Activity of L-carnitine and L-acetylcarnitine on cholinoceptive neocortical neurons of the rat in vivo
TL;DR: Results show that carnitine and acetylcarnitine are stereospecific neuroactive compounds with a cholinomimetic activity and may play a role in a modulatory system for the cholinoceptive cortical neuron.
Abstract: Carnitine and acetylcarnitine have been demonstrated to be present in the CNS and to be involved in cholinergic mechanisms, even if their exact role in neurotransmission is still unknown. This microiontophoretic study was carried out on single cholinoceptive neurons of the somatosensory cortex in the rat in order to analyze the effects of L- and D-carnitine and L-acetylcarnitine on the spontaneous firing and the neuronal responses to some putative transmitters. L-carnitine and L-acetylcarnitine increased the spontaneous discharge rate, while D-carnitine was found to be ineffective. L-acetylcarnitine clearly potentiated the cholinergic excitatory responses. On the contrary, L-carnitine was found to reduce cholinergic responses in a great percentage of units and to inhibit L-acetylcarnitine-induced excitatory responses. Atropine blocked the increase in firing rate induced by L-carnitine and L-acetylcarnitine, thus suggesting for both of them a muscarinic activity. No interactions were observed between carnitines and GABA and glutamate. These results show that carnitine and acetylcarnitine are stereospecific neuroactive compounds with a cholinomimetic activity. They may play a role in a modulatory system for the cholinoceptive cortical neuron.
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TL;DR: ALCAR is reported in double-blind controlled studies to have beneficial effects in major depressive disorders and Alzheimer's disease (AD), both of which are highly prevalent in the geriatric population.
Abstract: Acetyl-L-carnitine (ALCAR) contains carnitine and acetyl moieties, both of which have neurobiological properties. Carnitine is important in the beta-oxidation of fatty acids and the acetyl moiety can be used to maintain acetyl-CoA levels. Other reported neurobiological effects of ALCAR include modulation of: (1) brain energy and phospholipid metabolism; (2) cellular macromolecules, including neurotrophic factors and neurohormones; (3) synaptic morphology; and (4) synaptic transmission of multiple neurotransmitters. Potential molecular mechanisms of ALCAR activity include: (1) acetylation of -NH2 and -OH functional groups in amino acids and N terminal amino acids in peptides and proteins resulting in modification of their structure, dynamics, function and turnover; and (2) acting as a molecular chaperone to larger molecules resulting in a change in the structure, molecular dynamics, and function of the larger molecule. ALCAR is reported in double-blind controlled studies to have beneficial effects in major depressive disorders and Alzheimer's disease (AD), both of which are highly prevalent in the geriatric population.
291 citations
TL;DR: Treating anhedonia in detoxified alcohol-dependent subjects could be critical in terms of relapse prevention strategies, given its strong relationship with craving.
Abstract: Anhedonia is a condition in which the capacity of experiencing pleasure is totally or partially lost, and it refers to both a state symptom in various psychiatric disorders and a personality trait. It has a putative neural substrate, originating in the dopaminergic mesolimbic and mesocortical reward circuit. Anhedonia frequently occurs in mood disorders, as a negative symptom in schizophrenia, and in substance use disorders. In particular, we focus our attention on the relationships occurring between anhedonia and substance use disorders, as highlighted by many studies. Several authors suggested that anhedonia is an important factor involved in relapse as well as in the transition from recreational use to excessive drug intake. In particular, anhedonia has been found to be a frequent feature in alcoholics and addicted patients during acute and chronic withdrawal as well as in cocaine, stimulant, and cannabis abusers. Furthermore, in subjects with a substance dependence disorder, there is a significant correlation between anhedonia, craving, intensity of withdrawal symptoms, and psychosocial and personality characteristics. Therefore treating anhedonia in detoxified alcohol-dependent subjects could be critical in terms of relapse prevention strategies, given its strong relationship with craving.
201 citations
TL;DR: The efficacy of acetyl-L-carnitine in mild cognitive impairment (MCI) and mild (early) Alzheimer's disease (AD) was investigated with a meta-analysis of double-blind, placebo-controlled prospective, parallel group comparison studies.
Abstract: The efficacy of acetyl-L-carnitine (gamma-trimethyl- beta-acetylbutyrobetaine (Alcar) in mild cognitive impairment (MCI) and mild (early) Alzheimer's disease (AD) was investigated with a meta-analysis of double-blind, placebo-controlled prospective, parallel group comparison studies of at least 3 months duration. The duration of the studies was 3, 6 or 12 months and the daily dose varied between studies from 1.5-3.0 g/day. An effect size was calculated to reflect the results of the variety of measures used in the studies grouped into the categories of clinical tests and psychometric tests. The effect sizes from the categories were integrated into an overall summary effect size. The effect size for the Clinical Global Impression of Change (CGI-CH) was calculated separately. Meta-analysis showed a significant advantage for Alcar compared to placebo for the integrated summary effect [ES =0.201, 95% confidence interval (CI)=0.107-0.295] and CGI-CH (ES =0.32, 95% CI=0.18-0.47). The beneficial effects were seen on both the clinical scales and the psychometric tests. The advantage for Alcar was seen by the time of the first assessment at 3 months and increased over time. Alcar was well tolerated in all studies.
186 citations
TL;DR: There is compelling evidence from preclinical studies that l-carnitine and ALCAR can improve energy status, decrease oxidative stress and prevent subsequent cell death in models of adult, neonatal and pediatric brain injury.
Abstract: L-Carnitine functions to transport long chain fatty acyl-CoAs into the mitochondria for degradation by β-oxidation Treatment with L-carnitine can ameliorate metabolic imbalances in many inborn errors of metabolism In recent years there has been considerable interest in the therapeutic potential of L-carnitine and its acetylated derivative acetyl-L-carnitine (ALCAR) for neuroprotection in a number of disorders including hypoxia-ischemia, traumatic brain injury, Alzheimer's disease and in conditions leading to central or peripheral nervous system injury There is compelling evidence from preclinical studies that L-carnitine and ALCAR can improve energy status, decrease oxidative stress and prevent subsequent cell death in models of adult, neonatal and pediatric brain injury ALCAR can provide an acetyl moiety that can be oxidized for energy, used as a precursor for acetylcholine, or incorporated into glutamate, glutamine and GABA, or into lipids for myelination and cell growth Administration of ALCAR after brain injury in rat pups improved long-term functional outcomes, including memory Additional studies are needed to better explore the potential of L-carnitine and ALCAR for protection of developing brain as there is an urgent need for therapies that can improve outcome after neonatal and pediatric brain injury
152 citations
Cites background from "Activity of L-carnitine and L-acety..."
...The ability of ALCAR to increase nerve growth factor [105] and enhance cholinergic activity may be particularly important for neuroprotection in developing brain [1, 106]....
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...ALCAR has been found to have anti-inflammatory effects [7], lead to stabilization of membranes [1], act as an antioxidant protecting against oxidative stress [37, 53, 103, 104], enhance the activity of nerve growth factor [105], and potentiate energy metabolism [57, 97] and cholinergic responses [1, 106]....
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TL;DR: Intravenously ALC was effective in accelerating the abstinence-associated improvement of anhedonia, melancholic and negative symptoms, whereas oral ALC treatment starting on day 10 showed no further improvements, and ALC may be considered as a new potentially useful drug for the treatment ofAnhedonia.
Abstract: Objective Aim of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy of Acetyl- l -Carnitine (ALC), at different dosages, on specific anhedonic symptoms in detoxified alcohol dependent subjects. Secondary endpoints were the effect of ALC on melancholic and negative symptoms. Method Sixty-four anhedonic alcohol dependent patients with minor or absent withdrawal symptoms were randomized: 23 received ALC at a dosage of 3 g/day, 21 received ALC at a dosage of 1 g/day, and 20 were given placebo. ALC was given intravenously for 10 days, followed by 80 days of oral treatment plus a follow-up period of 45 days. The presence of anhedonic symptoms was determined by the SHAPS (Snaith–Hamilton Pleasure Scale) and the VASa (Visual Analogue Scale for Anhedonia); negative and melancholic symptoms were evaluated by the SANS (Scale for the Assessment of Negative Symptoms), and the BRMS (Bech–Rafaelsen Melancholia Scale). Results The natural course of anhedonia in the placebo group showed a decline until day 30 and remains stable for the rest of the study. Intravenously ALC accelerated the improvement of anhedonia reaching constant low levels early, on day 10. At this step levels of anhedonia (SHAPS, VASa) and melancholic symptoms (BRMES) resulted significantly reduced (p Conclusion Intravenously ALC was effective in accelerating the abstinence-associated improvement of anhedonia, melancholic and negative symptoms, whereas oral ALC treatment starting on day 10 showed no further improvements. Accordingly, in alcohol dependent subjects, ALC may be considered as a new potentially useful drug for the treatment of anhedonia.
81 citations
References
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TL;DR: Advances in neurotransmitter systems involved in the symptomatic manifestations of neurological and psychiatric disorders reflect a close interaction between experimental and clinical neuroscientists in which information derived from basic neurobiology is rapidly utilized to analyze disorders of the human brain.
Abstract: Great emphasis is being placed on identification of neurotransmitter systems involved in the symptomatic manifestations of neurological and psychiatric disorders. In the case of Alzheimer's disease, which now seems to be one of the most common causes of mental deterioration in the elderly, compelling evidence has been developed that acetylcholine-releasing neurons, whose cell bodies lie in the basal forebrain, selectively degenerate. These cholinergic neurons provide widespread innervation of the cerebral cortex and related structures and appear to play an important role in cognitive functions, especially memory. These advances reflect a close interaction between experimental and clinical neuroscientists in which information derived from basic neurobiology is rapidly utilized to analyze disorders of the human brain.
2,995 citations
"Activity of L-carnitine and L-acety..." refers background in this paper
..., 1983) and are relevant to the understanding of neurological diseases with cognitive impairment, such as Alzheimer's dementia (Coyle et al., 1983)....
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...Moreover, brain lesions of Alzheimer's dementia include subcortical regions rich in cholinergic neurons projecting to widespread muscarinic cholinoceptive field in the cerebral cortex (Coyle et al., 1983)....
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TL;DR: The organization of projections from the cholinergic neurons of the basal forebrain to neocortex and associated structures was investigated in the rhesus monkey with the help of horseradish peroxidase transport, acetyl‐cholinesterase histochemistry, and choline acetyltransferase immunohis‐tochemistry.
Abstract: The organization of projections from the cholinergic neurons of the basal forebrain to neocortex and associated structures was investigated in the rhesus monkey with the help of horseradish peroxidase transport, acetyl-cholinesterase histochemistry, and choline acetyltransferase immunohis-tochemistry. Four groups of neurons contained cholinergic perikarya and were designated as Chl-Ch4. The Ch1 group corresponds to the medial septal nucleus; about 10% of its neurons are cholinergic, and it provides a substantial projection to the hippocampus. The Ch2 group corresponds to the vertical nucleus of the diagonal band; at least 70% of its neurons are cholinergic, and it is the major source of innervation that the hippocampus and hypothalamus receive from the Chl-Ch4 complex. The Ch3 group most closely corresponds to the horizontal nucleus of the diagonal band; only 1% of its neurons can definitely be shown to be cholinergic, and it is the major source of Chl-Ch4 projections to the olfactory bulb. The Ch4 group most closely corresponds to the nucleus basalis of Meynert; at least 90% of its neurons are cholinergic, and it has projections to widespread areas of cortex and to the amygdala. In fact, the Ch4 group provides the single major source of cholinergic innervation for the entire cortical surface. In this respect, it is analogous to the raphe nuclei and to the nucleus locus coeruleus, which constitute the major sources of widespread cortical serotonergic and nor-adrenergic innervation, respectively.
The extensive Ch4 group can be divided into several subdivisions. Each subdivision has a preferential set of targets for its projections even though the connection patterns contain considerable overlap. The anteromedial subdivision of Ch4 is the major source of cholinergic projections to areas on the medial aspect of the cerebral hemispheres; the anterolateral Ch4 sub-division is the major source of cholinergic projections to frontoparietal op-ercular areas and to the amygdala; the intermediate Ch4 subdivision pro-vides the major cholinergic input for a variety of dorsal prefrontal, insular, posterior parietal, inferotemporal, and peristriate areas; and the posterior subdivision of Ch4 provides the major cholinergic innervation of superior temporal and immediately adjacent areas.
The basal forebrain in the human contains a cytoarchitechture analogous to that of the monkey. The Ch4 group (nucleus basalis) of the human is very extensive and can be subdivided into the same components that were identfied in the monkey brain. Pathological changes in Ch4 neurons have been described in a variety of human disease. In Alzheimer's disease, the relatively selective depression of neocortical cholinergic innervation may be closely associated with the neuronal loss in Ch4, which has also been described inthis condition.
In the rhesus monkey, all types of cortical areas receive substantial projections from the hippocampus. Virtually all of this hypothalamic input into neocortex arises from acetylcholinesterase-rich neurons which lack choline acetyltransferase. The hypothalamocortical pathway is therefore acetylcholinesterase-rich but not cholinergic.
1,866 citations
"Activity of L-carnitine and L-acety..." refers background in this paper
...Forebrain projections to cerebral cortex represent a prominent cholinergic input (Mesulam et al., 1983) and are relevant to the understanding of neurological diseases with cognitive impairment, such as Alzheimer's dementia (Coyle et al....
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TL;DR: Brain specimens from middle-aged and elderly normal as well as demented subjects and patients with provisional clinical diagnosis of other neurological and psychiatric diseases were assessed histologically, finding that terminal 'cerebral hypoxia' is responsible for the depletion of these brain constituents.
Abstract: Fifty-six brains from middle-aged and elderly normal as well as demented subjects and patients with provisional clinical diagnosis of other neurological and psychiatric diseases were assessed histologically. On this basis the specimens were classified into 14 diagnostic groups. A survey of potential indices of specific neurons has been carried out on these brains in which neurotransmitter-related enzymes, gamma-GTP (a potential index of capillaries) and specific proteins have been determined in up to 20 brain regions. In addition, the agonal state has been tentatively assessed by examining the post-mortem states of the circulatory and respiratory systems. CAT and gamma-GTP activities and the concentration of a soluble neuronal-type protein (neuronin S-5) were found to be relatively unaffected by the agonal state. When cases of senile dementia were compared to controls (matched with respect to the cause of death) the activity of CAT (the potential index of cholinergic neurons) appears to be reduced in the cerebral cortex. This is a preliminary finding, although a correlation was indicated between CAT activity and 'senile' morphological changes, the activity was markedly reduced in only 3 brains. However, despite inconsistencies in the literature (Karczmar, 1975) at least one pharmacological study on humans appears to show that the cholinergic system may be involved in age-related memory degeneration (Drachman and Leavitt, 1974). Cholinergic neurons may be abnormal in the other abiotrophies examined (Huntington's chorea, motor neuron disease and mixed vascular and senile dementia). gamma-GTP and neuronin S-5 (identical in most respects to the soluble acidic neuronal protein 14-3-2 of antigen alpha) were not reduced in senile dementia. The activities of brain decarboxylase (GAD and AAD) and the concentration of another soluble acidic brain protein (neuronin S-6) appear to be affected by the agonal state. This is remarkable because GAD and, in particular, neuronin S6, are relatively unaffected by post-mortem autolysis. As judged by the state of the extraneural systems which regulated the blood and oxygen supply to the brain it appears that terminal 'cerebral hypoxia' is responsible for the depletion of these brain constituents. This effect appears to be particularly marked in deep grey matter. In non-demented patients that die of bronchopneumonia, the areas of the cortex which are depleted in neuronin S-6 are consistent with the pattern of the 'selective vulnerability' of the cortex to hypoxia, suggesting that the terminal state can also affect the neocortex. If so, then this is particularly relevant to studies on senile dementia, for the effect of the terminal bronchopneumonia that so often occurs in these patients (and in patients with other abiotrophies) may be exacerbated by a terminal reduction in cerebral blood flow...
1,258 citations
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285 citations
"Activity of L-carnitine and L-acety..." refers background in this paper
...In fact the nerve cell loss associated with aging or degenerative diseases in animals as well as in humans could coexist with an impaired balance of synaptic regulatory systems (Bowen et al., 1976; Rossor, 1982)....
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