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Acetyl-L-carnitine improves aged brain function

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Abstract

The effects of acetyl-L-carnitine (ALCAR), an acetyl derivative of L-carnitine, on memory and learning capacity and on brain synaptic functions of aged rats were examined. Male Fischer 344 rats were given ALCAR (100 mg/kg bodyweight) per os for 3 months and were subjected to the Hebb-Williams tasks and AKON-1 task to assess their learning capacity. Cholinergic activities were determined with synaptosomes isolated from brain cortices of the rats. Choline parameters, the high-affinity choline uptake, acetylcholine (ACh) synthesis and depolarization-evoked ACh release were all enhanced in the ALCAR group. An increment of depolarization-induced calcium ion influx into synaptosomes was also evident in rats given ALCAR. Electrophysiological studies using hippocampus slices indicated that the excitatory postsynaptic potential slope and population spike size were both increased in ALCAR-treated rats. These results indicate that ALCAR increases synaptic neurotransmission in the brain and consequently improves learning capacity in aging rats.

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... The rise of life expectancy has amplified the interest in the prevention and improvement of age-related brain dysfunctions. In fact, cognitive deficits are hallmarks not only of pathological aging, as occurring in Alzheimer's disease and vascular dementia, but also of non-pathological aging processes (Kobayashi et al., 2010). Agerelated cognitive decline is due to a progressive impairment of the underlying brain cell processes due to neuroinflammation, oxidative stress, reduced synaptic plasticity and neurogenesis, thus leading to a consequent and irreversible neuronal loss of gray and white matter volume (Driscoll et al., 2006;Masliah et al., 2006;Brown, 2009). ...
... Finally, it has to be taken into account that the ameliorated mnesic performances of n-3 PUFA group were associated to high ALC blood levels, without differences in the other carnitines and amino acids analyzed. Crossing the blood-brain barrier, ALC shuttles acetyl groups and fatty acids into brain cell mitochondria for energy production and acts as direct anti-oxidant (Kobayashi et al., 2010;Goo et al., 2012). Remarkably, ALC improves cognitive deficits in aged or demented human subjects (Ames and Liu, 2004;Mancuso et al., 2007;Glade, 2010;Malaguarnera, 2012). ...
... Preclinical studies indicate that ALC counteracts cognitive decline even in the presence of β-amyloid toxicity (Kaur et al., 2001;Dhitavat et al., 2005;Abdul et al., 2006;Barhwal et al., 2009;Suchy et al., 2009). Moreover, ALC improves mnesic capacities, restores serum, heart, muscle and brain carnitine levels, and improves the cholinergic neurotransmission dysregulated by aging (Kobayashi et al., 2010). Notably, in animal studies also n-3 PUFA dietary supplementation improves cholinergic transmission in the brain (Willis et al., 2009). ...
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As major components of neuronal membranes, omega-3 polyunsaturated acids (n-3 PUFA) exhibit a wide range of regulatory functions, modulating from synaptic plasticity to neuroinflammation, from oxidative stress to neuroprotection. Recent human and animal studies indicated the n-3 PUFA neuroprotective properties in aging, with a clear negative correlation between n-3 PUFA levels and hippocampal deficits. The present multidimensional study was aimed at associating cognition, hippocampal neurogenesis, volume, neurodegeneration and metabolic correlates to verify n-3 PUFA neuroprotective effects in aging. To this aim 19 month-old mice were given n-3 PUFA mixture, or olive oil or no dietary supplement for 8 weeks during which hippocampal-dependent mnesic functions were tested. At the end of behavioral testing morphological and metabolic correlates were analyzed. n-3 PUFA supplemented aged mice exhibited better object recognition memory, spatial and localizatory memory, and aversive response retention, without modifications in anxiety levels in comparison to controls. These improved hippocampal cognitive functions occurred in the context of an enhanced cellular plasticity and a reduced neurodegeneration. In fact, n-3 PUFA supplementation increased hippocampal neurogenesis and dendritic arborization of newborn neurons, volume, neuronal density and microglial cell number, while it decreased apoptosis, astrocytosis and lipofuscin accumulation in the hippocampus. The increased levels of some metabolic correlates (blood Acetyl-L-Carnitine and brain n-3 PUFA concentrations) found in n-3 PUFA supplemented mice also pointed toward an effective neuroprotection. On the basis of the present results n-3 PUFA supplementation appears to be a useful tool in health promotion and cognitive decline prevention during aging.
... L-carnitine (LC) or γ-trimethylaminoβ-hydroxybutric acid is a small water-soluble quaternary amine that is present in different concentrations in human serum and tissues where they vary in relation to different factors such as environmental changes, diets, hormones, sex and age (9,10). Approximately half of the LC in the human body is supplied by biosynthesis and the rest of the LC can be supplied by food (11). Many physiological effects of LC have been shown. ...
... It has been speculated that LC protects cells from the oxidative damages, by inhibiting free-radical propagation and by contributing to repair of oxidized membrane phospho-lipids (17,18). Although many studies show the neurological effects of LC and ALC in the aging brain, but its accurate mechanisms are not clear (11). This study aimed to investigate the effects of LC in different doses on the hTERT gene expression, telomere length and on the cell proliferation rates of the aged human adipose tissue-derived MSCs. ...
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Background and objectives: Human mesenchymal stem cells (hMSCs) are attractive candidates for cell therapy and regenerative medicine due to their multipotency and ready availability, but their application can be complicated by the factors such as age of the donors and senescence-associated growth arrest during culture conditions. The latter most likely reflects the fact that aging of hMSCs is associated with a rise in intracellular reactive oxygen species, loss of telomerase activity, decrease in human telomerase reverse transcriptase (hTERT) expression and finally eroded telomere ends. Over-expression of telomerase in hMSCs leads to telomere elongation and may help to maintain replicative life-span of these cells. The aim of this study was to evaluate of the effect of L-carnitine (LC) as an antioxidant on the telomerase gene expression and telomere length in aged adipose tissue-derived hMSCs. Methods: For this purpose, cells were isolated from healthy aged volunteers and their viabilities were assessed by MTT assay. Quantitative gene expression of hTERT and absolute telomere length measurement were also performed by real-time PCR in the absence and presence of different doses of LC (0.1, 0.2 and 0.4 mM). Results: The results indicated that LC could significantly increase the hTERT gene expression and telomere length, especially in dose of 0.2 mM of LC and in 48 h treatment for the aged adipose tissue-derived hMSCs samples. Conclusion: It seems that LC would be a good candidate to improve the lifespan of the aged adipose tissue-derived hMSCs due to over-expression of telomerase and lengthening of the telomeres.
... In addition to these, natural compounds like huperzine A [127], galanthamine and vinpocetine [128] have been used for their nootropic effects. L-theanine [129,130], which is an amino-acid that is present in green tea (Camelia sinensis), L-tyrosine [131] (an amino acid precursor to catecholamine neurotransmitters such as dopamine and noradrenaline), L-taurine [132,133], a semi-essential, sulphur-containing amino acid and acetyl-l-carnitine [134], an endogenous antioxidant which also acts as a cellular energy carrier at the level of the mitochondrion are also notable compounds. Table 1 shows the specific mechanisms of action of synthetic nootropics as well as herbal and natural nootropic agents that have similar mechanisms, while Table 2 is a tabular presentation of the different preclinical and clinical studies that have examined the probable or confirmed roles and mechanisms (Fig. 2) of a number of herbal and food-derived nootropic agents. ...
... However, for many of the plants, only experimental evidence supported the empirical claims, thereby, pointing to the fact that there we are still a long way from confirming and establishing their clinical benefits and impacts of their long-term usage on general health. Gingko biloba [112] Nicotine [118,119], Kapikacchu (Mucuna pruriens) [123] Tyrosine [131] Increased acetylcholine and/or glutamate receptor activity, acetylcholinesterase inhibiton Racetams including piracetam, nefiracetam, nebracetam [101][102][103] Panax ginseng [114][115][116], Bacopa monnieri [117] ,Huperzine A [127] , Theanine [129,130], Taurine [132,133], Acetyl-l-carnitine [134] Ginkgolides, bilobalide and proanthocyanidins are potent free radical scavengers/antioxidants which confer neuroprotection. Enhanced monoaminergic transmission. ...
Article
Background: Age-related cognitive decline has been suggested to result from an increase in brain neurone loss, which is attributable to continued derangement of the brain's oxidant/antioxidant balance. Increased oxidative stress and a concomitant decrease in the brain's antioxidant defense system have been associated with functional senescence and organismal ageing. However, nature has configured certain foods to be rich sources of nootropic agents, with research showing that increased consumption of such foods or food ingredients may be protective against ageing-related memory decline. This knowledge is becoming increasingly valuable in an era when the boundary that separates food from medicine is becoming blurred. In this review, we examine extant literature dealing with the impact of ageing on brain structure and function, with emphasis on the roles of oxidative stress. Secondly, we review the benefits of food-based antioxidants with nootropic effects and/or food-based nootropic agents in mitigating memory decline; with a view to improving our understanding of likely mechanisms. We also highlight some of the limitations to the use of food-based nootropics and suggest ways in which they can be better employed in the clinical management of age-related cognitive decline. Conclusion: While it is known that the human brain endures diverse insults in the process of ageing, food-based nootropics are likely to go a long way in mitigating the impacts of these insults. Further research is needed before we reach a point where food-based nootropics are routinely prescribed.
... Growing preclinical evidence seems to support the aforementioned clinical observations. In rodent models, ALC supplementation improves synaptic transmission and learning capacity in aged rats (97,98) and attenuated age-related mitochondrial decay (99,100). Also, ALC was shown to directly affect the cholinergic system (101), which is substantially impaired in AD (102), and provide beneficial effects in experimental models of AD. ...
Article
Neurodegenerative disorders and diseases (NDDs) that are either chronically acquired or triggered by a singular detrimental event are a rapidly growing cause of disability and/or death. In recent times, there have been major advancements in our understanding of various neurodegenerative disease states that have revealed common pathologic features or mechanisms. The many mechanistic parallels discovered between various neurodegenerative diseases suggest that a single therapeutic approach may be used to treat multiple disease conditions. Of late, natural compounds and supplemental substances have become an increasingly attractive option to treat NDDs because there is growing evidence that these nutritional constituents have potential adjunctive therapeutic effects (be it protective or restorative) on various neurodegenerative diseases. Here we review relevant experimental and clinical data on supplemental substances (i.e., curcuminoids, rosmarinic acid, resveratrol, acetyl-l-carnitine, and ω-3 (n-3) polyunsaturated fatty acids) that have demonstrated encouraging therapeutic effects on chronic diseases, such as Alzheimer's disease and neurodegeneration resulting from acute adverse events, such as traumatic brain injury.
... Consequently, it has been hypothesized that boosting brain function through cholinergic enhancement during rehabilitation paradigms might help individuals with cognitive or sensory deficits related to aging with the hope of not only recovering sensory abilities, but also promoting brain plasticity. Indeed, the pharmacological potentiation of cholinergic neurotransmission has been shown to improve performance on cognitive tasks in the elderly [21][22][23] and chronic treatment with drugs that enhance cholinergic function has been used to ameliorate cognitive dysfunction [24,25]. ...
Article
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We used the rat primary auditory cortex (A1) as a model to probe the effects of cholinergic enhancement on perceptual learning and auditory processing mechanisms in both young and old animals. Rats learned to perform a two-tone frequency discrimination task over the course of two weeks, combined with either the administration of a cholinesterase inhibitor or saline. We found that while both age groups learned the task more quickly through cholinergic enhancement, the young did so by improving target detection, whereas the old did so by inhibiting erroneous responses to nontarget stimuli. We also found that cholinergic enhancement led to marked functional and structural changes within A1 in both young and old rats. Importantly, we found that several functional changes observed in the old rats, particularly those relating to the processing and inhibition of nontargets, produced cortical processing features that resembled those of young untrained rats more so than those of older adult rats. Overall, these findings demonstrate that combining auditory training with neuromodulation of the cholinergic system can restore many of the auditory cortical functional deficits observed as a result of normal aging and add to the growing body of evidence demonstrating that many age-related perceptual and neuroplastic changes are reversible.
... In addition to its demonstrated role in fat oxidation and energy generation, there is some evidence that LC may affect behavior. 2 Studies of this role have focused primarily on mood or affective behavior in aging patients, developmental disorders such as autism, or the therapeutic use of LC for chronic diseases such as celiac or neoplastic disease. 3,4,5 Reported benefits of LC supplementation manifest as behavioral changes that include improved subjective energy level, enhanced motivation to learn, and a reduction in mental fatigue. ...
Article
L-carnitine (LC) has been included in feline diets to enhance weight loss and reduce risk of hepatic lipidosis. However, many overweight cats are fed maintenance diets and are not undergoing weight loss. The objective of this study was to investigate how feeding lean and overweight adult cats dietary LC (100 mg/kg) during weight maintenance affected resting energy expenditure (EE), respiratory quotient (RQ), and play motivation. Twenty healthy adult cats were stratified by gender and body condition score (BCS) and randomly assigned to receive either a control food (CON) or the same food supplemented with 100 mg/ kg LC (LC+) for 42 days. EE was assessed using indirect calorimetry at 0, 21, and 42 days and play motivation was assessed at 0 and 42 days. Body weight did not differ between treatment groups at baseline and throughout the study (P>0.05), as expected. On days 21 and 42, area under the curve (AUC) for EE (kcal/ kg BW*d) and RQ did not differ between groups (P>0.05) for lean cats. However, overweight cats fed LC+ had greater (P<0.05) AUC for EE for at fasting and after receiving a meal on d 21 and 42 and a lower AUC for RQ from 0 - 210 minutes post feeding on d 42 than overweight cats fed CON. Overweight cats, but not lean cats, fed LC+ spent less time both in the start box and overall test and pushed more weight in the obstruction test than cats fed CON (P<0.05). These results suggest that dietary LC fed at a low level of supplementation results in greater EE, lower RQ, and greater motivation to play in overweight, but not lean, cats fed to maintain weight. Future research should investigate whether a similar mechanism is present in cats fed ad libitum, the feeding management strategy commonly used.
... Therefore, drugs can be able to modulate these processes affecting different neurotransmission systems or molecular targets. The acetyl derivative of LC, named acetyl-L-carnitine (ALCAR), has been shown to play a modulatory role in neural function by transferring acetyl groups for acetylcholine synthesis, with beneficial effects on memory (Jones et al., 2010;Kobayashi et al., 2010;Traina et al., 2004). Conversely, L-carnitine cannot donate the acetyl group, but it reacts with acetyl-coenzyme A to favor lipid metabolism, decreasing the pool of acetyl groups available for acetylcholine synthesis. ...
... In preclinical studies supplementation with ALCAR improved learning and synaptic transmission in aged rats [130][131][132]. Other studies showed that high doses of ALCAR led to improvement after ischemia [133]. ...
Article
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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.
... The animal trial of Acetyl L-Carnitine for Alzheimer's disease shows that it regularizes the variations in energy metabolism and membrane. It simply makes use of nerve growth factors in the central nervous system [36]. Hence some more research on this may give us positive results of acetyl L-Carnitine on Alzheimer's diseases. ...
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L-carnitine, an amino acid derivative, is naturally synthesized in human bodies in very few amounts and can also be taken as a dietary supplement. This amino acid derivative is very popular among various medical drugs and in gym dietary nutrients. In addition, it plays an intense role in brain functioning, in the generation of energy, known to provide more oxygen for muscles and improve stamina, strength, and power. Besides its various applications, several myths are reported but do not have adequate scientific evidence to date. This review aims to investigate the effects of L-Carnitine as a drug and the myths related to it. This paper contains significant facts about L-Carnitine, i.e., its benefits, side effects, and myths. It will give a clear idea about L-Carnitine and its applications. This review paper discussed the characteristics of L-carnitine, which finds vast applications and benefits. This review paper has also discussed the most recent finding of L-Carnitine promoting atherosclerosis by way of trimethylamine N-oxide Meta organismal pathway along with its solution on trial bases. L-Carnitine has many applications in the clinic and personalized medicine; hence, it has an excellent scope for future works, which requires the trials of its applications on a large scale.
... Acetyl-L-carnitine (ALCAR) is present in high concentrations in the brain [97], and it can be formed in the body or obtained through foods and can cross the blood-brain barrier [98,99]. Several reports indicate that ALCAR might be involved in synapse functions [100][101][102][103], cholinergic neural transmission [97], and mitochondrial metabolism of neurons [104]. Altogether, these data suggest that ALCAR may play a role in protection during AD progression, especially in terms of neurotoxicity. ...
Article
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In Alzheimer's disease (AD) and dementia of the Alzheimer's type (DAT), the role played by peroxisomes is not well known. Peroxisomes are present in all eukaryotic cells, with the exception of erythrocytes. They are involved in the β-oxidation process of long-chain fatty acids, very-long-chain fatty acids, and branched-chain fatty acids. They participate in the α-oxidation of phytanic acid, the biosynthesis of bile acids, and the breakdown of eicosanoids. Peroxisomes are also involved in the synthesis of specific fatty acids such as docosahexaenoic acid (DHA), which is essential for the brain and retina, and plasmalogens (PLGN), which play crucial roles in neural cells and are essential components of myelin. Several studies conducted in animal models and in humans provided evidence for a role of DHA in preventing brain degeneration. Significantly lower levels of PLGN were observed in patients with severe dementia. Moreover, a decreased activity of carnitine acetyltransferase, an enzyme present in peroxisome (but also detected in mitochondria, endoplasmic reticulum, and nucleus), was reported in AD patients. We give an overview of the potential role of peroxisomes, especially in the part played by DHA, PLGN, carnitine, and carnitine-dependent peroxisomal enzymes, on the development of AD and DAT. The potential of developing novel therapies targeted on peroxisomal metabolism to prevent cognitive decline and other age-related neurological disorders is discussed.
... Acetyl-L-carnitine (ALCAR) is present in high concentrations in the brain [97], and it can be formed in the body or obtained through foods and can cross the blood-brain barrier [98,99]. Several reports indicate that ALCAR might be involved in synapse functions [100][101][102][103], cholinergic neural transmission [97], and mitochondrial metabolism of neurons [104]. Altogether, these data suggest that ALCAR may play a role in protection during AD progression, especially in terms of neurotoxicity. ...
Article
Full-text available
In Alzheimer's disease (AD) and dementia of the Alzheimer's type (DAT), the role played by peroxisomes is not well known. Peroxisomes are present in all eukaryotic cells, with the exception of erythrocytes. They are involved in the β-oxidation process of long-chain fatty acids, very-long-chain fatty acids, and branched-chain fatty acids. They participate in the α-oxidation of phytanic acid, the biosynthesis of bile acids, and the breakdown of eicosanoids. Peroxisomes are also involved in the synthesis of specific fatty acids such as docosahexaenoic acid (DHA), which is essential for the brain and retina, and plasmalogens (PLGN), which play crucial roles in neural cells and are essential components of myelin. Several studies conducted in animal models and in humans provided evidence for a role of DHA in preventing brain degeneration. Significantly lower levels of PLGN were observed in patients with severe dementia. Moreover, a decreased activity of carnitine acetyltransferase, an enzyme present in peroxisome (but also detected in mitochondria, endoplasmic reticulum, and nucleus), was reported in AD patients. We give an overview of the potential role of peroxisomes, especially in the part played by DHA, PLGN, carnitine, and carnitine-dependent peroxisomal enzymes, on the development of AD and DAT. The potential of developing novel therapies targeted on peroxisomal metabolism to prevent cognitive decline and other age-related neurological disorders is discussed.
...  [81]  Phosphatidylserine 215mg [82][83][84]  Acetyl-L-Carnitine 1050mg [85,86]  Alpha-Lipoic Acid 200mcg [87]  Ginko Extract 60mg [88]  N-Acetyl-L-Cysteine 400mg [89]  Vinpocetine 5mg [90]  Huperzine A 100mcg [91]  Benfotiamine 50mg [92]  transResveratrol 1mg [93] In addition to the basic supplement panel described above, patients were also prescribed supplements that targeted any other individual nutritional deficits as identified by the physician on the team. ...
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This study, published in the Open Biomedical (OBM) journal Integrative and Complementary Medicine, examined a multifaceted anti-neuroinflammatory intervention that included physical exercise, mental exercise (LearningRx cognitive training), grain-free/sugar-free diet, anti-inflammatory nutritional supplements, sleep optimization, and stress management within the context of a functional medicine practice for five patients with varying levels of cognitive impairment. In a prospective chart review, we examined impact measures including assessment of (1) cognitive skills, (2) brain connectivity, and (3) daily functioning. Three of the five patients were no longer classified as cognitively impaired, while a fourth patient improved from moderately-to-severely impaired to mildly impaired. Patients reported improved memory, mental clarity, and outlook on life. fMRI analyses revealed changes in brain connectivity and efficiency. The current study provides preliminary support for and feasibility of the use of a multi-component approach to slowing cognitive decline.
... From another point of view, it was reported that acetylcarnitine exhibits some nerve functions passing through the blood-brain barrier (39). A human positronemission tomography (PET) study showed the cerebral uptake of acetylcarnitine reaching several crucial brain areas: the prefrontal and temporal cortices, anterior cingulate, cerebellum, and then, the acetyl moiety is incorporated into brain metabolism (40,41). Kuratsune et al. reported that the blood acetylcarnitine concentration of individuals with chronic fatigue syndrome (CFS) is lower than that of the healthy population (42). ...
Article
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The acute metabolic effect of low dosages of L-carnitine under fat-mobilizing conditions was investigated. Healthy subjects (Study 1: n=5; Study 2: n=6) were asked to fast overnight. Then, 30 min of aerobic exercise on a cycle ergometer was performed after supplementation, followed by a 3.5-h sedentary recovery phase. The following ingestion patterns were used: Study 1 (i) noningestion, (ii) 750 mg of L-carnitine (LC), and (iii) 750 mg of LC+50 g of carbohydrate (CHO); Study 2 (iv) noningestion, (v) 500 mg of LC, (vi) 30 mg of CoQ10, and (vii) 500 mg of LC+30 mg of CoQ10. The energy expenditure (EE) and nonprotein respiratory quotient (npRQ) were measured during the pre-exercise, postexercise, and recovery periods. Serum free carnitine, acetylcarnitine, total carnitine (Study 1 and 2), and ketone bodies (Study 2) were measured. The 750 mg LC treatment significantly facilitated fat oxidation during the recovery phases (p<0.05) without elevating EE. The higher fat oxidation associated with LC was completely suppressed by CHO. CoQ10 affected neither npRQ nor EE. npRQ was significantly correlated with the serum total ketone bodies (R=−0.68, p<0.001) and acetylcarnitine (R=−0.61-−0.70, p<0.001). The highest correlation was found between acetylcarnitine and total ketone bodies immediately after exercise (R=0.85, p<0.001). In conclusion, LC enhanced liver fat utilization and ketogenesis in an acute manner without stimulating EE under fat-mobilizing conditions.
... Although their significance has been questioned [63,67], these age-associated changes have led to the cholinergic hypothesis of aging, which suggests cholinergic alterations contribute to the deficits in working memory, attention, and other cognitive functions observed during aging [25,62,68,69 • ]. The pharmacological potentiation of cholinergic neurotransmission improves performance on cognitive tasks in the elderly [37,38,70], and chronic treatment with drugs that enhance the cholinergic function is used to ameliorate cognitive dysfunction in the elderly [71,72]. ...
Article
The present review develops a framework from which to understand the role of the cholinergic system in healthy cognition and in cognitive dysfunction. Traditionally, the cholinergic system has been thought to have direct influence on cognitive processes such as working memory and attention. Although the influence of cholinergic function on stimulus processing has been long appreciated, the notion that cholinergic effects on stimulus processing is the mechanism by which acetylcholine influences cognitive processes has only more recently been considered. Literature supporting the hypothesis that cholinergic modulation influences cognitive functions through stimulus processing mechanisms has been growing for over a decade. Recent conceptualizations of the developing literature have argued for a new interpretation to an old and developing literature. The argument that cholinergic function modulates cognitive processes by direct effects on basic stimulus processing extends to cognitive dysfunction in neuropathological conditions including dementia and mood disorders. Memory and attention deficits observed in these and other conditions can be understood by evaluating the impact of cholinergic dysfunction on stimulus processing, rather than on the cognitive function in general.
... Во многих преклинических исследованиях с экспериментальной моделью церебральной ишемии было выявлено, что АЛК уменьшает зону повреждения головного мозга у пожилых экспериментальных животных (крысы) [19]. На экспериментальных моделях стареющих и подвергшихся воздействию вредоносных факторов лабораторных животных было показано улучшение памяти, повышение способности к запоминанию новой информации и повышению способности к обучению в группе животных, получающих ацетил-L-карнитин [20]. ...
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An analysis of literature data on the acetyl-L-carnitine treatment in gerontological practice is performed. This review describes the range of biochemical activity and mechanism of action of the drug. The profile and specificity of acetyl-L-carnitine action and the possibility of combining nicergoline with other drugs is discussed. The results of preclinical and clinical studies on the application of acetyl-L-carnitine in the world medical practice are analyzed. The analysis of the studies demonstrates the high efficacy and a broad spectrum of acetyl-L-carnitine treatment.
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The current study was undertaken to investigate the protective role of melatonin (MEL) and acetyl-L-carnitine (ALC) against dexamethasone (DM)-induced neurotoxicity. Adult female rats (60) were divided into: (1) control group, (2) DM-treated group, (3) MEL-treated group, (4) ALC-treated group, (5) MEL- and DM-treated, and (6) ALC- and DM-treated group. Serum acetylcholinesterase (AchE) activity, malondialdehyde (MDA), nitric oxide (NO) level, catalase (CAT), superoxide dismutase (SOD) and glutathione-S-transferase (GST) activities were estimated. Gene expression of the prooxidants (NO synthases NOS-1, NOS-2 and heme oxygenases HO-1, HO-2) and antioxidant enzyme (GST-P1) as well as deoxyribonucleic acid (DNA) fragmentation analysis of brain tissue were investigated. Histological examination of the brain tissue was carried out. DM administration caused significant increase in serum AchE activity, MDA and NO levels accompanied with significant decrease in the antioxidant enzymes activity. Pretreatment with MEL or ALC prior DM has been found to reverse all the former parameters. On the genetic level, DM administration significantly increased the expression level of NOS-1, NOS-2, HO-1, and HO-2 messenger ribonucleic acids (mRNAs) and decreased that GST-P1-mRNA in brain tissue. Also, DM produced DNA fragmentation in brain tissue. Treatment with MEL or ALC prior DM administration tend to normalize the above mentioned parameters. These results were documented by the histological examination of brain tissue. The present study suggests that oxidative stress is involved in the pathogenesis of DM-induced neurotoxicity. The inhibition of oxidative stress via stimulation of the antioxidant enzymes by MEL and ALC pretreatment plays a central protective role in modulation of neurotoxicity induced by DM.
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The maximum rate (Vmax) of some enzymatic activities related to energy consumption was evaluated in synaptic plasma membranes from rat brain striatum, being the synaptic energy state a crucial factor in neurodegenerative diseases etiopathogenesis. Two types of synaptic plasma membranes were isolated from rats subjected to in vivo treatment with L-acetylcarnitine at two different doses (30 and 60 mg x kg(-1) i.p., 28 days, 5 days/week). The following enzyme activities were evaluated: Acetylcholinesterase (AChE); Na(+), K(+), Mg(2+)-ATP-ase; ouabain insensitive Mg(2+)-ATP-ase; Na(+), K(+)-ATP-ase; direct Mg(2+)-ATP-ase; Ca(2+), Mg(2+)-ATP-ase; low- and high-affinity Ca(2+)-ATP-ase. In control (vehicle-treated) animals, enzymatic activities are differently expressed in synaptic plasma membranes type I (SPM1) respect to synaptic plasma membranes type II (SPM2), being the evaluated enzymatic activities higher in SPM2. Subchronic treatment with L-acetylcarnitine decreased AChE on SPM1 and SPM2 at the dose of 30 mg x kg(-1). Pharmacological treatment decreased ouabain insensitive Mg(2+)-ATP-ase activity and high affinity Ca(2+)-ATP-ase activity at the dose of 30 and 60 mg x kg(-1) respectively on SPM1, while decreased Na(+), K(+)-ATP-ase, direct Mg(2+)-ATP-ase and Ca(2+), Mg(2+)-ATP-ase activities at the dose of 30 mg x kg(-1) on SPM2. These results suggest that the sensitivity to drug treatment is different between these two populations of synaptic plasma membranes from striatum, confirming the micro-heterogeneity of these subfractions, possessing different metabolic machinery respect to energy consumption and utilization and the regional selective affect of L-acetylcarnitine on cerebral tissue, depending on the considered area. The drug potential effect at the synaptic level in Parkinson's Disease neuroprotection is also discussed respect to acetylcholine and energy metabolism.
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Scurvy is a disease with well-known peripheral symptoms, such as bleeding and pain. The clinical and historical evidence for a distinct form of scurvy affecting the central nervous system, called neuropsychiatric scurvy, is reviewed. Pathophysiologic factors are described, as well as its diagnosis and management. Published by Elsevier Inc.
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For the purpose of promoting the utilization of venison as a functional food, we investigated the carnitine content and physical properties of venison subjected to different sous-vide (cooking by steam heating under vacuum) processing temperatures. The present work aimed to quantify free carnitine and acylcamitine using liquid chromatography-tandem mass spectrometry. Compared to meat samples heated at 100 degrees C, those heated at 80 degrees C showed a slow temperature increase and a low rate of weight loss. Moreover, heating at 80 degrees C resulted in greater hydrophilic L-carnitine and low molecular weight acetylcarnitine than heating at 100 degrees C. On the other hand, levels of hydrophobic hexanoylcarnitine, myristoylcarnitine, and palmitoylcarnitine were greater at 100 degrees C. Determinations of physical properties showed that samples heated at 80 degrees C were significantly tenderer than those heated at 100 degrees C. Furthermore, sensory evaluation results showed that samples heated at 80 degrees C scored highly in the following three attributes : toughness (palatability); umami; and overall palatability. Based on these results, we propose that heating at 80 degrees C is more desirable with respect to functionality and palatability for promoting the utilization of venison as a functional food.
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Abstract We here described the antioxidant effects of carnitine supplementation on 14-3-3 protein isoforms in the aged rat hippocampus using the fully automated two-dimensional chip gel electrophoresis system (Auto2D). This system was easy and convenient to use, and the resolution obtained was more sensitive and higher than that of conventional two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). We separated and identified five isoforms of the 14-3-3 protein (beta/alpha, gamma, epsilon, zeta/delta, and eta) using the Auto2D system. We then examined the antioxidant effects of carnitine supplementation on the protein profiles of the cytosolic fraction in the aged rat hippocampus, demonstrating that carnitine supplementation suppressed the oxidation of methionine residues in these isoforms. Since methionine residues are easily oxidized to methionine sulfoxide, the convenient and high-resolution 2-D PAGE system can be available to analyze methionine oxidation avoiding artifactual oxidation. We here showed that the Auto2D system was very useful tool for studying antioxidant effects through proteomic analysis of protein oxidation.
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Background & Aims: Diabetes mellitus is a chronic metabolic disorder that in the long-term is accompanied with deficits in learning, memory, and cognitive skills. Due to the existing evidence regarding the anti-diabetic potential of acetyl-L-carnitine (ALC), the effect of its long-term administration on learning and spatial memory deficits was investigated in diabetic rats. Methods: In this experimental study, 32 male Wistar rats were randomly divided into 4 groups: control, ALC-treated control, diabetic, and ALC-treated diabetic. ALC was injected IP at a dose of 50 mg/kg for 5 weeks after 7th day and for induction of diabetes streptozotocin was injected intraperitoneally (IP) at a single dose of 60 mg/kg. For evaluation of learning and memory, initial latency (IL) and step-through latency (STL) were determined at the end of the study using the passive avoidance test. Moreover, alternation behavior percentage, as an index of spatial memory, was obtained using Y-maze. In addition, brain malondialdehyde (MDA) level, as a marker of oxidative stress, was evaluated. Results: At the end of the study, a significant decrease was observed in STL in diabetic groups. Moreover, STL was significantly higher in the ALC-treated diabetic group than the diabetic group. Furthermore, alternation behavior percentage in both diabetic groups was lower than the control group. This parameter showed a significant increase in the ALC-treated diabetic group in comparison with the diabetic group. Administration of ALC to animals did not produce any significant changes in memory and learning in the treated control group. In addition, brain malondialdehyde level was significantly lower in the ALC-treated diabetic group than the diabetic group. Conclusion: Long-term administration of ALC at a dose of 50 mg/kg increases the ability to save information in the memory reservoir and remember in passive avoidance test, and enhances short-term spatial recognition memory in diabetic animals. This is in part due to the attenuation of brain oxidative stress. © 2015, Kerman University of Medical Sciences. All rights reserved.
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Objective: To evaluate the effectiveness of sequential therapy with levocarnitine and acetylcarnitine in patients with cardiovascular pathology (arterial hypertension and/or coronary heart disease) and moderate cognitive deficits. Material and methods: The study included 120 patients aged 54-67 years. The main group of patients (n=60) in addition to the basic treatment of the underlying disease received l-carnitine (Elkar solution for intravenous and intramuscular injection of 100 mg/ml, the company «PIK-FARMA»)/jet during 10 days in a dose of 1000 mg/day, with following transition to oral administration of acetyl-l-carnitine (Carnitin, the company «PIK-FARMA»), 500 mg (2 cap Sula) 2 times a day for 2 months. The comparison group (n=60) received basic therapy for major diseases. The total duration of follow-up was 70 days. Results: The results obtained indicate that in such comorbid patients, the use of levocarnitine and acetylcarnitine reduces the severity of cognitive deficits. An important aspect of their pathogenetic effect on the severity of cognitive deficits may be the possibility of correcting endothelial dysfunction. The use of levocarnitine and acetylcarnitine in patients with cardiovascular pathology has demonstrated good tolerability and safety.
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The identification of factors capable of enhancing neurogenesis has great potential for cellular therapies in neurodegenerative diseases. Multiple studies have shown the neuroprotective effects of L-carnitine (LC). This study determined whether neuronal differentiation of rat adipose tissue-derived mesenchymal stem cells (ADSCs) can be activated by LC. In this study, protein kinase A (PKA) and Wnt/β-catenin pathways were detected to show if this activation was due to these pathways. The expression of LC-induced neurogenesis markers in ADSCs was characterized using real-time PCR. ELISA was conducted to assess the expression of cyclic adenosine monophosphate (cAMP) and PKA. The expression of β-catenin, reduced dickkopf1 (DKK1), low-density lipoprotein receptor-related protein 5 (LRP5), Wnt1, and Wnt3a genes as Wnt/β-catenin signaling members were used to detect the Wnt/β-catenin pathway. It was observed that LC could promote neurogenesis in ADSCs as well as expression of some neurogenic markers. Moreover, LC causes to increase the cAMP levels and PKA activity. Treatment of ADSCs with H-89 (dihydrochloride hydrate) as PKA inhibitor significantly inhibited the promotion of neurogenic markers, indicating that the PKA signaling pathway could be involved in neurogenesis induction. Analyses of real-time PCR data showed that the mRNA expressions of β-catenin, DKK1, LRP5c-myc, Wnt1, and Wnt3a were increased in the presence of LC. Therefore, the present study showed that LC promotes ADSCs neurogenesis and the LC-induced neurogenic markers could be due to both the PKA and Wnt/β-catenin signaling pathway. Impact statement Neural tissue has long been believed as incapable of regeneration and the identification of cell types and factors capable of neuronal differentiation has generated intense interest. Mesenchymal stem cells (MSCs) are considered as potential targets for stem cell-based therapy. L-carnitin (LC) as an antioxidant may have neuroprotective effects in oxidative damage and possibly in neurodegenerative disorders. We have tried to evaluate the effect of LC as an antioxidant on the neurogenic differentiation of ADSCs in order to further elucidate the simultaneous effects on the capability of the neural regeneration. In this study, PKA and Wnt/β-catenin signaling pathways were detected to see if LC could also activate these pathways. The results of this study showed that 200 µM LC promoted ADSCs neurogenic differentiation, and that it was correlated with the PKA and Wnt/β-catenin signaling pathways.
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We gathered some theoretic and practical concepts related to the importance of nutrition in the prevention and management of Alzheimer disease (AD). Besides the role of nutrients in brain development and functioning, some nutrients exert special control in the development of AD, due to their participation in neurotransmitter synthesis, their modulation in epigenetics mechanisms, and as antioxidants. In addition, some non-nutrient food–derived substances have shown potential in the control of neuroinflammation and consequently in the prevention of AD. Finally, it is important to be aware of the nutritional status and food intake patterns of the patient with AD.
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Published data on the efficacy and safety of using acetyl-L-carnitine (ALC) in gerontological practice are analyzed and the spectrum of biochemical activity and mechanism of action are discussed. The profile and specificity of the actions of ALC are assessed, as is the potential for combining ALC with other drugs. Results from preclinical and clinical trials of the use of ALC in world clinical practice are analyzed. ALC has been shown to have high efficacy and a wide spectrum of actions. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.
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Parkinson disease (PD) is the second most common neurodegenerative disorder with approximately 60 000 newly diagnosed patients yearly in the United States. PD is traditionally described as a motor system condition, although numerous nonmotor symptoms exist, and typically manifest within elderly patients. The hallmark pathogenesis of PD is the loss of dopaminergic neurons within the substantia nigra region. This leads to a traditional treatment goal of dopamine replacement. We outline an integrative medicine and health strategy for PD that utilizes not only traditional but also nontraditional therapeutic approaches. This strategy supports the neuronal microenvironment and restorative health of both the brain and the body.
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The maximum rates (V max) of some enzymatic activities related to energy consumption (ATP-ases) were evaluated in two types of synaptic plasma membranes (SPM) isolated from cerebral cortex of rats subjected to in vivo treatment with l-acetylcarnitine at two different doses (30 and 60 mg kg−1 i.p., 28 days, 5 days/week). The following enzyme activities were evaluated: acetylcholinesterase (AChE); Na+, K+, Mg2+-ATP-ase; ouabain insensitive Mg2+-ATP-ase; Na+, K+-ATP-ase; direct Mg2+-ATP-ase; Ca2+, Mg2+-ATP-ase; Low- and High-affinity Ca2+-ATP-ase. Sub-chronic treatment with l-acetylcarnitine increased Na+, K+-ATP-ase activity on SPM 2 and Ca2+, Mg2+-ATP-ase activity on both SPM fractions. These results suggest (1) that the sensitivity to drug treatment is different between the two populations of SPM, confirming the micro-heterogeneity of these sub-fractions, probably originating from different types of synapses, (2) the specificity of the molecular site of action of the drug on SPM and (3) its interference on ion homeostasis at synaptic level.
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Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.
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Acetylcholine may set the dynamics of cortical networks to those appropriate for learning of new information, while decreased cholinergic modulation may set the appropriate dynamics for recall. In slice preparations of the olfactory cortex, acetylcholine selectively suppresses intrinsic but not afferent fiber synaptic transmission, while decreasing the adaptation of pyramidal cells. In biologically realistic models of this region, the selective suppression of synaptic transmission prevents recall of previously learned memories from interfering with the learning of new memories, while the decrease in adaptation enhances the response to afferent input and the modification of synapses. This theoretical framework may serve to guide future studies linking neuromodulators to cortical memory function.
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To evaluate whether any degenerative changes affect the brain cholinergic systems during natural aging, we compared various cholinergic biochemical markers (number of muscarinic receptors, mAChR; choline acetyltransferase activity, ChAT; acetylcholinesterase activity, AChE; and sodium-dependent high affinity choline uptake) in the cortical (CR) and subcortical (SS) regions of the brains of aged (24 month) and young (2 month) rats. Using [3H]-quinuclidinyl benzilate ([3H]-QNB) as the ligand of muscarinic receptor binding, the numbers of mAChR decreased about 30% in both the CR and the SS of aged rats compared with those in young rats, while a significant age-related increase in the affinity of mAChR was observed. [3H]-QNB binding in both the young and aged rat brain was displaced markedly by pirenzepine, while [3H]-QNB binding in the SS of the aged rat brain was displaced at low concentrations of atropine. The Vmax values of ChAT and AChE also decreased about 20-30% compared with those of young rats. The sodium-dependent high affinity choline uptake was lower in the crude synaptosomal fraction prepared from aged rat brain than in young brain. Hemicholinium-3 inhibited the choline uptake in young rat brain at a concentration range of 1 microM-10 nM, but choline uptake in aged brain was insensitive to hemicholinium-3. These results indicate that natural aging brings about a diffuse and multiple depletion of various biochemical markers in cholinergic neurons.
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Aged rats have impairments in several types of cognitive functions, including spatial working memory (WM), that are dependent upon the septohippocampal cholinergic system. The present series of experiments was designed to assess the effectiveness of pharmacological manipulations of the medial septal area (MSA) in order to influence the physiology of the septohippocampal pathway and, therefore, the brain functions in which this pathway participates. Aged (22MO) and young (4MO) Fischer-344 rats received microinfusions into the MSA with either saline, the muscarinic agonist, oxotremorine (OXO), or the muscarinic antagonist, scopolamine (SCOP). Working memory was tested in a T-maze spatial alternation task, prior to infusion, immediately after infusion, and 90 min after infusion. Hippocampal theta activity and the population excitatory postsynaptic potential (pEPSP) of the dentate gyrus to perforant path stimulation were recorded immediately following behavioral testing at each of the three time periods. In 22MO rats, intraseptal OXO (0.5 micrograms, 2 micrograms, 5 micrograms) produced a dose-dependent improvement in choice accuracy, a shift of the hippocampal theta peak to a lower frequency and a higher peak power, and an increase in the initial slope of pEPSP. OXO, 0.1 microgram, did not have an effect on behavior or hippocampal physiology and OXO, 10 micrograms, produced an impairment in performance. In 4MO rats, OXO did not affect choice accuracy, nor the pEPSP slope, but altered hippocampal theta peak frequency and power similarly as in 22MO. The lowest behaviorally effective dose, 0.5 microgram OXO, did not influence WM performance when infused into the lateral ventricles (intracerebroventricularly) of either 22MO or 4MO rats. SCOP (2 micrograms, 5 micrograms, 15 micrograms) decreased choice accuracy in a dose-dependent fashion in both 22MO and 4MO rats. However, in 22MO rats, the behavioral dose-response curve for scopolamine was shifted towards greater sensitivity. SCOP produced a shift of the hippocampal theta to a higher frequency and a lower peak power, and a decrease in the initial slope of pEPSP. In 4MO rats, SCOP altered hippocampal theta similarly to 22MO, but did not affect the pEPSP slope. These results indicate that (1) cholinergic receptors in the MSA are a useful target for drugs to improve WM in aging rats, (2) age-related changes in the activity of the septohippocampal pathway may increase its sensitivity to drugs which alter its activity, and (3) alterations in hippocampal physiology may contribute differently to changes in WM in young and in old rats.
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Monkeys with immunotoxic lesions of both the basal nucleus of Meynert and the vertical limb of the diagonal band of Broca (NBM+VDB) lost cholinergic innervation throughout the cortex and hippocampus. They were impaired at learning discriminations between objects differing in either few, or many, attributes and at learning visuospatial conditional discriminations. Monkeys with immunotoxic lesions of the NBM lost cholinergic innervation of the neocortex only. Initially, they were unable to learn a simple visual discrimination where the stimuli differed in a limited number of attributes but they were unimpaired at learning discriminations between objects that differed in more attributes. They were mildly impaired at learning a visuospatial conditional task. The impairment exhibited by monkeys with lesions of the NBM alone ameliorated with time but that following NBM+VDB lesions did not. Previous experiments have shown that monkeys with immunotoxic lesions of the VDB alone are impaired at learning visuospatial conditional discriminations but are unimpaired at learning simple visual discriminations. When monkeys with NBM lesions were given excitotoxic lesions of the CA1 field of the hippocampus the learning impairment on discriminations between objects which differed in few attributes was reinstated. Pretreatment with a cholinergic agonist improved learning ability on visual discrimination learning in all monkeys but this improvement was significantly greater in monkeys with lesions of the NBM. On conditional discrimination learning, which is particularly sensitive to hippocampal damage, pilocarpine produced a significant improvement in monkeys with NBM+VDB lesions (where the hippocampal dysfunction was cholinergic) but not in monkeys with NBM+CA1 lesions (where the hippocampal damage was structural).
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Carnitine (L-3-hydroxy-4-N-trimethylaminobutyric acid) forms esters with a wide range of acyl groups and functions to transport and excrete these groups. It is found in most cells at millimolar levels after uptake via the sodium-dependent carrier, OCTN2. The acylation state of the mobile carnitine pool is linked to that of the limited and compartmentalised coenzyme A pools by the action of the family of carnitine acyltransferases and the mitochondrial membrane transporter, CACT. The genes and sequences of the carriers and the acyltransferases are reviewed along with mutations that affect activity. After summarising the accepted enzymatic background, recent molecular studies on the carnitine acyltransferases are described to provide a picture of the role and function of these freely reversible enzymes. The kinetic and chemical mechanisms are also discussed in relation to the different inhibitors under study for their potential to control diseases of lipid metabolism.
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Alzheimer’s disease is a devastating illness that will become more common as the population ages. Although clinical diagnosis of the illness is not certain without histological examination of the brain, and misdiagnosis may occur, broad working criteria to help diagnose the likely presence of Alzheimer’s disease are available. Thoughtful clinical evaluation improves diagnostic accuracy, and appropriately diagnosed patients are critical for involvement in research into new antidementia agents. Essential to the discovery of new drugs is careful measurement of illness response. A variety of scales — some aimed at patients, others at their caregivers, and yet others for clinicians — assess Alzheimer’s disease severity, progression, symptom response, and quality of life. Of note, patient response is not the only measurement of treatment benefit today. Growing interest is also being placed on tracking the possible amelioration of caregiver ‘burden’. This burden refers to the psychological, physical, and material costs of providing care for an Alzheimer’s patient over long periods of time. A number of scales and questionnaires have been developed and are occasionally used. Many drugs have been tried in Alzheimer’s disease, but very few have produced any benefit, and this is often modest. Ergoloid mesylates, initially thought to be effective, are now considered of little value. The cholinomimetic drugs, especially the acetylcholinesterase inhibitor tacrine, have provided a very modest benefit, slowing the progression of the illness for a number of months. No cognitive improvement has been noted with the various nootropic agents such as piracetam. Early studies with levacecarnine (acetyl-L-carnitine), a substance that facilitates the use of fatty acids, memantidine, the dimethyl derivative of amantidine, and the calcium channel blocker nimodipine, have shown some promise, but require larger, more rigorous studies. As mentioned above, documenting effects in individual patients is crucial; examining for potential benefit to caregivers is a growing part of research design. Current treatment efforts will become more sophisticated as a deeper understanding of the neurobiology of Alzheimer’s disease develops. For the immediate future, the goal is not cure but slowing of the disease process. Achieving this limited goal would have a substantial impact on the financial and human costs of the illness.
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(This reprinted article originally appeared in the Journal of Experimental Psychology, 1946, Vol 36, 13–24. The following abstract of the original article appeared in PA, Vol 20:2297.) The original rough formulation of the expectancy theory is difficult to distinguish from the alternative stimulus-response doctrines, partly because of the implicit definition of the matrix " x expects a goal at location L " which makes it equivalent to the matrix " x runs down the practiced path" when certain conditions are fulfilled. A substitute definition is suggested which makes the former matrix equivalent to " x runs down the path which points directly to the location L " when certain conditions are fulfilled. To determine whether the class defined by this latter definition has members, 56 "maze-wise" female rats were trained to run in a simple maze to obtain food. When the original path was blocked and a choice among 18 different paths was presented, 36% chose the path pointing directly toward the goal. The other rats chose the other paths in a chance fashion… (PsycINFO Database Record (c) 2012 APA, all rights reserved)
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Although L-carnitine is not considered as an essential nutrient, endogenous synthesis may fail to ensure adequate L-carnitine levels in neonates, especially those born prematurely. Free L-carnitine is found in many foods, mainly those from animal sources. Absorption of free L-carnitine is virtually complete. Lysine and methionine are necessary ingredients for the biosynthesis of L-carnitine. All tissues in the body can produce deoxy-carnitine but, in humans, the enzyme that enables hydroxylation of deoxy-carnitine to carnitine is found only in the liver, brain and kidneys. Complex exchanges of carnitine and its precursors occur between tissues. Muscles take up carnitine from the bloodstream and contain most of the body carnitine stores. L-carnitine and L-carnitine esters are eliminated mainly through the kidneys, which may play a central role in the homeostasis of this compound. Thyroid hormones adrenocorticotrophin (ACTH), and diet all influence urinary excretion of L-carnitine. Free L-carnitine can be assayed in plasma and urine and is occasionally measured in muscle biopsy specimens. Plasma L-carnitine levels may not accurately reflect L-carnitine body stores. L-carnitine ensures transfer of fatty acids to the mitochondria where they undergo oxidation. This process is associated with production of short-chain acylcarnitine which exit from the mitochondria or peroxisomes. L-carnitine ensures regeneration of coenzyme A and is thus involved in energy metabolism. L-carnitine also ensures elimination of xenobiotic substances. Carnitine deficiencies are common. Currently, these deficiencies are classified into two groups. In deficiencies with myopathy, only the muscles are deficient in L-carnitine, perhaps as a result of a primary anomaly of the L-carnitine transport system in muscles. In systemic deficiencies, L-carnitine levels are low in the plasma and in all body tissues. Systemic L-carnitine deficiencies are usually the result of a variety of disease states including deficient intake in premature infants or long-term parenteral nutrition; renal failure; organic acidemias; and Reye's syndrome. Modifications in L-carnitine metabolism have also been reported in patients with diabetes mellitus, malignancies, myocardial ischemia, and alcohol abuse. A large number of supplementation trials have been carried out.
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Rats distributed over five different age groups, 3, 12, 18, 24 and 30 months of age, were screened for their spatial learning and memory ability in the Morris water maze, and the degree of place navigational impairments was correlated with morphological changes in the four major forebrain cholinergic cell groups (medial septum, MS; vertical limb of the diagonal band of Broca, VDB; nucleus basalis magnocellularis, NBM; and striatum) using choline acetyltransferase (ChAT) and nerve growth factor receptor (NGFr) histochemistry. Impaired place navigation developed progressively with age, such that 8% of the 12-month-old rats, 45% of the 18-month-old, 53% of the 24-month-old, and over 90% of the 30-month-old rats were behaviorally impaired. Significant reductions in the number of ChAT/NGFr-positive cell bodies, amounting to between 19 and 45%, were observed in all four cell groups, and the remaining cells were reduced in size (6-24% reduction in cross-sectional area in the oldest age groups). Although the morphological changes were less severe and tended to develop later than the behavioral impairments, there was overall a significant correlation between water maze performance and ChAT/NGFr-positive cell counts, and to a lesser degree also cell size in all four cell groups. These changes were also highly correlated with age. The highest correlations were seen in MS, VDB and NBM, which are known to play a role in spatial memory performance in young rats. The results indicate that degenerative and/or atrophic changes in the forebrain cholinergic system and decline in spatial learning ability are parallel processes during aging. Although the magnitude of the morphological changes does not appear to be substantial enough, by itself, to explain the severe spatial learning impairments that develop in the oldest animals, the present data are consistent with the view that impaired function in the forebrain cholinergic system can contribute to age-dependent cognitive decline in rodents.
Article
1. Population excitatory postsynaptic potentials (EPSPs) and population spikes evoked in area CA1 of hippocampal slices from aged Fischer 344 rats were significantly smaller in amplitude than responses obtained in slices from young Fischer 344 rats. 2. The A1 adenosine receptor antagonist 8-cyclopentyltheophylline (8-CPT) produced a concentration-dependent increase in synaptic potentials in slices from both young and aged rats. Low concentrations (1 nM) of 8-CPT were effective in producing increases in both population spike amplitudes and population EPSP slopes in young and aged rat slices. Response increases were maximized by 100 nM 8-CPT in slices from rats of both age groups. 3. Adenosine antagonism produced greater average increases in synaptic responses in hippocampal slices from aged rats at all concentrations tested (1.0 nM-1.0 microM). A qualitative age-related difference in the response to 8-CPT was also observed; 8-CPT produced a late component, consisting of multiple population spikes, in evoked responses in slices obtained from aged but not young rats. 4. Adenosine antagonism significantly increased the maximum evocable response (both spike amplitude and EPSP slope) in slices from aged rats, relative to increases observed in slices from young rats. This suggested that smaller synaptic potentials seen in slices from aged rats were in part due to greater levels of "tonic" adenosinergic inhibition. 5. Slices from young and aged rats were incubated in the adenosine reuptake inhibitor soluflazine (R64719; 1.0, 10, and 100 microM) and the inhibition of population EPSPs was observed for 60 min. No difference was observed in the rate of inhibition or the maximal level of inhibition produced by soluflazine, in slices from rats of either age group. 6. Application of (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclo-hepten- 5,10-imine hydrogen maleate (MK-801) and 2-amino-5-phosphonopentanoic acid (2-AP5), antagonists of N-methyl-D-aspartate (NMDA) excitatory amino acid (EAA) receptors, reduced the late multiple population spike component in slices from aged rats incubated in 8-CPT. A smaller direct effect of the NMDA antagonists was observed in slices from aged rats in the absence of 8-CPT treatment at maximal response levels. No effect of NMDA receptor antagonism was observed in slices from young rats under either condition. 7. Hippocampal tissue, from young and old rats utilized in the electrophysiological experiments, was assayed for A1 adenosine binding site density with a saturating concentration of radiolabeled agonist and antagonist. Guanine nucleotide modulation of agonist binding was also measured.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
1. The original rough formulation of the expectancy theory is difficult to distinguish from the alternative stimulus-response doctrines. Part of this difficulty results from the fact that implicit in this rough formulation, is a definition of the matrix "x expects a goal at location L," which makes it equivalent to the matrix "x runs down the practiced path," when certain conditions are fulfilled. Because of this difficulty, we have rejected this definition. 2. We have suggested instead a definition of the matrix "x expects a goal at location L" which makes it equivalent to the matrix "x runs down the path which points directly to the location L," when certain conditions are fulfilled. 3. To determine whether rats will run down such a path, whenever the original path is blocked, we have run 56 female rats in a situation which conformed to these conditions. 4. Thirty-six percent of the rats chose the path which pointed directly towards the location of the goal. The remaining rats were distributed over the other paths in a chance fashion. 5. We have concluded (1) that rats do learn to expect goals in specific locations, (2) that there are important similarities between this behavior and human symbolic behavior, and (3) that these similarities justify our using the word 'expectation' as a name for the disposition to short-cut when the original patch is blocked.
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Preliminary data are reported from a multicentred double-blind placebo-controlled study concerned with the effects of acetyl-L-carnitine (LAC) on some cognitive deficits of at least one month-abstinent alcoholics. Fifty-five patients, showing impaired performance in at least two out of six mnemonic, praxic and verbal tasks, were randomly assigned to either LAC 2 g/day or a placebo group. They were tested by means of a neuropsychological battery exploring the areas of memory, constructional praxia, deductive-logical functions and language. Testing time was on baseline (T0), after 45 (T45) and 90 (T90) days. On the Rey's 15 word memory test (long-term), the Wechsler memory scale (logical memory), and the Similarities WAIS subtest, the T90 difference between LAC and the placebo was significant in favour of the former treatment. On the copying drawing test (simple copy), the placebo group did not show any T0-T90 variation, while significant improvement in the LAC group was greater than in the placebo group. As LAC has proved to ameliorate the performance or to accelerate the recovery on tests representative of all cognitive areas explored, it is conceivable that the drug acts diffusely, either at the cholinergic transmission or at the neuronal metabolism level. It is concluded that acetyl-L-carnitine can be a useful and safe therapeutic agent in the subtle cognitive disturbances of chronic alcoholics.
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Synthesis of [3H]acetylcholine from [3H]acetyl-L-carnitine was demonstrated in vitro by coupling the enzyme systems choline acetyltransferase and carnitine acetyltransferase. Likewise, both [3H] and [14C] labeled acetylcholine were produced when [3H]acetyl-L-carnitine and D-[U-14C] glucose were incubated with synaptosomal membrane preparations from rat brain. Transfer of the acetyl moiety from acetyl-L-carnitine to acetylcholine was dependent on concentration of acetyl-L-carnitine and required the presence of coenzyme A, which is normally produced as an inhibitory product of choline acetyltransferase. These results provide further evidence for a role of mitochondrial carnitine acetyltransferase in facilitating transfer of acetyl groups across mitochondrial membranes, thus regulating the availability in the cytoplasm of acetyl-CoA, a substrate of choline acetyltransferase. They are also consistent with a possible utility of acetyl-L-carnitine in the treatment of age-related cholinergic deficits.
Article
The release of endogenous and newly synthesized acetylcholine (ACh) was examined in neostriatal slices prepared from young adult (10-month) and aged (28-month) Fischer 344 rats. Both spontaneous and potassium-stimulated release were tested after various in vitro incubation times (1, 3 or 5 hr). The potassium-stimulated release of ACh from slices of 28-month rats was decreased by 53% when tested after incubating the slices 1 hr. The age-related differences in ACh release lessened if the slices were incubated for longer times (3 or 5 hr) before monitoring release. The spontaneous release of ACh was similar among the slices from both age-groups and at all times points monitored. When the neostriatal slices were incubated in medium supplemented with deuterated choline, the release of both the endogenous and newly synthesized ACh from slices of 28-month rats was decreased by 33% when tested after a 1-hr incubation, but was again similar to that released from slices of 10-month rats when tested after a 3-hr incubation. Choline release from slices of the 28-month rats was similar to that released from the slices of the 10-month rats when acetylcholinesterase (AChE) was inhibited during the release incubation. In slices with intact AChE activity, however, the age-related difference in choline release was similar to that observed for ACh release when AChE was inhibited. That is, when AChE activity was intact, the potassium-stimulated choline release from slices of 28-month rats was less than that released from slices of 10-month rats when release was tested after a 1-hr incubation.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Galanin coexists with acetylcholine in medial septal neurons projecting to the ventral hippocampus, a projection thought to modulate memory functions. Neurochemical lesions of the nucleus basalis-medial septal area in rats impaired choice accuracy on a delayed alternation t-maze task. Acetylcholine (7.5 or 10 micrograms intraventricularly or 1 micrograms micro-injected into the ventral hippocampus) significantly improved performance in the lesioned rats. Atropine (5 mg/kg intraperitoneally or 10 micrograms intraventricularly), but not mecamylamine (3 mg/kg intraperitoneally or 20 micrograms intraventricularly), blocked this action of acetylcholine, suggesting involvement of a muscarinic receptor. Galanin (100-500 ng intraventricularly or 200 ng into the ventral hippocampus) attenuated the ability of acetylcholine to reverse the deficit in working memory in the lesioned rats. The antagonistic interaction between galanin and acetylcholine suggests that endogenous galanin may inhibit cholinergic function in memory processes, particularly in pathologies such as Alzheimer disease that involve degeneration of basal forebrain neurons.
Article
The effect of aging and subchronic treatment with acetyl-L-carnitine (50 mg/kg per day) was studied on mitochondrial bioenergetics and cholinergic metabolism in non-synaptic mitochondria and synaptosomes isolated from cerebral cortex, hippocampus and striatum of rats aged 4, 11 and 18 months. Respiratory activity and cytochrome oxidase specific activity were unaffected by aging in non-synaptic mitochondria. In synaptosomes, pyruvate dehydrogenase, choline acetyltransferase and acetylcholinesterase specific activity remained unchanged, but the high-affinity choline uptake decreased in cerebral cortex and striatum of 18-month-old rats. Acetyl-L-carnitine treatment increased the high-affinity choline uptake in cerebral cortex of 18-month-old rats. The treatment caused also an increase in cytochrome oxidase activity in all the three cerebral regions and in choline uptake in the hippocampus, parameters that were not directly affected by aging processes.
Article
The capacity of calcium ions to trigger acetylcholine release was studied in cerebral cortical synaptosomes from adult (6-month-old) and senescent (24-month-old) rats, using a calcium ionophore, A23187, that bypasses voltage-sensitive calcium channels. The potency but not the efficacy of the A23187 was reduced with respect to releasing acetylcholine (ACh) in the aged animals. There was no age-related difference in the synthesis of ACh or potency of the ionophore with respect to increasing 45calcium uptake. These results suggest that aging reduces the sensitivity of cerebral cortical nerve terminals to calcium-triggered ACh-release.
Article
Microdissection techniques were utilized to measure the activity of choline acetyltransferase (ChAT) (enzyme responsible for synthesis of acetylcholine) in individual basal forebrain nuclei of aged (24 month) and young (4 month) male and female rats. Small but consistent decreases in the activity of ChAT in aged rats were found, and the location of the changes was dependent on the sex of the rat. Aged female rats showed approximately 30% lower ChAT and 40% lower acetylcholinesterase (AChE) activity in the ventral globus pallidus (vGP). Aged males did not show decreased ChAT in the vGP but activity in the medial aspect of the horizontal diagonal band nucleus was 50% lower than in the young males. ChAT activity in four other closely aligned basal forebrain nuclei was not different between the young and aged rats. Analysis of cell number, density and area in the vGP by AChE histochemistry showed no significant differences between aged and young females. In addition, age and sex-dependent changes were measured in pituitary glucose-6-phosphate dehydrogenase activity. The relationship of the changes to age-dependent decrements in memory, the possible influence of gonadal hormones on aging, and the mechanisms responsible for age-related declines in ChAT activity are discussed.
The aim of this study was to evaluate the efficacy and tolerability of L-acetylcarnitine therapy in the senile brain. The trial was conducted on a double-blind basis, with a total of 40 patients divided into two groups of 20, treated for 40 days with L-acetylcarnitine and placebo, respectively--the therapeutic regimen being two 500 mg tablets t.i.d. Mental parameters of the senile brain were assessed at 0, 20 and 40 days of treatment, while basal and final values were recorded for a number of laboratory tests. Statistical analysis of results confirmed that short-term, intensive L-acetylcarnitine treatment can determine a significant improvement of the main mental parameters of the senile brain, without incidence of significant side effects.
Article
Perfused rat liver was shown to be the proper model for studies on hepatic cellular transport of carnitine. During recirculating perfusion the livers kept equilibrium with 45 nmol/ml total carnitine in perfusate, exhibited concentrative uptake and there was no sign of artificial leakage. The release side of the carnitine transport was characterized by utilizing outflow perfusions. The livers from fed rats exported daily 9.93 mumol per 100 g body weight total carnitine. This release rate is 4- or 10-fold higher than the estimated daily turnover in vivo or the measured urinary excretion. Therefore, the major part of the released carnitine has to re-enter the liver. The outward carnitine transport does not depend on energy or the Na+-K+ pump, since it did not respond to metabolic poisons and ouabain. However, the release rate was strongly inhibited by mersalyl and showed saturability in function of tissue carnitine levels. The Vmax of the saturable outward transport system was 2.47 nmol . min-1 . g-1 liver, the apparent Km was 0.27 mM tissue level (both as compared to total carnitine). These data showed the outward transport of carnitine from the liver to be protein mediated. The contribution of a diffusion (nonsaturable) component was estimated to be 20-25% in the range of tissue levels occurring in vivo. The rate of carnitine release from the liver decreased as an effect of 24 h starvation from the daily 9.92 mumol release to 6.55 mumol on 100 g body weight basis. This decrease is more pronounced when the release rates are expressed on the basis of tissue carnitine levels. The resulting value can be called rate constant (at the linear part of the saturation curve, Fig. 5) and it decreased to 5.00 min-1 from 8.41 min-1 as an effect of starvation. We have concluded that the altered parameters of carnitine transport across the liver cell is decisive in developing the higher hepatic carnitine concentration in the fasted state.
Article
1. [14C]Acetylcholine synthesis and 14CO2 production from [U-14C]glucose has been measured in tissue prism preparations from human neocortex. 2. Electron micrographs of prisms from human and rat neocortex show that both contain intact synaptic endings with evenly-distributed vesicles and normal-appearing mitochondria, but only poorly preserved cell body structure. 3. Synthesis of [14C]acetylcholine in prisms from rat neocortex is similar to estimates for turnover in vivo. Synthesis in prisms from human neocortex is 18% of that in rat tissue and 64% of that in tissue from baboon neocortex for incubations performed in 31 mM-K+. 4. Investigations of prisms prepared from rat brains stored at 37 degrees C after death revealed that synthesis of [14C]acetylcholine in the presence of 31 mM-K+ was greatly decreased within 30 min of post-mortem incubation, whereas synthesis at 5 mM-K+ and production of 14CO2 at both K+ concentrations were only significantly affected after longer periods. Changes were similar in neocortex and striatum. Thus human autopsy material is unlikely to be suitable for use with this system. 5. Investigations using animal models suggest that [14C]acetylcholine synthesis and 14CO2 production are not affected by surgical or anaesthetic procedures. 6. Neither [14C]acetylcholine synthesis nor 14CO2 production in human prisms was significantly changed with age between 15 and 68 years. 7. Samples from patients with the dementing condition Alzheimer's disease showed a significant decrease in [14C]acetylcholine synthesis to 47% of normal samples and a significant increase of 39% in production of 14CO2.
Article
Production of [14C]acetylcholine and 14CO2 was examined by using tissue prisms from neocortex, hippocampus, and striatum from rats aged approximately 5 months, 13 months, and 27 months. [14C]Acetylcholine synthesis in the striatum showed highly significant decreases with age for measurements in the presence of both 5 mM- and 31 mM-K+, contrasting with the lack of significant change in 14CO2 production in this region. The neocortex and hippocampus showed only small changes, especially when comparison was made between 13-month and senescent animals. Measurements of the release of [14C]acetylcholine and influence of atropine on this release confirmed the relative stability with age of the cholinergic system in the neocortex.
Article
Acetylcholine release from cortical slices superfused with choline-enriched Krebs solution containing physostigmine was investigated at birth, at 7, 20 and 30 days, and at 3 and 24 months of age, in order to assess age influence on the functional efficiency of the cortical cholinergic network. The slices were electrically stimulated at frequencies from 1 to 10 Hz for 5 min periods, preceded and followed by rest periods. The superfusate was collected every 5 min and acetylcholine content quantified by bioassay. In the newborn and 7 day-old pups acetylcholine release was approximately 50% lower than that of the 3 month-old rats at all frequencies tested. The highest release was elicited in the 30 day-old rats. Beginning with this age the evoked ACh release underwent a decline which in the 24 month-old rats brought it back to the same level as in the newborn ones. The blockade of the muscarinic autoreceptors by atropine 1.5 X 10(-8) M caused an increase in acetylcholine release at 20 day, 3 and 24 months of age but not in the newborn and 7 day-old pups. Adenosine 3 X 10(-5) M decreased acetylcholine output in newborn and adult but had no effect in the senescent rats.
Article
L-Carnitine transport was studied in cultured muscle cells and skin fibroblasts of patients with primary systemic carnitine deficiency and control subjects. In both cell culture types, two systems for carnitine transport were identified. The kinetic parameters for carnitine transport were remarkably similar in cultured muscle cells and skin fibroblasts. Normal rates and kinetic properties of carnitine transport were observed for both cell lines from patients with systemic carnitine deficiency. These studies do not rule out a defect in carnitine transport in vivo.
Article
The synthesis of whole brain acetylcholine is reduced in two strains (C57BL and BALB/c) of senescent mice. The incorporation of [U-14C]glucose into acetylcholine decreased in both strains by 40 +/- 4 per cent in 10-month-old mice and by 58 +/- 9 percent in 30-month-old mice compared with mice 3 months old. The incorporation of [2H4]choline into acetylcholine declined 60 and 73 percent in 10- and 30-month-old mice, respectively. Deficits in the cholinergic system may contribute to brain dysfunctions that complicate senescence.
Article
A new generation of cholinesterase inhibitors is expected to overcome some limitations of the therapeutic use of anticholinesterases. Phenserine is a long-acting and selective inhibitor of acetylcholinesterase with a preferential brain uptake. We have assessed the effects of chronic phenserine tartrate treatment on performance of aged Fischer-344 rats in the 14-unit T-maze. Phenserine (1-3 mg kg-1, i.p.) treatment for 5 days significantly reduced the number of errors made in the Stone maze. Other performance variables were also improved. No side effects were noted across 5 days treatment at doses of 1-2 mg kg-1. Phenserine can therefore improve the performance of aged rats in this complex maze task without producing obvious side effects.
Article
Aged rats were chronically administered acetyl-L-carnitine (AC) for 10 months. During this period they were tested on learning and sensorimotor tasks and were then subsequently tested electrophysiologically to assess induction and decay rates of long-term synaptic enhancement (LTE) in the hippocampus. Four groups were tested: young controls (4 mo-con), middle-aged controls (16 mo-con), old controls (24 mo-con), and old AC-treated rats (24 mo-AC). After completion of electrophysiological testing, each rat was sacrificed and investigated for age- or drug-related changes in three neurotransmitter markers; including, NMDA-sensitive glutamate receptors, high affinity choline uptake, and adenosine receptor number in the neocortex, hippocampus or caudate nucleus. Aging impaired spatial learning and there was a robust positive correlation between NMDA receptors in the hippocampus and acquisition of the spatial learning task. Induction of hippocampal LTE was reduced in 24 mo-AC rats and NMDA receptor number and high-affinity choline uptake in the frontal cortex was increased. Several suggestions are offered to explain the action of AC on these neurobiological parameters in old rats.
Article
Isolated nerve terminals were prepared from the neocortices and striate cortices of Fischer 344 rats from 6 to 26 months of age and then assayed for release of newly synthesized [3H]acetylcholine (ACh) triggered by secretagogues with different mechanisms of action: 35 mM K+, 10 microM veratridine and 5 microM A23187. Secretagogue-induced release of newly synthesized [3H]ACh decreased with age in both brain regions, with reductions in A23187-induced release paralleling those seen with depolarizing agents. This observation was consistent with the hypothesis that aging attenuates the release-triggering ability of calcium ions coincident with or before it affects voltage-sensitive calcium influx. In neocortex, phorbol-stimulated translocation of protein kinase C (PKC) activity was attenuated in isolated nerve terminals concomitantly with A23187-induced release deficits. These results suggest that one of the earliest deficits in the ACh-release process may involve intracellular calcium potency, which may be associated with the onset of functional PKC deficits. Both brain regions also displayed gradual, age-related reductions in [3H]ACh synthesis, but this effect was more pronounced in the striatum. Choline acetyltransferase (CAT) activity decreased only in the striatum with aging.
Article
To assess neurochemical and neuroanatomical correlates of age and spatial learning, aged Sprague-Dawley male rats (20-22 mo) were divided into two groups based on their ability to locate a hidden platform in a Morris water maze. An "old good" group of rats acquired the task as rapidly as young (3-6 mo) animals, whereas an "old poor" group of rats failed to show improvement on subsequent testing days. Age-related changes included (a) a significant decrease in the number of choline acetyltransferase (CHAT) immunoreactive cells in the ventral cell group of the septal complex (28%); (b) a decrease in caudate dopamine levels (-11%); and (c) an increase in 5-HIAA levels in the n. accumbens (+25%) and hippocampus (+18%). Spatial learning related changes in aged rats included: (a) an increase in medial frontal cortex 5-HIAA levels (52%) in the old good learners but not old poor learners with (b) a decrease in medial frontal cortex dopamine levels (-24%) only in the old poor learners group and (c) a decrease in n. accumbens DOPAC (-22%) and HVA (-23%) in the old good learners group only. The present study demonstrates age-related but not spatial learning related decrease in CHAT immunoreactive cells in the ventral cell group of the septal complex. Therefore, either the cholinergic cell loss in the septum is unrelated to the acquisition of spatial learning measured by the Morris water maze, or it is a permissive effect along with specific alterations in forebrain dopaminergic and serotonergic systems, particularly in the medial frontal cortex and n. accumbens. The above findings are consistent with findings seen in Alzheimer's disease where both basal forebrain cholinergic nuclei and cortical projecting brainstem monoamine systems are affected.
Article
We examined Fisher 344 female rats aged 6, 27, and 33 months old. Prior to sacrifice and morphometric analyses of forebrain cholinergic neurons all rats underwent behavioral characterization in a spatial learning task using the Morris water maze. Performance on the spatial task permitted subsequent grouping of the 27- and 33-month-old animals into impaired or nonimpaired groups. Importantly, the percentage of animals that displayed spatial impairments increased sharply with advancing age. Quantitative assessment of the size and density of choline acetyltransferase (ChAT)-positive neurons throughout the basal forebrain revealed a significant enlargement of forebrain cholinergic neurons within 27-month-old nonimpaired rats compared to 6-month-old rats and 27- and 33-month-old impaired animals. This increase in size was most noted in the medial septum and nucleus of the diagonal band. Significant decreases in the density of ChAT-positive neurons was observed only in the nucleus of the diagonal band of 27-month-old impaired rats compared to 6-month-old controls. Although the significance of enlarged forebrain cholinergic neurons is unclear, we discuss the possibility that within aged rodents neuronal swelling is an active event and represents an early manifestation of the aging process and may constitute a restorative and/or compensatory event in that these rats are relatively asymptomatic with respect to their behavioral deficits. In addition, we discuss in some detail various technical and life effect issues which may vary the outcome of investigations of aged rodents.
Article
Alzheimer's disease is a devastating illness that will become more common as the population ages. Although clinical diagnosis of the illness is not certain without histological examination of the brain, and misdiagnosis may occur, broad working criteria to help diagnose the likely presence of Alzheimer's disease are available. Thoughtful clinical evaluation improves diagnostic accuracy, and appropriately diagnosed patients are critical for involvement in research into new antidementia agents. Essential to the discovery of new drugs is careful measurement of illness response. A variety of scales--some aimed at patients, others at their caregivers, and yet others for clinicians--assess Alzheimer's disease severity, progression, symptom response, and quality of life. Of note, patient response is not the only measurement of treatment benefit today. Growing interest is also being placed on tracking the possible amelioration of caregiver 'burden'. This burden refers to the psychological, physical, and material costs of providing care for an Alzheimer's patient over long periods of time. A number of scales and questionnaires have been developed and are occasionally used. Many drugs have been tried in Alzheimer's disease, but very few have produced any benefit, and this is often modest. Ergoloid mesylates, initially thought to be effective, are now considered of little value. The cholinomimetic drugs, especially the acetylcholinesterase inhibitor tacrine, have provided a very modest benefit, slowing the progression of the illness for a number of months. No cognitive improvement has been noted with the various nootropic agents such as piracetam. Early studies with levacecarnine (acetyl-L-carnitine), a substance that facilitates the use of fatty acids, memantidine, the dimethyl derivative of amantidine, and the calcium channel blocker nimodipine, have shown some promise, but require larger, more rigorous studies. As mentioned above, documenting effects in individual patients is crucial; examining for potential benefit to caregivers is a growing part of research design. Current treatment efforts will become more sophisticated as a deeper understanding of the neurobiology of Alzheimer's disease develops. For the immediate future, the goal is not cure but slowing of the disease process. Achieving this limited goal would have a substantial impact on the financial and human costs of the illness.
Article
A new sensitive high-performance liquid chromatographic procedure for the determination of L-carnitine (LC), acetyl-L-carnitine (ALC) and propionyl-L-carnitine (PLC) in human plasma has been developed. Precolumn derivatization with 1-aminoanthracene (1AA), performed in phosphate buffer in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) as catalyst, is involved. The fluorescent derivatives were isocratically separated on a reversed-phase column (C18). The eluate was monitored with a fluorimetric detector set at 248 nm (excitation wavelength) and 418 nm (emission wavelength). Because of the presence of endogenous carnitines, the validation was performed using dialyzed plasma. The identity of the derivatized compounds was assessed by mass spectrometry and the purity of the chromatographic peaks was confirmed by HPLC-tandem mass spectrometry. The limits of quantitation were 5 nmol/ml for LC, 1 nmol/ml for ALC and 0.25 nmol/ml for PLC. The recovery of the extraction procedure was in the range 82.6%-95.4% for all 3 compounds. Good linearity (R approximately 0.99) was observed within the calibration ranges studied: 5-160 nmol/ml for LC, 1-32 nmol/ml for ALC and 0.25-8 nmol/ml for PLC. Precision was in the range 0.3-16.8% and accuracy was always lower than 10.6%.
Article
Individual differences in spatial memory among young and aged rats were assessed using memory tasks related to integrity of the hippocampus and the neostriatum. Relationships were then examined between measures of spatial memory and regional choline acetyltransferase (ChAT) activity, a marker for cholinergic integrity. Twenty-four-month-old Long-Evans rats were impaired in comparisons with 6-month-old rats on measures of place learning, working memory, reference memory, and perseveration in water-maze tasks. Aged rats that were impaired on one measure of memory, however, were not necessarily impaired on other measures. ChAT activity in the ventromedial and dorsolateral neostriatum of aged rats was significantly reduced in comparisons with young rats whereas no difference was found in the hippocampus. Aged rats with the most ChAT activity in the anterior ventromedial neostriatum performed best on the place-learning and reference memory tasks but also made the most perseverative errors on the working memory task. In addition, young and aged rats with the most ChAT activity in the anterior dorsolateral neostriatum were those with the least accurate working memory. No relationships were found between ChAT activity in the hippocampus and spatial memory. Thus age-related memory impairment has components that can be segregated by measuring relationships between cholinergic integrity in subregions of the anterior neostriatum and memory tasks with different strategic requirements.
Article
We have examined if age-related deterioration of spatial memory and cholinergic innervation of the dentate gyrus is gender-specific. Aging progressively affected the performance of male and female rats in place discrimination version of the water maze task. On repeated acquisition task, only old males, but not old females, were significantly impaired relative to young and adult animals of both sexes. In parallel, we found that the age-associated reduction of the density of cholinergic fibers in the dentate gyrus was significantly more profound in old males than in age-matched females. These results suggest that, although male and female rats have an identical pattern of reference memory decline, impairment of the working memory and deterioration of the hippocampal cholinergic system are slower to develop in females than in males.
Article
We have demonstrated in the present study that novel organic cation transporter (OCTN) 2 is a transporter for organic cations as well as carnitine. OCTN2 transports organic cations without involving Na(+), but it transports carnitine only in the presence of Na(+). The ability to transport organic cations and carnitine is demonstrable with human, rat, and mouse OCTN2s. Na(+) does not influence the affinity of OCTN2 for organic cations, but it increases the affinity severalfold for carnitine. The short-chain acyl esters of carnitine are also transported by OCTN2. Two mutations, M352R and P478L, in human OCTN2 are associated with loss of transport function, but the protein expression of these mutants is comparable to that of the wild-type human OCTN2. In situ hybridization in the rat shows that OCTN2 is expressed in the proximal and distal tubules and in the glomeruli in the kidney, in the myocardium, valves, and arterioles in the heart, in the labyrinthine layer of the placenta, and in the cortex, hippocampus, and cerebellum in the brain. This is the first report that OCTN2 is a Na(+)-independent organic cation transporter as well as a Na(+)-dependent carnitine transporter and that OCTN2 is expressed not only in the heart, kidney, and placenta but also in the brain.
Article
Alterations in brain metabolism after ischemia and reperfusion are described herein. Several roles played by carnitine and acetylcarnitine can be of particular relevance in counteracting these brain metabolism alterations. The effects of acetylcarnitine in several experimental models of brain ischemia in rats are described. The data obtained show that acetylcarnitine can have significant clinical neuroprotective effects when administered shortly after the onset of focal or global cerebral ischemia. In the canine cardiac arrest model, acetylcarnitine improved the postischemic neurological outcome and tissue levels of lactate and pyruvate were normalized. A trend toward reversal of pyruvate dehydrogenase inhibition in acetylcarnitine-treated dogs was also observed. The immediate postischemic administration of acetylcarnitine prevents free radical-mediated protein oxidation in the frontal cortex of dogs submitted to cardiac arrest and resuscitation. The transfer of the acetyl group to coenzyme A (CoA) to form acetyl-CoA as the primary source of energy is a plausible mechanism of action of acetylcarnitine.
Article
The cholinergic basal forebrain (CBF) degenerates in Alzheimer's Disease (AD), and the degree of this degeneration correlates with the degree of dementia. In the present study we have modeled this degeneration in the rat by injecting various doses of the highly selective immunotoxin 192 IgG-saporin (192-sap) into the ventricular system. The ability of 192-sap-treated rats to perform in a previously learned radial maze working memory task was then tested. We report here that 192-sap created lesions of the CBF and, to a lesser extent, cerebellar Purkinje cells in a dose-dependent fashion. Furthermore, we found that rats harboring lesions of the entire CBF greater than 75% had impaired spatial working memory in the radial maze. Correlational analysis of working memory impairment and lesion extent of the component parts of the CBF revealed that high-grade lesions of the hippocampal-projecting neurons of the CBF were not sufficient to impair working memory. Only rats with high-grade lesions of the hippocampal and cortical projecting neurons of the CBF had impaired working memory. These data are consistent with other 192-sap reports that found behavioral deficits only with high-grade CBF lesions and indicate that the relationship between CBF lesion extent and working memory impairment is a threshold relationship in which a high degree of neuronal loss can be tolerated without detectable consequences. Additionally, the data suggest that the CBF modulates spatial working memory via its connections to both the hippocampus and cortex.
Article
To assess the activity of septohippocampal cholinergic neurons during the learning of a radial-arm maze task we measured changes in extracellular acetylcholine levels in the hippocampus by means of the vertical microdialysis technique. During the 12 days spent learning the spatial task the extracellular concentration of acetylcholine in the hippocampus was monitored while rats performed the test. One week before radial-arm maze training a guide cannula was implanted unilaterally in the hippocampus. On each day of testing a removable microdialysis probe was inserted through the guide cannula and the dialysate was collected during the test performance. The concentration of acetylcholine in the dialysate was detected by means of a high-performance liquid chromatograph coupled to an electrochemical detector. We found that hippocampal acetylcholine release progressively increased from 139% to 245% during the 12 days of radial-maze learning and the magnitude of change in acetylcholine output was positively correlated with spatial memory performance, thus suggesting that changes in the functioning of these neurons are involved in learning.
Article
A description, photograph, training and testing procedure for the closed-field test are presented. In the standardization study the test was found to discriminate between groups of animals with cortical damage, normals, and rats raised in a "free environment."
Article
In the past few years several spontaneous or engineered mouse models with mutations in Ca2+ channel genes have become available, providing a powerful approach to defining Ca2+ channel function in vivo. There have been recent advances in outlining the phenotypes and in the functional analysis of mouse models with mutations in genes encoding the pore-forming subunits of Ca(V)2.1 (P/Q-type), Ca(V)2.2 (N-type) and Ca(V)2.3 (R-type) Ca2+ channels, the channels involved in controlling neurotransmitter release at mammalian synapses. These data indicate that Ca(V)2.1 channels have a dominant and efficient specific role in initiating fast synaptic transmission at central excitatory synapses in vivo, and suggest that the Ca(V)2.1 channelopathies are primarily synaptic diseases. The different disorders probably arise from disruption of neurotransmission in specific brain regions: the cortex in the case of migraine, the thalamus in the case of absence epilepsy and the cerebellum in the case of ataxia.
100 years of mazes in psychology & neuroscience A method of rating animal intel-ligence
  • Clements Rl Brown
  • Hebb
  • Do
  • Ka Williams
15 Clements RL, Brown RE. 100 years of mazes in psychology & neuroscience. Soc Neurosci Abstr 1999; 25: 261. 16 Hebb DO, Williams KA. A method of rating animal intel-ligence. J Gen Psychol 1946; 34: 59–65.
Zur Kenntnis der Extrktionsstofe der Muskeln. 2. Mitteilung uber das Carnitin
  • Gulewtisch
Gulewtisch W, Krimberg R. Zur Kenntnis der Extrktionsstofe der Muskeln. 2. Mitteilung uber das Carnitin. Hoppe Seylers Physiol Chem 1905; 45: 326-330.
100 years of mazes in psychology & neuroscience
  • Clements
Clements RL, Brown RE. 100 years of mazes in psychology & neuroscience. Soc Neurosci Abstr 1999; 25: 261.