Smeland OB, Meisingset TW, Borges K, Sonnewald U. Chronic acetyl-L-carnitine alters brain energy metabolism and increases noradrenaline and serotonin content in healthy mice. Neurochem Int 61: 100-107

Dept. of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Neurochemistry International (Impact Factor: 3.09). 04/2012; 61(1):100-7. DOI: 10.1016/j.neuint.2012.04.008
Source: PubMed


Acetyl-L-carnitine (ALCAR), the short-chain ester of carnitine, is a common dietary supplement readily available in health food stores, claimed to improve energy levels and muscle strength. ALCAR has numerous effects on brain and muscle metabolism, protects against neurotoxic insults and may be an effective treatment for certain forms of depression. However, little is known about the effect of chronic ALCAR supplementation on the brain metabolism of healthy mice. Here, we investigated ALCAR's effect on cerebral energy and neurotransmitter metabolism after supplementing the drinking water of mice with ALCAR for 25 days, providing a daily dose of about 0.5 g/kg. Thereafter the animals were injected with [1-(13)C]glucose, and (13)C incorporation into and levels of various metabolites were quantified in extracts of the hippocampal formation (HF) and cortex using (1)H- and (13)C-nuclear magnetic resonance (NMR) spectroscopy and high performance liquid chromatography (HPLC). Increased glucose levels were detected in both regions together with a decreased amount of [3-(13)C]lactate, but no alterations in incorporation of (13)C derived from [1-(13)C]glucose into the amino acids glutamate, GABA and glutamine. These findings are consistent with decreased metabolism of glucose to lactate but not via the TCA cycle. Higher amounts of the sum of adenosine nucleotides, phosphocreatine and the phosphocreatine/creatine ratio found in the cortex of ALCAR-treated mice are indicative of increased energy levels. Furthermore, ALCAR supplementation increased the levels of the neurotransmitters noradrenaline in the HF and serotonin in cortex, consistent with ALCAR's potential efficacy for depressive symptoms. Other ALCAR-induced changes observed included reduced amounts of GABA in the HF and increased myo-inositol. In conclusion, chronic ALCAR supplementation decreased glucose metabolism to lactate, resulted in increased energy metabolite and altered monoamine neurotransmitter levels in the mouse brain.

Download full-text


Available from: Olav B Smeland, Jan 29, 2014
  • Source
    • "In our studies on the zebrafish embryos, ALCAR enhanced 5-HT turnover and prevented loss of 5- HT and 5-HIAA observed in 2 mM ketamine-treated embryos. ALCAR's effects on neurotransmitter (monoamine) regulations, especially serotonergic activities, are considered to have antidepressant actions in rodents [2] [25] [40] [47] [48]. Here, we show that ALCAR accelerated 5-HT metabolism. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ketamine, a pediatric anesthetic, is a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist. Studies show that ketamine is neurotoxic in developing mammals and zebrafish. In both mammals and zebrafish, acetyl l-carnitine (ALCAR) has been shown to be protective against ketamine toxicity. Ketamine is known to modulate the serotonergic system in mammals. Here, we measured the levels of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in the embryos exposed to ketamine in the presence and absence of ALCAR. Ketamine, at lower doses, did not produce significant changes in the 5-HT or 5-HIAA levels in 3 dpf (day post-fertilization) embryos. However, 2mM ketamine (internal embryo exposure levels comparable to human anesthetic plasma concentration) significantly reduced 5-HT level and 5-HIAA was not detectable indicating that 5-HT metabolism was abolished. In the presence or absence of 2mM ketamine, ALCAR by itself did not significantly alter 5-HT or 5-HIAA levels compared to the control. Ratios of metabolite/5-HT indicated that 2mM ketamine inhibited 5-HT metabolism to 5-HIAA whereas lower doses (0.1-0.3mM) of ketamine did not have any effect. ALCAR reversed the effects of 2mM ketamine not only by restoring 5-HT and 5-HIAA levels but also 5-HT turnover rate to control levels. Whole mount immunohistochemical studies showed that 2mM ketamine reduced the serotonergic area in the brain whereas ALCAR expanded it with increased axonal sprouting and branching. These results indicate that ketamine and ALCAR have opposing effects on the zebrafish serotonergic system.
    Full-text · Article · Sep 2015 · Neuroscience Letters
  • Source
    • "Acetyl-L-carnitine (ALC), the short-chain ester of carnitine, is endogenously produced within mitochondria and peroxisomes and it can readily cross the blood–brain barrier (Kido et al., 2001). In addition, ALC is found naturally in the central nervous system (CNS) and involved in several neural pathways, the brain energy and phospholipid metabolism, the activity of neurotrophic factors and neurohormones, the synaptic morphology and multiple neurotransmitters (Vivoli et al., 2010; Schaevitz et al., 2012; Smeland et al., 2012). Moreover, in previous studies, ALC showed beneficial effects in major depression (Cuccurazzu et al., 2013; Nasca et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The possible involvement of the PI3K/AKT/BDNF/VGF signaling in rapid-acting antidepressant-like effects of antidepressants has been explored progressively by more studies. However, whether this signaling participates in the antidepressant-like effects of acetyl-l-carnitine (ALC) has not been examined. Herein, we assessed the antidepressant-like effects of ALC using the forced swimming test (FST). Our results demonstrated the dose–effect relationship of acute administration of ALC (5, 25, 50 and 100 mg/kg, i.p.) and showed that it dose-dependently decreased the immobility time on FST of mice. In addition, ALC (100 mg/kg, i.p.) also reversed depressive-like behavior and the down-regulation of phosphorylated AKT (pAKT), brain-derived neurotrophic factor (BDNF) and neuropeptide VGF in the hippocampus and prefrontal cortex of mice induced by chronic unpredictable mild stress (CUMS) paradigm. Further, intra-cerebroventricular (i.c.v.) infusions of LY294002 (10 nmol/side), a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, significantly prevented the antidepressant-like effect of ALC (100 mg/kg, i.p.). In conclusion, our results demonstrated that ALC exerts rapid-acting antidepressant-like effects that might be mediated by the PI3K/AKT/BDNF/VGF signaling pathway.
    Full-text · Article · Nov 2014 · Neuroscience
  • Source
    • "rgy phosphates and myo - inositol ( Nakamura et al . , 1998 ; Smeland et al . , 2012 ; Stevens et al . , 1996 ) . Its effect in neurotrans - mitter regulations , especially serotonergic and possibly dopami - nergic activities , could also contribute to antidepressant actions ( Alves et al . , 2009 ; Forster et al . , 1995 ; Levine et al . , 2005 ; Smeland et al . , 2012 ) . ALC ' s clinical efficacy in patients with depression , dysthymic disorder , and depressive symptoms were investigated in 14 RCTs . 4 RCTs demonstrated the superior efficacy of ALC over PBO in patients with depression ( Garzya et al . , 1990 ; Gecele M , 1991 ; Nasca D , 1989 ; Villardita C , 1993 ) and its superior efficacy over PB"
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite numerous antidepressants available, many patients with depression do not achieve adequeate response rendering needs for novel antidepressants with different mechanism of actions. Acetyl-L-carnitine (ALC) is a potential antidepressant with novel mechanism of action because of its diverse functions related with neuroplasticity. Animal and cellular models suggest that ALC’s neuroplasiticity effect, membrane modulation, and neurotransmitter regulation may play an important role in treatment of depression. Four randomized clinical studies (RCT) demonstrated the superior efficacy of ALC over placebo (PBO) in patients with depression. Two RCTs showed its superior efficacay over PBO in dysthymic disorder, and 2 other RCTs showed that it is equally effective as fluoxetine and amisulpride in treatment of dysthmic disorder. ALC was also effective in improving depressive symptoms in patients with fibromyalgia and minimal hepatic encephalopathy. It was also found to be equally toletable to PBO and better tolerable than fluoxetine and amisulpride. In conclusion, ALC may be potentially effective and tolerable next treatment option with novel action mechanisms for patients with depression, in particular older population and patients with comorbid medical conditions who are vulnerable to adverse events from antidepressants. However, more clinical trial data with adequately-powered, well-designed and advanced methodology will be mandatory to conclude whether ALC as a monotherpay or augmentation agent may be efficacious and clinically beneficial for depression.
    Full-text · Article · Jun 2014 · Journal of Psychiatric Research
Show more