decay and oxidative damage resulting from aging, the activities/kinetics of the mitochondrial complexes were examined in the brains of young and old rats as well as in old rats fed R-alpha-lipoic acid plus acetyl-L-carnitine (LA/ALC). The brain mitochondria of old rats, compared with young rats, had significantly decreased endogenous antioxidants and superoxide dismutase activity; more oxidative damage to lipids and proteins; and decreased activities of complex I, IV and V. Complex I showed a decrease in binding affinity (increase in K(m)) for substrates. Feeding LA/ALC to old rats partially restored age-associated mitochondrial dysfunction to the levels of the young rats. These results indicate that oxidative mitochondrial decay plays an important role in brain aging and that a combination of nutrients targeting mitochondria, such as LA/ALC, could ameliorate mitochondrial decay through preventing mitochondrial oxidative damage.
Article
Background: Centenarians are characterized by weakness, decreasing mental health, impaired mobility, and poor endurance. l-Carnitine is an important contributor to cellular energy metabolism. Objective: This study evaluated the efficacy of l-carnitine on physical and mental fatigue and on cognitive functions of centenarians. Design: This was a placebo-controlled, randomized, double-blind, 2-phase study. Sixty-six centenarians with onset of fatigue after even slight physical activity were recruited to the study. The 2 groups received either 2 g levocarnitine once daily (n = 32) or placebo (n = 34). Efficacy measures included changes in total fat mass, total muscle mass, serum triacylglycerol, total cholesterol, HDL cholesterol, LDL cholesterol, Mini-Mental State Examination (MMSE), Activities of Daily Living, and a 6-min walking corridor test. Results: At the end of the study period, the levocarnitine-treated centenarians, compared with the placebo group, showed significant improvements in the following markers: total fat mass (−1.80 compared with 0.6 kg; P < 0.01), total muscle mass (3.80 compared with 0.8 kg; P < 0.01), plasma concentrations of total carnitine (12.60 compared with −1.70 μmol; P < 0.05), plasma long-chain acylcarnitine (1.50 compared with −0.1 μmol; P < 0.001), and plasma short-chain acylcarnitine (6.0 compared with −1.50 μmol; P < 0.001). Significant differences were also found in physical fatigue (−4.10 compared with −1.10; P < 0.01), mental fatigue (−2.70 compared with 0.30; P < 0.001), fatigue severity (−23.60 compared with 1.90; P < 0.001), and MMSE (4.1 compared with 0.6; P < 0.001). Conclusions: Our study indicates that oral administration of levocarnitine produces a reduction of total fat mass, increases total muscular mass, and facilitates an increased capacity for physical and cognitive activity by reducing fatigue and improving cognitive functions.
Article
Recent research has clarified many of the clinical applications of L-Carnitine and its related compounds, leading into new areas of potential use. Promising therapeutic applications of an ester form of carnitine, acetyl-L-Carnitine (ALC) are derived from observations that this compound readily crosses the blood- brain barrier and improves neuronal energetics and repair mechanisms while modifying acetylcholine production in the CMS. Studies show that HIV infection and CFIDS, Alzheimer's dementia and depression of the elderly, and diabetic neuropathies may respond positively to ALC administration. Effects of ALC on ethyl alcohol (ETOH) metabolism have been observed and hold significant potential in preventing sequelae of habitual ETOH abuse.
Article
Acetylcarnitine is an endogenous substance, active in the CNS, but its exact role in neurotransmission is still unknown. The present study was made to analyze by means of iontophoretic administration on single neurones of the medullary-pontine reticular formation in the rat the effects of the d- and l-acetylcarnitine on spontaneous and glutamate-evoked firing and on responses to applications of some other putative transmitters, such as acetylcholine, 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA) and noradrenaline. l-Acetylcarnitine increased both spontaneous and evoked discharges, and potentiated cholinergic and serotonergic responses. The d-isomer was found to be almost ineffective. Neuronal responses to l-acetylcarnitine were reduced by dihydro-β-erythroidine and enhanced by eserine, while atropine was ineffective. l-Acetylcarnitine increased both excitatory and inhibitory responses to 5-HT and its effect on the increase in firing rate induced by serotonergic drugs was reduced by dihydro-β-erythroidine, but not by atropine. l- and d-Acetylcarnitine did not affect GABAergic or noradrenergic transmission. These results suggest a stereospecific facilitatory action of acetylcarnitine on neuronal responses to acetylcholine and 5-HT. It is hypothesized that this action could be exerted at a presynaptic level, at least with regard to serotonergic-induced responses, and that nicotinic receptors may be involved in the synaptic mechanism of release or reuptake of both acetylcholine and 5-HT.
Article
Acetyl-l-carnitine (ALC) is the principal acetyl ester of L-carnitine and it plays an essential role in intermediary metabolism. ALC affects several targets in the nervous system. Along this line of investigation, we analyzed the long-term effects of ALC on elementary nonassociative learning in the swimming induction model of the leech Hirudo medicinalis, in which nociceptive stimulation of the dorsal skin produces a more rapid swim response to a test stimulus (sensitization). In this simplified model a single ALC administration blocked the sensitizing effects of nociceptive stimulation in swim induction showing increasingly long lasting effects. Herein, we have analyzed the long-term effects of ALC on sensitization and dishabituation. Leeches were treated with inhibitors of either transcription or protein synthesis 30 min after the administration of ALC and, subsequently, subjected to noxious stimuli: the animals exhibited a sensitized swimming response 6 days after ALC treatment but not after 2 hours indicating that the long-term suppressive effects of ALC on sensitization/dishabituation needed mRNA and protein synthesis.
Article
Several studies suggest that acetyl-l-carnitine (ALC) might influence learning processes. Along this line of investigation, we have previously shown that ALC impaired sensitization and dishabituation induced by nociceptive stimulation of the dorsal skin of the leech Hirudo medicinalis, in the behavioral paradigm of the swim induction (SI). In previous works we showed that 5HT was involved in both sensitization and dishabituation of SI acting through the second messenger cAMP. In this work, we have reported that for given doses and temporal ranges ALC was able to block sensitization and to impair dishabituation mimicked by the injection of 5-HT or 8Br-cAMP, a membrane permeable analogue of cAMP. Our results show that a single treatment with 2mM ALC was the most effective concentration to block the onset of sensitization induced by 5-HT injection and its major effects occurred 11 days after ALC treatment. 2mM ALC also blocked sensitization induced by 8Br-cAMP injection, whereas, ALC did not completely abolish dishabituation induced by 5-HT or 8Br-cAMP injection at the tested concentrations and at every time point.
Article
Objective and Study Participants: We evaluated serum carnitine concentrations in a group of 17 centenarians (six males, 11 females: mean age 102.35 ±2.21 years), and compared them with a control group that comprised 20 elderly volunteers (age range: 66 to 75 years). Results: The mean serum carnitine level in the centenarian group was 8.99 ±5.1 mg/L compared with 7.71 ±0.92 mg/L in the control group (p = NS). Serum carnitine levels were not significantly correlated with lipid pattern, kidney function, daily activity, body mass index and daily diet in the centenarians. Analysis of the lipid pattern revealed that the mean serum total cholesterol, low density lipoprotein (LDL) cholesterol, apoprotein B100 and triglyceride concentrations were higher in the controls than in the centenarians (p = 0.01 for total cholesterol, LDL cholesterol, and apoprotein B100; p = 0.05 for triglycerides). High density lipoprotein (HDL) cholesterol and apoprotein A levels were significantly lower in the controls than in the centenarians (p = 0.01). We postulated that an endogenous synthesis is responsible for the increased serum carnitine levels observed in the centenarians. Conclusion: In our study series, the association between a good lipid profile and elevated serum carnitine levels, although nonsignificant, might be considered an important factor in achieving longevity.
Chapter
Reduction of cellular expression and activity of antioxidant proteins and the consequent increase of oxidative stress are fundamental causes for both the aging processes and neurodegenerative diseases. Oxidative stress has been implicated in mechanisms leading to neuronal cell injury in various pathological states of the brain. Alzheimer’s disease (AD) is a progressive disorder with cognitive and memory decline, speech loss, personality changes and synapse loss. Many approaches have been undertaken to understand AD, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. There is now evidence to suggest that networks of responses exist in the brain to detect and control diverse forms of stress. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes. Among these, heat shock proteins form a highly conserved system responsible for the preservation and repair of the correct protein conformation. Recent studies have shown that the heat shock response contributes to establish a cytoprotective state in a wide variety of human diseases, including inflammation, cancer, aging and neurodegenerative disorders. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. Acetylcarnitine (LAC) is proposed as a therapeutic agent for several neurodegenerative disorders, and there is evidence that LAC may play a critical role as a modulator of cellular stress response in health and disease states. In the present review we discuss the role of the heme oxygenase pathway in cellular stress response. We then review the evidence for the role of acetylcarnitine in modulating redox-dependent mechanisms leading to up-regulation of vitagenes in brain, and hence potentiate brain stress tolerance.
Article
Palmitoyl-CoA (Pal-CoA) lowered the respiratory control ratio (RCR), and induced mitochondrial membrane permeability transition (MPT) and cytochrome c (Cyt. c) release from isolated rat liver mitochondria. l-Carnitine suppressed the Pal-CoA-induced dysfunction, MPT, and Cyt. c release of isolated mitochondria. This suppression was inhibited by cephaloridine, an inhibitor of carnitine uptake into mitochondria. Cyclosporin A (CsA), an inhibitor of MPT, and BSA also suppressed the Pal-CoA-induced MPT. In the presence of inorganic phosphate (Pi), Ca2+-induced MPT was suppressed by BSA, l-carnitine, and chlorpromazine, an inhibitor of phospholipase A2. In the presence of a low concentration of Ca2+, 3,3′,5-triiodothyronine, long chain fatty acids, salicylic acid, and diclofenac induced MPT by a mechanism that was suppressed by BSA, l-carnitine, or chlorpromazine. During the incubation of mitochondria on ice, their respiratory competence decreased; l-carnitine and BSA also prevented this decrease. Mitochondrial depolarization in pheochromocytoma PC12 cells was induced by either serum deprivation or arachidonic acid by a mechanism that was suppressed by acetyl-l-carnitine. These results indicate that some MPTs may be regulated by fatty acid metabolism and that the Pal-CoA-induced MPT plays an important role in the induction of apoptosis.
Article
In a double-blind, placebo study, acetyl-L-carnitine was administered to 7 probable Alzheimer's disease patients who were then compared by clinical and 31P magnetic resonance spectroscopic measures to 5 placebo-treated probable AD patients and 21 age-matched healthy controls over the course of 1 year. Compared to AD patients on placebo, acetyl-L-carnitine-treated patients showed significantly less deterioration in their Mini-Mental Status and Alzheimer's Disease Assessment Scale test scores. Furthermore, the decrease in phosphomonoester levels observed in both the acetyl-L-carnitine and placebo AD groups at entry was normalized in the acetyl-L-carnitine-treated but not in the placebo-treated patients. Similar normalization of high-energy phosphate levels was observed in the acetyl-L-carnitine-treated but not in the placebo-treated patients. This is the first direct in vivo demonstration of a beneficial effect of a drug on both clinical and CNS neurochemical parameters in AD.
Article
Endogenous acetylcarnitine is an indicator of acetyl-CoA synthesized by multiple metabolic pathways involving carbohydrates, amino acids, fatty acids, sterols, and ketone bodies, and utilized mainly by the tricarboxylic acid cycle. Acetylcarnitine supplementation has beneficial effects in elderly animals and humans, including restoration of mitochondrial content and function. These effects appear to be dose-dependent and occur even after short-term therapy. In order to set the stage for understanding the mechanism of action of acetylcarnitine, we review the metabolism and role of this compound. We suggest that acetylation of mitochondrial proteins leads to a specific increase in mitochondrial gene expression and mitochondrial protein synthesis. In the aged rat heart, this effect is translated to increased cytochrome b content, restoration of complex III activity, and oxidative phosphorylation, resulting in amelioration of the age-related mitochondrial defect.
Article
Carnitine and its derivatives are natural substances involved in both carbohydrate and lipid metabolism. This review summarizes the recent progress in the field in relation to the molecular mechanisms. The pool of different carnitine derivatives is formed by acetyl-L-carnitine (ALC), propionyl-L-carnitine (PLC), and isovaleryl-carnitine. ALC may have a preferential effect on the brain tissue. ALC represents a compound of great interest for its wide clinical application in various neurological disorders: it may be of benefit in treating Alzheimer's dementia, depression in the elderly, HIV infection, chronic fatigue syndrome, peripheral neuropathies, ischemia and reperfusion of the brain, and cognitive impairment associated with various conditions. PLC has been demonstrated to replenish the intermediates of the tricarboxylic acid cycle by the propionyl-CoA moiety, a greater affinity for the sarcolemmal carrier, peripheral vasodilator activity, a greater positive inotropism, and more rapid entry into myocytes. Most studies of the therapeutic use of PLC are focused on the prevention and treatment of ischemic heart disease, congestive heart failure, hypertrophic heart disease, and peripheral arterial disease. ALC and PLC are considered well tolerated without significant side-effects. A number of therapeutic effects possibly come from the interaction of carnitine and its derivatives with the elements of cellular membranes.
Article
In order to examine the involvement of oxidative stress in developmental brain disorders, we have performed immunohistochemistry in autopsy brains and enzyme-linked immunosorbent assay (ELISA) in the cerebrospinal fluid and urines of patients. Here, we review our data on the hereditary DNA repair disorders, congenital metabolic errors and childhood-onset neurodegenerative disorders. First, in our studies on hereditary DNA repair disorders, increased oxidative DNA damage and lipid peroxidation were carried out in the degeneration of basal ganglia, intracerebral calcification and cerebellar degeneration in patients with xeroderma pigmentosum, Cockayne syndrome and ataxia-telangiectasia-like disorder, respectively. Next, congenital metabolic errors, apoptosis due to lipid peroxidation seemed to cause neuronal damage in neuronal ceroid-lipofuscinosis. Oxidative stress of DNA combined with reduced expression of antioxidant enzymes occurred in the lesion of the cerebral cortex in mucopolysaccharidoses and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. In childhood-onset neurodegenerative disorders, increased oxidative DNA damage and lipid peroxidation may lead to motor neuron death in spinal muscular atrophy like in amyotrophic lateral sclerosis. In patients with dentatorubral-pallidoluysian atrophy, a triplet repeat disease, deposition of oxidative products of nucleosides and reduced expression of antioxidant enzymes were found in the lenticular nucleus. In contrast, the involvement of oxidative stress is not definite in patients with Lafora disease. Rett syndrome patients showed changes of oxidative stress markers and antioxidant power in urines, although the changes may be related to systemic complications.