Article

Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy

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  • Penumbra, Inc.
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Abstract

Citicoline supplementation has been used to ameliorate memory disturbances in older people and those with Alzheimer's disease. This study used MRS to characterize the effects of citicoline on high-energy phosphate metabolites and constituents of membrane synthesis in the frontal lobe. Phosphorus ((31)P) metabolite data were acquired using a three-dimensional chemical-shift imaging protocol at 4 T from 16 healthy men and women (mean +/- SD age 47.3 +/- 5.4 years) who orally self-administered 500 mg or 2000 mg Cognizin Citicoline (Kyowa Hakko Kogyo Co., Ltd, Ibaraki, Japan) for 6 weeks. Individual (31)P metabolites were quantified in the frontal lobe (anterior cingulate cortex) and a comparison region (parieto-occipital cortex). Significant increases in phosphocreatine (+7%), beta-nucleoside triphosphates (largely ATP in brain, +14%) and the ratio of phosphocreatine to inorganic phosphate (+32%), as well as significant changes in membrane phospholipids, were observed in the anterior cingulate cortex after 6 weeks of citicoline treatment. These treatment-related alterations in phosphorus metabolites were not only regionally specific, but tended to be of greater magnitude in subjects who received the lower dose. These data show that citicoline improves frontal lobe bioenergetics and alters phospholipid membrane turnover. Citicoline supplementation may therefore help to mitigate cognitive declines associated with aging by increasing energy reserves and utilization, as well as increasing the amount of essential phospholipid membrane components needed to synthesize and maintain cell membranes.

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... In vitro studies have demonstrated that maximum CCT activity in cultured cells is reached after about a day of forced induction of enzyme expression (35). Similar findings have been reported in a 31 P-MRS study by Silveri et al. (36), who found increased PEtn in healthy adults following six weeks of treatment with CDP-choline. However, in contrast to our findings, they also found a significant decrease in PCho without any change in total PME. ...
... However, in contrast to our findings, they also found a significant decrease in PCho without any change in total PME. Since PtdCho is the most abundant membrane phospholipid, it is possible that PCho is more avidly incorporated in membranes, resulting in only minimal changes in the short term, or, as Silveri et al. reported (3,36), in a decrease in PCho. ...
... Higher PDE levels were correlated with improved scores on the California Verbal Learning Test (37). In contrast, neither the present study nor the study by Silveri et al. (36) detected an increase in PDE. ...
Article
  Altered metabolism of membrane phospholipids has been implicated in bipolar disorder. In humans, uridine is an important precursor of cytidine diphosphate (CDP)-choline, which plays a critical role in phospholipid synthesis and is currently being evaluated as a potential treatment for bipolar depression.   A total of 17 healthy males (mean age ± SD: 32.73 ± 7.2 years; range: 21.8-46.4 years) were enrolled in this study. Subjects underwent a 31-phosphorus magnetic resonance spectroscopy ((31) P-MRS) acquisition at baseline and then again after seven days of either 2 g of uridine or placebo administration. A two-dimensional chemical shift imaging (31) P-MRS acquisition collected spectral data from a 4 × 4 cluster of voxels acquired in the axial plane encompassing the subcortical structures as well as frontal-temporal cortical gray and white matter. The slab thickness was 3 cm and the approximate total volume of brain sampled was 432 cm(3) . The spectra obtained were analyzed using a fully automated in-house fitting algorithm. A population-averaged generalized estimating equation was used to evaluate changes both in phosphomonoesters (PME) [phosphocholine (PCho) and phosphoethanolamine (PEtn)] and phosphodiesters (PDE) [glycerophosphocholine (GPCho) and glycerophosphethanolamine (GPEtn)]. Metabolite ratios were reported with respect to the total integrated (31) P resonance area.   The uridine group had significantly increased total PME and PEtn levels over the one-week period [6.32 and 7.17% for PME and PEtn, respectively (p<0.001)]. Other metabolite levels such as PCho, PDE, GPEtn and GPCho showed no significant changes following either uridine or placebo (all p>0.05).   This is the first study to report a direct effect of uridine on membrane phospholipid precursors in healthy adults using (31) P-MRS. Sustained administration of uridine appears to increase PME in healthy subjects. Further investigation is required to clarify the effects of uridine in disorders with altered phospholipid metabolism such as bipolar disorder.
... One particular example (Nawgan) contains citicoline (cognizin w ), choline, lycopene and vitamin E. The former ingredients are of particular interest as they have shown in previous studies to increase overall levels of choline, a brain chemical that occurs naturally in the body. Choline is a key ingredient that has been used for Alzheimer's disease and other types of dementia, stroke and agerelated memory loss (Gatti et al. 1992;Silveri et al. 2008 (Secades 2011). In Europe, citicoline is frequently prescribed for cognitive dysfunction associated with circulation problems in the brain. ...
... Most previous work on citicoline supplementation has focused on 500 mg to 2 g daily consumption (Babb et al. 2002;Silveri et al. 2008), with no increase in response associated with doses above 500 mg per day (Babb et al. 2002). No published studies have examined lower doses of citicoline supplementation either alone or in combination with other ingredients important for brain health. ...
... In fact, Babb et al. found a significant correlation between increased PDE concentrations and improved verbal learning in healthy older subjects, which suggests that the administration of citicoline may be of use in reversing age-related cognitive changes. In another recent study citicoline supplements were also found to increase PDE concentrations especially in the frontal lobes, which the authors suggest that citicoline 'may therefore help to mitigate cognitive declines associated with aging by increasing energy reserves and utilization, as well as increasing the amount of essential phospholipid membrane components needed to synthesize and maintain cell membranes' (Silveri et al. 2008). ...
Article
The present study examined the impact of a taurine-free drink enhanced with citicoline and other natural ingredients on electrophysiological markers of mental alertness. Ten healthy adult participants enrolled in a double-blind, placebo-controlled crossover study and were randomized to receive either placebo or the citicoline supplement on the first visit. Measures of electrical brain activity using electroencephalogram (EEG) were collected 30 min after consuming the beverage. Seven days after the initial assessment participants completed the alternative condition (placebo or citicoline beverage). Compared to placebo, significant improvements were found in frontal alpha EEG and N100 event related potentials (ERP) associated with the citicoline-enhanced supplement. These preliminary findings suggest that a novel brain drink containing compounds known to increase choline in the brain significantly improved attention as measured by ERP and EEG. These findings suggest that a viable and alternative brain supplement without potential compounds such as taurine may augment attentional mechanisms in healthy individuals.
... The test product contained DHA; EPA; phospholipids; choline; UMP; selenium; folic acid; and vitamins B 6 , B 12 , C, and E (Table 1). On the basis of previous publications in which 31 P-MRS brain metabolites in humans were already affected after 1-week administration of uridine [25] and 6-week administration of citicoline [26], it was expected that an intervention period of 4 weeks was sufficient to observe an effect of the test product on 31 P-MRS brain metabolites. ...
... However, the effect of this multinutrient combination on brain phospholipid metabolism appears to be driven mainly by the ethanolamine pathway because PEth/ GPEth, but not PCh/GPCh, showed a trend toward an increase. This is in line with other studies that show that oral phospholipid precursors (pyrimidines and choline) in healthy populations [25,26,43] predominantly affect the ethanolamine pathway. However, in the present study, both relative and absolute tCho levels were higher at follow-up in the group receiving the multinutrient intervention than in the control group, indicating an effect on phosphocholine metabolism as well. ...
Article
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Background Synaptic dysfunction contributes to cognitive impairment in Alzheimer’s disease and may be countered by increased intake of nutrients that target brain phospholipid metabolism. In this study, we explored whether the medical food Souvenaid affects brain phospholipid metabolism in patients with Alzheimer’s disease. Methods Thirty-four drug-naive patients with mild Alzheimer’s disease (Mini Mental State Examination score ≥20) were enrolled in this exploratory, double-blind, randomized controlled study. Before and after 4-week intervention with Souvenaid or an isocaloric control product, phosphorus and proton magnetic resonance spectroscopy (MRS) was performed to assess surrogate measures of phospholipid synthesis and breakdown (phosphomonoesters [PME] and phosphodiesters [PDEs]), neural integrity (N-acetyl aspartate), gliosis (myo-inositol), and choline metabolism (choline-containing compounds [tCho]). The main outcome parameters were PME and PDE signal intensities and the PME/PDE ratio. ResultsMRS data from 33 patients (60–86 years old; 42% males; Souvenaid arm n = 16; control arm n = 17) were analyzed. PME/PDE and tCho were higher after 4 weeks of Souvenaid compared with control (PME/PDE least squares [LS] mean difference [95% CI] 0.18 [0.06–0.30], p = 0.005; tCho LS mean difference [95% CI] 0.01 [0.00–0.02], p = 0.019). No significant differences were observed in the other MRS outcome parameters. ConclusionsMRS reveals that Souvenaid affects brain phospholipid metabolism in mild Alzheimer’s disease, in line with findings in preclinical studies. Trial registrationNetherlands Trial Register, NTR3346. Registered on 13 March 2012.
... Altered cerebral levels of a choline-containing compound (Cho), consisting of PC and glycerophosphocholine (GPC) (Bluml et al, 1999 ), have also been observed in most MAdependent patients (Chang et al, 2005; Ernst et al, 2000; Nordahl et al, 2002 Nordahl et al, , 2005 Salo et al, 2007). Considering that PC and GPC are products of synthesis and breakdown, respectively, of cerebral membranes (Babb et al, 2002; Silveri et al, 2008), lower NAA levels along with altered Cho signals in MA-dependent patients suggest that chronic MA exposure causes neuronal loss with accelerated membrane turnover (Deicken et al, 1998; Winsberg et al, 2000). Oral CDP-choline administration has the ability to increase the membrane production of neurons and has been proposed as a potential treatment option for psychostimulant dependence (Brown et al, 2007; Lukas et al, 2001; Renshaw et al, 1999). ...
... This potentially reflects increased phospholipid membrane turnover. This finding is in accord with earlier proton and phosphorous MRS studies, which examined the effects of oral CDPcholine administration on brain Cho levels (Babb et al, 2002; Silveri et al, 2008). In this study, a daily intake of 2000 mg of CDP-choline seems to be safe and well tolerated in MA-dependent subjects. ...
Article
Full-text available
Cytidine-5'-diphosphate choline (CDP-choline), as an important intermediate for major membrane phospholipids, may exert neuroprotective effects in various neurodegenerative disorders. This longitudinal proton magnetic resonance spectroscopy ((1)H-MRS) study aimed to examine whether a 4-week CDP-choline treatment could alter neurometabolite levels in patients with methamphetamine (MA) dependence and to investigate whether changes in neurometabolite levels would be associated with MA use. We hypothesized that the prefrontal levels of N-acetyl-aspartate (NAA), a neuronal marker, and choline-containing compound (Cho), which are related to membrane turnover, would increase with CDP-choline treatment in MA-dependent patients. We further hypothesized that this increase would correlate with the total number of negative urine results. Thirty-one treatment seekers with MA dependence were randomly assigned to receive CDP-choline (n=16) or placebo (n=15) for 4 weeks. Prefrontal NAA and Cho levels were examined using (1)H-MRS before medication, and at 2 and 4 weeks after treatment. Generalized estimating equation regression analyses showed that the rate of change in prefrontal NAA (p=0.005) and Cho (p=0.03) levels were greater with CDP-choline treatment than with placebo. In the CDP-choline-treated patients, changes in prefrontal NAA levels were positively associated with the total number of negative urine results (p=0.03). Changes in the prefrontal Cho levels, however, were not associated with the total number of negative urine results. These preliminary findings suggest that CDP-choline treatment may exert potential neuroprotective effects directly or indirectly because of reductions in drug use by the MA-dependent patients. Further studies with a larger sample size of MA-dependent patients are warranted to confirm a long-term efficacy of CDP-choline in neuroprotection and abstinence.
... Neuroprotection represents a new chapter in the disease treatment, intended to preserve structures and functions of the visual system (Rejdak et al., 2003;Tian et al., 2015). Several molecules have neuroprotective properties, and, among them, citicoline (CT) appears to be very interesting and has been tested in different studies (Oshitari et al., 2002;Yücel et al., 2003;Saver, 2008;Silveri et al., 2008;Tian et al., 2015). ...
... CT is a nucleotide formed by ribose, cytosine, pyrophosphate, and choline, which play a crucial role in the synthesis of phospholipids, particularly glycerophospholipid phosphatidylcholine (Secades and Lorenzo, 2006;Silveri et al., 2008). Phospholipids are the main components of the cell membrane, as they guarantee the structural integrity of cells and are the fundamental compound for several enzymes (D'Orlando and Sandage, 1995). ...
Article
Full-text available
Aims: To study the neuroprotective effect of oral citicoline (CT) therapy in primary open-angle glaucoma (POAG). Methods: This study included one eye each of 60 POAG patients. Patients were randomly divided into two groups (A and B) of 30 participants each. Only patients of group A were administered with CT therapy. Age, sex, and disease duration were matched between groups. Despite a stable intraocular pressure (IOP), a slow disease progression—assessed by standard automated white-on-white perimetry (SAP) in the previous 3 years—occurred in all patients. All patients underwent a complete eye examination, including IOP measurement, SAP, retinal nerve fiber layer (RNFL) thickness, and ganglion cell complex (GCC) thickness measurements with optical coherence tomography (OCT), before starting CT treatment and at 6, 12, 18, and 24 months’ follow-up. Parameter differences between groups were evaluated at each eye check. Results: After 18 months, mean values of SAP mean deviation (MD) of group A were significantly (p = 0.039) higher (−7.25 db) than those of group B (−8.64 db). Moreover, they appeared stable in the following visits, whereas in group B, mean MD values continued to significantly (p < 0.001) decrease (−9.28 db) over time. Mean RNFL and GCC thickness in group A were significantly (p < 0.01) higher (70.39 and 71.19 μm, respectively) than in group B (64.91 and 65.60 μm, respectively) after 12 months of CT therapy. Furthermore, they appeared to be stable over the later visits, whereas they thinned significantly (p < 0.001) over time in group B. Conclusion: These findings suggest that CT therapy seems to be effective in slowing POAG progression. Further studies on a larger population and with a longer follow-up are needed to confirm this pilot investigation.
... CDP-choline likely alters multiple biochemical parameters for the reciprocal relationships existing between synthesis and function of phospholipid membranes and efficient energy production and utilization (Farooqui et al., 2004). These observations were confirmed by Silveri et al. (2008) that studied in elderly human subjects the effects of CDP-choline on frontal lobe bioenergetics using phosphorus magnetic resonance spectroscopy. ...
... In FM, the drug enhanced energy metabolism in steady-state conditions, decreasing CS activity and supporting the well-known improving effects of CDP-choline on energy metabolism, as previous studies have shown that this drug increases the availability of total adenine nucleotides (Benzi et al., Table 1 Comparative scheme of the qualitative effects of physiological aging and CDP-choline sub-chronic treatment (20 mg kg À1 body weight i.p., 28 days) on catalytic activities of indicated enzymes evaluated on non-synaptic ''free'' mitochondria (FM) and intra-synaptic ''light'' (LM) and ''heavy'' (HM) mitochondria of frontal cerebral cortex from brain of male Wistar rats aged 18 months. 1990; Hurtado et al., 2005;Silveri et al., 2008;Villa et al., 1982Villa et al., , 1993. In fact, ATP exerts a negative feedback control towards CS, whose activity declines after drug administration. ...
Article
The effect of aging and CDP-choline treatment (20 mg · kg(-1) body weight i.p. for 28 days) on the maximal rates (V(max)) of representative mitochondrial enzyme activities related to Krebs' cycle (citrate synthase, α-ketoglutarate dehydrogenase, malate dehydrogenase), glutamate and related amino acid metabolism (glutamate dehydrogenase, glutamate-oxaloacetate- and glutamate-pyruvate transaminases) were evaluated in non-synaptic and intra-synaptic "light" and "heavy" mitochondria from frontal cerebral cortex of male Wistar rats aged 4, 12, 18 and 24 months. During aging, enzyme activities vary in a complex way respect to the type of mitochondria, i.e. non-synaptic and intra-synaptic. This micro-heterogeneity is an important factor, because energy-related mitochondrial enzyme catalytic properties cause metabolic modifications of physiopathological significance in cerebral tissue in vivo, also discriminating pre- and post-synaptic sites of action for drugs and affecting tissue responsiveness to noxious stimuli. Results show that CDP-choline in vivo treatment enhances cerebral energy metabolism selectively at 18 months, specifically modifying enzyme catalytic activities in non-synaptic and intra-synaptic "light" mitochondrial sub-populations. This confirms that the observed changes in enzyme catalytic activities during aging reflect the bioenergetic state at each single age and the corresponding energy requirements, further proving that in vivo drug treatment is able to interfere with the neuronal energy metabolism.
... Results from this study are consistent with prior research that suggests citicoline may play a role in increasing attention and alertness (Babb et al., 2002;Bruce, 2012;Cotroneo et al., 2013;Silveri et al., 2008). Citicoline is a compound that consists of cytidine and choline. ...
... Other investigators have also found that increases in PDE from citicoline supplements have led to improved memory in older adults (Babb et al., 2002). Silveri et al. (2008) conclude that citicoline may assist in reducing cognitive declines associated with aging. ...
Article
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Abstract This study examined the neurocognitive and electrophysiological effects of a citicoline-caffeine-based beverage in 60 healthy adult participants enrolled in a randomized, double-blind, placebo-controlled trial. Measures of electrical brain activity using electroencephalogram (EEG) and neuropsychological measures examining attention, concentration and reaction time were administered. Compared to placebo, participants receiving the citicoline-caffeine beverage exhibited significantly faster maze learning times and reaction times on a continuous performance test, fewer errors in a go/no-go task and better accuracy on a measure of information processing speed. EEG results examining P450 event-related potentials revealed that participants receiving the citicoline-caffeine beverage exhibited higher P450 amplitudes than controls, suggesting an increase in sustained attention. Overall, these findings suggest that the beverage significantly improved sustained attention, cognitive effort and reaction times in healthy adults. Evidence of improved P450 amplitude indicates a general improvement in the ability to accommodate new and relevant information within working memory and overall enhanced brain activation.
... The study findings showed an increase in brain phosphodiesters that correlated with memory improvement as measured by the California Verbal Learning Test [8]. To further examine the potential effects of citicoline supplementation on brain metabolism, Silveri and colleagues used phosphorrus MRS [9] to measure brain metabolites in healthy adults 40 -60 years old who received citicoline supplementation for six weeks at doses of either 500 or 2000 mg/day. Increased phosphocreatine levels were observed in the anterior cingulate, suggesting improved bioenergetics and enhanced phospholipid membrane maintenance in the frontal lobe. ...
... However, the current study shows improved attention in healthy women between the ages of 40 and 60 who received significantly smaller amounts of citicoline, specifically 250 and 500 mg. In addition to extending findings from patient populations to healthy aging women using smaller doses of citicoline, the current study also provides behavioral support for prior studies suggesting improved bioenergetics in the frontal lobe [9], where much of attentional focus is believed to occur. ...
Article
Full-text available
Objectives: The present study assessed the potential cognitive-enhancing effects of citicoline, a dietary supplement, in healthy adult women. Specifically, it was hypothesized that citicoline supplementation would be associated with im-proved attention compared to placebo. Methods: The investigation was a double-blind, randomized, placebo-controlled three-arm study. Sixty healthy adult women ages 40 -60 completed a clinical screening visit, including a medical exam. After study enrollment each subject was randomly assigned to one of three groups: a daily oral dose of 250 mg citi-coline, 500 mg citicoline, or placebo for 28 days. Participants were evaluated with the Continuous Performance Test II (CPT-II), a measure sensitive to attentional function, during a baseline visit and 28 days after baseline. Results: All 60 participants were included in the analyses, which included an ANOVA with Tukey's post-hoc tests and t-tests. After 28 days of supplementation, individuals in the 250 mg group made fewer omission (p = 0.04) and commission (p = 0.03) errors compared to those in the placebo group. Individuals in the 500 mg group made significantly fewer commission errors compared to those in the placebo group (p = 0.03) and trended toward making fewer omission errors (p = 0.07). Conclusion: After 28 days of daily citicoline supplementation, participants who were administered either the 250 mg or the 500 mg citicoline doses showed significantly better ability to produce correct responses on the CPT-II, likely due to improved cognitive inhibition. Our findings suggest that citicoline may improve attentional performance in middle-aged women and may ameliorate attentional deficits associated with central nervous system disorders.
... Нейропротекторные эффекты ЦДФ-холина осуществляются посредством различных молекулярных механизмов, включая: 1) улучшение энергетического обмена головного мозга (увеличение фосфокреатина, АТФ в лобной доли мозга по данным МРТ) [37], в том числе при участии ионов магния [38], 2) снижение апоптоза нейронов (снижение экспрессии прокаспазы-3, активированной каспазы-3, и фрагментации ядерной ДНК) [39,40]. Были установлены и более специфические молекулярные эффекты ЦДФ-холина при церебральной ишемии: снижение активности фосфолипазы PLA2 [41], ингибирование сигнальных путей ERK1/2, MEK1/2 [42], регуляция белков IRS1 [43] и сиртуин-1 [44]. ...
Article
Full-text available
Objectives. To systematize publications on drugs based on cytidine diphosphocholine (CDP-choline). Materials and methods. Systematic computer analysis of all currently available publications on CDPcholine (1750 publications in PubMed) using topological analysis theory for big data. Results. CDP-choline is required for acetylcholine biosynthesis, phospholipid metabolism, and DNA methylation. This article sequentially considers the effects of CDP-choline on acetylcholinergic and other types of neurotransmission and the anti-inflammatory and neuroprotective effects of CDP-choline, as well as the influences of this molecule on fat metabolism and gene expression in the context of the postgenomic paradigm (particularly elevated expression of nicotinic and muscarinic acetylcholine receptors). Results from basic and clinical studies of CDP-choline in the treatment of cognitive impairments associated with cerebral ischemia and neurodegeneration are presented. Conclusions. The pharmacological effects of CDP-choline are realized via multiple molecular mechanisms contributing to the nootropic actions of this molecule.
... Alternatively, in light of the slow upward dosage escalation in the study, it is possible that the lower initial dosage of 500 mg/day was more effective than higher dosages. Consistent with this idea are somewhat counterintuitive phosphorous MR spectroscopy data suggesting that a 500 mg/day dosage of citicoline is associated with a greater change in membrane phospholipids than the 2000 mg/day dosage (41). However, a linear dose-dependent relationship was observed in stroke patients, with better outcomes associated with higher dosages of citicoline (2000-4000 mg/day) (42). ...
Article
Although drug dependence is common in patients with bipolar disorder, minimal data are available on the treatment of drug dependence in this patient population. The authors previously reported a decreased risk of relapse to cocaine use in a pilot study of citicoline in patients with bipolar disorder and cocaine dependence. The primary aim of the present study was to determine whether citicoline reduces cocaine use in outpatients with bipolar I disorder and current cocaine dependence and active cocaine use. A total of 130 outpatients with bipolar I disorder (depressed or mixed mood state) and cocaine dependence received citicoline or placebo add-on therapy for 12 weeks. Results of thrice-weekly urine drug screens were analyzed using a generalized linear mixed model that was fitted to the binary outcome of cocaine-positive screens at each measurement occasion for 12 weeks. Mood was assessed with the Inventory of Depressive Symptomatology-Self Report, the Hamilton Depression Rating Scale, and the Young Mania Rating Scale. In the intent-to-treat sample (N=61 in both groups), significant treatment group and group-by-time effects were observed, whether or not missing urine screens were imputed as cocaine positive. The group effect was greatest early in the study and tended to decline with time. No between-group differences in mood symptoms or side effects were observed. Citicoline was well tolerated for treatment of cocaine dependence in patients with bipolar disorder. Cocaine use was significantly reduced with citicoline initially, although treatment effects diminished over time, suggesting the need for augmentation strategies to optimize long-term benefit.
... Literature survey revealed High performance liquid chromatography (HPLC) method for determination of citicoline sodium in pharmaceutical preparation and in biological fluids, the active principle as well as its metabolites have been determined by HPLC through UV detection, [7] proton-decoupled phosphorus magnetic resonance spectroscopy, [8] and diffusion-weighted magnetic resonance imaging. [9] The latter report includes limited stress testing. More intensive stress studies in our laboratory showed various degradation products under different stress conditions. ...
Article
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Aim: High performance liquid chromatography presents a useful aspect for the development of stability indicating assays. Objective of the current study was to establish inherent stability of citicoline sodium through stress studies under a variety of international conference on harmonization recommended test conditions and to develop a stability-indicating assay. Materials and Methods: Thermal stability studies were performed in a hot air oven (Hicon) and photo stability studies were carried out under the sunlight. The chromatographic separations were carried out on a reverse phase phenomenox C18 (250 mm΄4.6 mm i.d., particle size 5 ΅m) column. The chromatographic method was fine tuned using the sample generated from forced degradation studies. Mobile phase consists of mixture of buffer (potassium dihydrogen orthophosphate, tetra butyl ammonium, triethyl amine; pH 5.5; 0.002M) and methanol (95:5, v/v). Results: Good resolution between the peaks corresponds to degradation products and the analyte was achieved on 5 ΅, 250 mm΄4.6 mm i.d., C18 column (Luna, phenomenox, USA). The method was validated for accuracy, precision, linearity, range, and selectivity. Conclusion: The study shows that citicoline sodium is a labile molecule in acid, oxidative, and alkali conditions. It is stable to light and dry heat. A stability-indicating method was developed and is recommended for analysis of the drug and degradation products in stability samples.
... However, it is unlikely that repeated scans are responsible for our results because previous 31 P MRS studies conducted in our laboratory have demonstrated stability of 31 P MRS metabolites on test-retest protocols. 62 Finally, our analysis divides brain tissue into two tissue types, gray and white matter, and is not able to discern metabolic differences that may occur in specific nuclei or areas within the brain over the course of sleep deprivation and recovery. Thus future studies that use advances in MRS technology (e.g., ultra-high field 7 Tesla magnetic resonance scanners) and/or the use of regression modeling to examine metabolic changes in specific brain regions may be fruitful areas of further investigation. ...
Article
Study objectives: A principal function of sleep may be restoration of brain energy metabolism caused by the energetic demands of wakefulness. Because energetic demands in the brain are greater in gray than white matter, this study used linear mixed-effects models to examine tissue-type specific changes in high-energy phosphates derived using 31P magnetic resonance spectroscopy (MRS) after sleep deprivation and recovery sleep. Design: Experimental laboratory study. Setting: Outpatient neuroimaging center at a private psychiatric hospital. Participants: A total of 32 MRS scans performed in eight healthy individuals (mean age 35 y; range 23-51 y). Interventions: Phosphocreatine (PCr) and β-nucleoside triphosphate (NTP) were measured using 31P MRS three dimensional-chemical shift imaging at high field (4 Tesla) after a baseline night of sleep, acute sleep deprivation (SD), and 2 nights of recovery sleep. Novel linear mixed-effects models were constructed using spectral and tissue segmentation data to examine changes in bioenergetics in gray and white matter. Measurements and results: PCr increased in gray matter after 2 nights of recovery sleep relative to SD with no significant changes in white matter. Exploratory analyses also demonstrated that increases in PCr were associated with increases in electroencephalographic slow wave activity during recovery sleep. No significant changes in β-NTP were observed. Conclusions: These results demonstrate that sleep deprivation and subsequent recovery-induced changes in high-energy phosphates primarily occur in gray matter, and increases in PCr after recovery sleep may be related to sleep homeostasis.
... Studies have reported effects on brain activity and energy use that are consistent with increased mental alertness, but no effects on behavioral measures have been reported. 119,120 Its effects in combination with caffeine have not been assessed. L-arginine. ...
Article
Sales of energy products have grown enormously in recent years. Manufacturers claim that the products, in the form of drinks, shots, supplements, and gels, enhance physical and cognitive performance, while users believe the products promote concentration, alertness, and fun. Most of these products contain caffeine, a mild psychostimulant, as their foremost active ingredient. However, they also contain additional ingredients, e.g., carbohydrates, amino acids, herbal extracts, vitamins, and minerals, often in unspecified amounts and labeled as an "energy blend." It is not clear whether these additional ingredients provide any physical or cognitive enhancement beyond that provided by caffeine alone. This article reviews the available empirical data on the interactive effects of these ingredients and caffeine on sleep and cognitive performance and suggests objectives for future study.
... Уменьшение двигательных нарушений под влиянием цитиколина могло быть связано не только с влиянием препарата на размеры очага, что было ранее показано в исследовании S. Warrach и соавт. [22], но и с его избирательным действием на метаболизм двигательных областей коры больших полушарий головного мозга [25] и на структуру пирамидных нейронов V слоя коры [16]. Экспериментальные исследования показывают, что включение на протяжении длительного времени в диету цитиколина сопровождается увеличением роста и усилением ветвления дендритов пирамидных клеток преимущественно в V слое [26]. ...
Article
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The dynamics of neurological symptoms assessed with the Scandinavian stroke scale, the Barthel index and the modified Rankin scale was studied in 89 patients with moderate ischemic stroke who received citicoline (ceraxone) intravenously and orally. The results were compared to a group of 52 age-, sex- and stroke-matched patients who did not receive citicoline. To the date of discharge from the hospital (days 21-24), the full restoration (p<0.05) was noted in patients of the main group. Efficacy of citicoline was significantly (p<0.05) higher in patients younger than 70 years and when the drug was used in the first hours of disease.
... Moreover, the authors observed a positive correlation between the change in results of California Verbal Learning Test (a popular neuropsychological test used to assess verbal memory) and the change in the level of brain phosphodiesters. In the second study [38] 31 P-MRS was used to show effects of citicoline on the level of metabolites containing phosphorus in the frontal cortex and the occipito-parietal cortex. The study group contained 16 healthy subjects of middle age (47.3±5.4 years), who received citicoline at the dose of 500 mg or 2 g daily for 6 weeks. ...
Article
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Attempts to improve memory function with drugs affecting the brain have given unimpressive results. Dietary supplements are more widely available, and there also has been little evidence of their positive effect on memory. Citicoline may be a valuable exception. In several countries it has been registered as a nootropic drug for decades, but recently it did not prove effective in treatment of acute ischemic strokes and brain injuries. In the USA, citicoline attained the status of " generally recognized as safe " , and in the European Union recently it was qualified as a " novel food ". Small randomized, placebo-controlled trials involving healthy volunteers revealed that permissible doses of this novel food produce positive effects in the human brain recognized electrophysi-ologically, neurochemically, and functionally. Citicoline supplementation may be useful for subjects with memory disorders of mild-to-moderate intensity, those undergoing neurorehabilitation following brain strokes, and for healthy subjects facing requirements for enhanced attention and mental effort.
... The scope of citicoline's therapeutic potential extends beyond its ability to be neuroprotective. Citicoline not only reduces neuronal free fatty acid accumulation and free radical production (3) while improving bioenergetics and increasing the rate of phospholipid turnover (4,5), but it also enhances neurotransmission. Citicoline has been shown to increase monoaminergic levels within the central nervous system by increasing dopamine and norepinephrine production (6,7), and its metabolites contribute to the synthesis of acetylcholine (8). ...
Article
Many pharmacotherapies for treating cocaine dependence are aimed at reducing drug effects, alleviating craving, and preventing relapse. We demonstrated previously that citicoline, a compound used to repair neuronal damage in stroke and brain injury, is safe in cocaine-abusing volunteers. This study assessed the effectiveness of an 8-week citicoline treatment period and 4-week follow-up in cocaine-dependent individuals. Twenty-nine healthy nontreatment-seeking, cocaine-dependent male and female volunteers were randomized in this double-blind, placebo-controlled study, 18 of whom completed the treatment period of the study. Participants took citicoline (500 mg twice daily) or matched placebo each day and recorded the measures of craving and drug use. Participants visited the laboratory twice a week for urine screens and to attend weekly group therapy sessions. Citicoline had no effect on cocaine craving or total use. Although the current preliminary results from this small trial suggest that citicoline is not an effective treatment for heavy cocaine users, further investigation on efficacy citicoline as a treatment for substance dependence in other settings may be warranted.
... Postmortem studies indicate that cocaine dependence causes a depletion of neuronal phospholipid metabolism in the putamen of cocaine dependent individuals (Ross et al., 2002); citicoline treatment improves neuronal membrane integrity. A recent phosphorus magnetic resonance spectroscopy study in healthy adults found that six weeks of oral citicoline dose-dependently increases high energy phosphates and membrane phospholipids (Silveri et al., 2008). Much of the research on the role of citicoline in membrane phospholipid turnover has come from studying the feasibility of using citicoline to augment neuronal repair after brain damage. ...
Article
Citicoline (cytidine-5'-diphosphate) is a mononucleotide composed of ribose, cytosine, pyrophosphate, and choline, and is involved in the biosynthesis of the structural phosopholipids of cell membranes. Treatment with citicoline, improves memory in patients with dementia, and reduces damage to the brain after traumatic brain injury or stroke. Recent research has been conducted to assess whether citicoline is an effective treatment for cocaine dependence. In cocaine-dependent individuals, withdrawal from cocaine is associated with disturbed sleep, which may contribute to the high rate of relapse to cocaine use. Therefore, it is important to know the impact of citicoline on the sleep/wake cycle in these individuals in order to rate its overall efficacy. In this double-blind, placebo-controlled trial, the effects of citicoline treatment on the sleep/wake cycles of cocaine dependent participants were assessed. The results of the current study are reported as part of a larger study, consisting of an eight-week treatment period to assess the efficacy of longer-term treatment with citicoline at decreasing cocaine consumption in cocaine-dependent polydrug using participants. In this non-abstinent, cocaine-dependent population, citicoline had no effect on any of the sleep parameters measured including sleep efficiency, sleep latency, total sleep time, number of waking episodes, time awake per episode, amount of time in bed spent moving, number of sleep episodes, time asleep per episode, and amount of time in bed spent immobile. These data suggest that eight weeks of citicoline administration does not disturb sleep/wake cycles of cocaine-dependent individuals.
... 27 In an experimental stroke model, Hurtado et al 28 showed that citicoline can produce re-growth of dendritic spines, which correlated with functional recovery. Using phosphorus magnetic resonance spectroscopy, Silveri et al 29 showed in elderly human subjects that citicoline treatment for 6 weeks produced significant increases in frontal lobe (anterior cingulate cortex) phosphocreatine (ϩ17%), ␤-nucleoside triphosphates (largely ATP in the brain [ϩ14%]), and in the ratio of phosphocreatine to inorganic phosphate (ϩ32%). Also, significant increase in membrane phospholipids was demonstrated. ...
Article
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Cognitive decline after stroke is more common than stroke recurrence. Stroke doubles the risk of dementia and is a major contributor to vascular cognitive impairment and vascular dementia. Neuropathological studies in most cases of dementia in the elderly reveal a large load of vascular ischemic brain lesions mixed with a lesser contribution of neurodegenerative lesions of Alzheimer disease. Nonetheless, few pharmacological studies have addressed vascular cognitive impairment and vascular dementia after stroke. Citicoline has demonstrated neuroprotective effects in acute stroke and has been shown to improve cognition in patients with chronic cerebrovascular disease and in some patients with Alzheimer disease. A recent trial lasting 6 months in patients with first-ever ischemic stroke showed that citicoline prevented cognitive decline after stroke with significant improvement of temporal orientation, attention, and executive function. Experimentally, citicoline exhibits neuroprotective effects and enhances neural repair. Citicoline appears to be a safe and promising alternative to improve stroke recovery and could be indicated in patients with vascular cognitive impairment, vascular dementia, and Alzheimer disease with significant cerebrovascular disease.
... Нейропротекторные эффекты ЦДФ-холина осуществляются посредством различных молекулярных механизмов, включая: 1) улучшение энергетического обмена головного мозга (увеличение фосфокреатина, АТФ в лобной доли мозга по данным МРТ) [37], в том числе при участии ионов магния [38], 2) снижение апоптоза нейронов (снижение экспрессии прокаспазы-3, активированной каспазы-3, и фрагментации ядерной ДНК) [39,40]. Были установлены и более специфические молекулярные эффекты ЦДФ-холина при церебральной ишемии: снижение активности фосфолипазы PLA2 [41], ингибирование сигнальных путей ERK1/2, MEK1/2 [42], регуляция белков IRS1 [43] и сиртуин-1 [44]. ...
Article
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Objective: Systematization of the array of publications on cytidyldiphosphocholine (CDP-choline). Material and methods: Systematic computer analysis of all currently available publications on CDP-choline (1750 publications in PUBMED) using the topological theory of big data analysis. Results: CDP-choline is essential for acetylcholine biosynthesis, phospholipid metabolism, and DNA methylation. The article describes the effects of CDP-choline on acetylcholinergic and other types of neurotransmission, anti-inflammatory, neuroprotective and neurotrophic effects of CDP-choline. Also, the paper presents the effects of the molecule on lipid metabolism and gene expression within the post-genomic paradigm (in particular, an increase in the expression of nicotinic and muscarinic acetylcholine receptors). The results of fundamental and clinical studies of CDP-choline in the treatment of cognitive impairments associated with cerebral ischemia and neurodegeneration are presented. Conclusion: The pharmacological effects of CDP-choline are mediated through multiple molecular mechanisms that contribute to the nootropic action of this molecule.
... Citicoline prevents memory impairment resulting from poor environmental conditions [2]. Citicoline supplements help improve focus and mental energy and may possibly be useful in the treatment of attention deficit disorder [3]. It seems to increase a brain chemical called phosphatidylcholine. ...
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Simple, sensitive, selective, and precise stability-indicating thin-layer chromatography (TLC)-densitometric and reversed-phase high-performance liquid chromatography (RP-HPLC) methods were developed and validated for the determination of citicoline sodium (CT) in the presence of its alkaline degradation products (CT Deg.) and in pharmaceutical oral solution. TLC-densitometry employs aluminum TLC plates precoated with silica gel 60 F254 as the stationary phase and ammonia-ethyl acetate-triethylamine (6:3.5:0.5, v/v) as the mobile phase to give compact spots for citicoline sodium (RF = 0.35) and its degradation product (RF = 0.1); the chromatogram was scanned at 272 nm. RP-HPLC utilizes a C18 column and a mobile phase consisting of methanol-water-acetic acid (60:40:0.1, v/v); the pH level was adjusted to 4 using 0.1% orthophosphoric acid, at a flow rate of 1 mL min-1 for the separation of citicoline sodium (tR = 1.801) and its degradation product (tR = 3.422). Quantitation was achieved by ultraviolet (UV) detection at 272 nm. Citicoline sodium was exposed to alkaline hydrolysis, and a comparative study was carried out to show the advantages of the proposed chromatographic methods in determination of citicoline sodium in the presence of its alkaline degradation products. The chromatographic methods were developed and validated as per the International Conference on Harmonization guidelines. As the methods could effectively separate the drug from their degradation products, these techniques can be employed as stability-indicating methods that have been successively applied to pharmaceutical formulations without interference from the excipients.
... CDP-choline exerts effects to increase cerebral dopamine and norepinephrine levels (Martinet et al, 1978(Martinet et al, , 1979Agut et al, 1984;Saligaut et al, 1985). Specifically, pyrimidine-induced increase in ATP levels (Silveri et al, 2008) may enhance tyrosine hydroxylase activity (Martinet et al, 1978(Martinet et al, , 1979Saligaut et al, 1985), an ATP-dependent and rate-limiting enzyme for dopamine and norepinephrine synthesis. Similar effects on glutamate synthesis or turnover have not been studied. ...
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Targeting the glutamatergic system has been suggested as a promising new option for developing treatment strategies for bipolar depression. Cytidine, a pyrimidine, may exert therapeutic effects through a pathway that leads to altered neuronal-glial glutamate cycling. Pyrimidines are also known to exert beneficial effects on cerebral phospholipid metabolism, catecholamine synthesis, and mitochondrial function, which have each been linked to the pathophysiology of bipolar depression. This study was aimed at determining cytidine's efficacy in bipolar depression and at assessing the longitudinal effects of cytidine on cerebral glutamate/glutamine levels. Thirty-five patients with bipolar depression were randomly assigned to receive the mood-stabilizing drug valproate plus either cytidine or placebo for 12 weeks. Midfrontal cerebral glutamate/glutamine levels were measured using proton magnetic resonance spectroscopy before and after 2, 4, and 12 weeks of oral cytidine administration. Cytidine supplementation was associated with an earlier improvement in depressive symptoms (weeks 1-4; p=0.02, 0.001, 0.002, and 0.004, respectively) and also produced a greater reduction in cerebral glutamate/glutamine levels in patients with bipolar depression (weeks 2, 4, and 12; p=0.004, 0.004, and 0.02, respectively). Cytidine-related glutamate/glutamine decrements correlated with a reduction in depressive symptoms (p=0.001). In contrast, these relationships were not observed in the placebo add-on group. The study results suggest that cytidine supplementation of valproate is associated with an earlier treatment response in bipolar depression. Furthermore, cytidine's efficacy in bipolar depression may be mediated by decreased levels of cerebral glutamate and/or glutamine, consistent with alterations in excitatory neurotransmission.
... Accordingly, several clinical trials have been carried out to evaluate the effects of CDP-choline in the treatment of cognitive disorders [208,209]. Citicoline stimulates phosphatidylcholine synthesis in the brain [210][211][212][213] and improves the energetic cerebral metabolism of elderly subjects [214]; a fact that is correlated to an improvement on cognitive capacities [215][216][217][218][219]. In healthy volunteers, the administration of citicoline has been associated with improvement in attention [220,221], memory [222,223] and in some neurophysiological parameters [224][225][226][227]. ...
Article
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Vascular cognitive impairment is a process which is more frequent in patients with cardiovascular risk factors. The etiology of this kind of impairment could be related to different types of cerebrovascular disorders, given that silent cerebral infarctions or microinfarcts, correlated with small vessel disease, are one of the principal etiologies. Microinfarcts, associated with small vessel diseases, should be considered one of the possible causes of clinical suspicion in patients with cardiovascular risk factors who are asking for help for cognitive complaints. Among the proposed treatments for cognitive impairment there is citicoline. This is an updated review of the possible use of citicoline in the treatment of cognitive impairment.
... Based on these facts, many clinical trials have been conducted to assess the efficacy of citicoline in the treatment of cognitive disorders associated to brain aging, chronic cerebral vascular disease, and dementia [536]. Using magnetic resonance spectroscopy techniques, citicoline has been shown to stimulate phosphatidylcholine synthesis in the brain [537][538][539][540] and improves the energetic cerebral metabolism of elderly subjects [541], which is related to an improvement in their cognitive capacities [542], particularly memory [543][544][545] and reaction time [546]. In healthy volunteers, the administration of citicoline has been associated with improvement in attention [547,548], memory [549,550] and in some neurophysiological parameters [551][552][553][554]. ...
Article
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Summary. This review is based on the previous one published in 2006 –Secades JJ, Lorenzo JL. Citicoline: pharmacological and clinical review, 2006 update. Methods Find Exp Clin Pharmacol 2006; 28 (Suppl B): S1-56–, incorporating the new references until now, having all the information available to facilitate the access to the información in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications. Key words. Alcoholism. Alzheimer disease. Amblyopia. Apoptosis. CDP-choline. Cerebral edema. Cerebral ischemia. Citicoline. Cognitive disorder. Drug addiction. Glaucoma. Head injury. Memory. Neuronal membrane. Neuroplasticity. Neuroprotection. Neurorepair. Neurotransmission. Parkinson disease. Phosphatidylcholine. Phospholipase. Senile dementia. Stroke. Structural phospholipids. Traumatic brain injury.
... Because citicoline's effect was most prominent in this brain region, this is a likely explanation for its clinical benefit of improved cognitive function. 13 Citicoline may further benefit patients experiencing ischemia by decreasing the accumulation of free fatty acids at the site of the lesion, which occurs as a result of neuronal cell damage and death. Soon after initiation of ischemia, there is a significant increase in proinflammatory arachidonic acid, glycerols, and free fatty acids, caused by the breakdown of neuronal membranes. ...
Chapter
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Difference between citicoline and choline; bioavailability/pharmacokinetics; mechanism of action; clinical applications for its use in learning and memory, attention, Alzheimer's disease, and dementia, Parkinson's disease, stroke, and cerebral ischemia, traumatic head injuries; eye health and visual function, including amblyopia, glaucoma, ischemic optic neuropathy; substance abuse, infectious diseases, as well as, toxicology and safety, dosage, and drug interactions.
... Because citicoline's effect was most prominent in this brain region, this is a likely explanation for its clinical benefit of improved cognitive function. 13 Citicoline may further benefit patients experiencing ischemia by decreasing the accumulation of free fatty acids at the site of the lesion, which occurs as a result of neuronal cell damage and death. Soon after initiation of ischemia, there is a significant increase in proinflammatory arachidonic acid, glycerols, and free fatty acids, caused by the breakdown of neuronal membranes. ...
Chapter
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Citicoline is an endogenous mononucleotide composed of ribose, cytosine, pyrophosphate, and choline, and an essential precursor for the synthesis of neuronal plasma membrane phospholipids, important as a rate-limiting step in phosphatidylcholine synthesis. Choline is a component of the diet and is produced in the brain, albeit in small amounts. The chapter discusses the broad spectrum of benefits in conditions associated with neurological disorders and dysfunctions that citicoline plays a role in, in addition to toxicological studies that lend support to its use as an oral dietary source.
... En base a estos hechos, se han llevado a cabo numerosos ensayos clínicos para valorar la eficacia de la citicolina en el tratamiento de los trastornos cognitivos asociados al envejecimiento cerebral, la patología vascular cerebral crónica y las demencias [536]. Mediante técnicas de espectroscopia por RM se ha demostrado que, en ancianos, la citicolina estimula la síntesis de fosfatidilcolina en el cerebro [537][538][539][540] y mejora el metabolismo energético cerebral [541], lo que se correlaciona con la mejoría de sus capacidades cognitivas [542], especialmente de la memoria [543][544][545] y del tiempo de reacción [546]. En voluntarios sanos, la administración de citicolina se ha asociado con mejorías en la atención [547,548], la memoria [549,550] y algunos parámetros neurofisiológicos [551][552][553][554]. ...
Article
Full-text available
This review is based on the previous one published in 2010 -Secades JJ. Citicoline: pharmacological and clinical review, 2010 update. Rev Neurol 2011; 52 (Suppl 2): S1-62-, incorporating 183 new references, having all the information available to facilitate the access to the information in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
... Based on these facts, many clinical trials have been conducted to assess the efficacy of citicoline in the treatment of cognitive disorders associated to brain aging, chronic cerebral vascular disease, and dementia [536]. Using magnetic resonance spectroscopy techniques, citicoline has been shown to stimulate phosphatidylcholine synthesis in the brain [537][538][539][540] and improves the energetic cerebral metabolism of elderly subjects [541], which is related to an improvement in their cognitive capacities [542], particularly memory [543][544][545] and reaction time [546]. In healthy volunteers, the administration of citicoline has been associated with improvement in attention [547,548], memory [549,550] and in some neurophysiological parameters [551][552][553][554]. ...
Article
Full-text available
This review is based on the previous one published in 2010 -Secades JJ. Citicoline: pharmacological and clinical review, 2010 update. Rev Neurol 2011; 52 (Suppl 2): S1-62-, incorporating 183 new references, having all the information available to facilitate the access to the information in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
... A controlled study in 17 healthy volunteers showed that administration of uridine increases brain membrane phospholipid precursors (measured using 31-phosphorus magnetic resonance spectroscopy [MRS]) [111]. Another MRS study in healthy volunteers (n = 16) showed that administration of cytidine diphosphate-choline (CDP-choline) also affects phospholipid membrane turnover and may increase the availability of phospholipid membrane components needed to synthesize and maintain cell membranes [112]. ...
Article
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In mild cognitive impairment (MCI) due to Alzheimer disease (AD), also known as prodromal AD, there is evidence for a pathologic shortage of uridine, choline, and docosahexaenoic acid [DHA]), which are key nutrients needed by the brain. Preclinical and clinical evidence shows the importance of nutrient bioavailability to support the development and maintenance of brain structure and function in MCI and AD. Availability of key nutrients is limited in MCI, creating a distinct nutritional need for uridine, choline, and DHA. Evidence suggests that metabolic derangements associated with ageing and disease-related pathology can affect the body’s ability to generate and utilize nutrients. This is reflected in lower levels of nutrients measured in the plasma and brains of individuals with MCI and AD dementia, and progressive loss of cognitive performance. The uridine shortage cannot be corrected by normal diet, making uridine a conditionally essential nutrient in affected individuals. It is also challenging to correct the choline shortfall through diet alone, because brain uptake from the plasma significantly decreases with ageing. There is no strong evidence to support the use of single-agent supplements in the management of MCI due to AD. As uridine and choline work synergistically with DHA to increase phosphatidylcholine formation, there is a compelling rationale to combine these nutrients. A multinutrient enriched with uridine, choline, and DHA developed to support brain function has been evaluated in randomized controlled trials covering a spectrum of dementia from MCI to moderate AD. A randomized controlled trial in subjects with prodromal AD showed that multinutrient intervention slowed brain atrophy and improved some measures of cognition. Based on the available clinical evidence, nutritional intervention should be considered as a part of the approach to the management of individuals with MCI due to AD, including adherence to a healthy, balanced diet, and consideration of evidence-based multinutrient supplements.
... [19] MRS study showed citicoline therapy for 6 weeks in healthy volunteers could significantly increase creatine phosphate and triphosphate and markedly alter the phospholipids in membrane in the cortex of frontal anterior cingulate, suggesting that citicoline is able to improve the frontal bioenergy and the fluidity of phospholipids in the cell membrane. [20] In summary, LA patients have abnormality in the network connectivity of the corpus callosum, which deteriorates over time. Citicoline therapy may delay the damage to the axons and myelins in the corpus callosum, exerting protective effects on the corpus callosum. ...
Article
This study aimed to investigate the effects of citicoline therapy on the network connectivity of the corpus callosum in patients with leukoaraiosis (LA) by diffusion tension imaging (DTI). A total of 30 LA patients with Fazekas score of 2 to 3 were voluntarily assigned into citicoline group (n = 14) and control group (n = 16). In citicoline group, citicoline was administered at 0.6 g/d for 1 year. In control group, central nervous system drugs should not be used, except for sleeping pills and antidepressants. Interventions for pre-existing diseases should be conducted in both groups. During the periods of citicoline therapy and post-treatment follow-up, cranial magnetic resonance imaging and DTI were routinely performed in these patients, and the genu, body, and splenium of corpus callosum were selected as the regions of interest (ROIs). The fractional anisotropy (FA) and mean diffusivity (MD) of each ROI were determined with PANDA software. On recruitment, there were no significant differences in the general characteristics, blood biochemical results, cognition function, and the FA and MD of the corpus callosum between 2 groups (P > 0.05). After 1-year treatment, the FA of the corpus callosum reduced gradually, but the MD of the corpus callosum tended to increased in both group, although significant differences were not observed. However, the reductions in FA of genu and splenium of corpus callosum in citicoline group were significantly lower than in control group (P < 0.05); the reductions in MD of genu, body, and splenium of corpus callosum in citicoline group were significantly lower than in control group (P < 0.05). In LA patients, the disruption of the network connectivity of the corpus callosum deteriorates over time. Citicoline treatment may delay the reduction in FA of corpus callosum, which might be beneficial for the improvement of network connectivity of the corpus callosum.
... Data acquired using MRSI requires additional post-processing to integrate the quantified signal with available anatomical information. A frequency ramp can also be applied to shift the voxels relative to the anatomy, thereby centering the voxels on an anatomical region of interest [15]. Voxels can be assigned to anatomical brain regions, either by a trained rater [3] or by an automated approach [16,17]. ...
... Owen (20) reported activation of the mid-ventrolateral frontal cortex during the Spatial Span and Paired Associates tasks. Citicoline has been shown to improve frontal lobe bioenergetics and alter phospholipid membrane turnover in humans (29). Age-related declines in cognitive abilities, particularly related to function in frontal lobe has been demonstrated in humans (30,31). ...
Article
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Background Supplementation of citicoline (CDP-choline), a naturally occurring mononucleotide, has shown beneficial effects on memory function and behavior in populations with a wide range of impairments. However, few studies have investigated its effect in healthy older populations. Objective The objective of this study was to investigate the effects of citicoline (Cognizin®), on memory in healthy elderly populations with age-associated memory impairment (AAMI). Methods A total of 100 healthy men and women aged between 50 and 85 y with AAMI participated in this randomized, double-blind, placebo-controlled trial. Participants were randomized to receive placebo (n = 51) or citicoline (n = 49; 500 mg/d) for 12 wk. Memory function was assessed at baseline and end of the intervention (12 wk) using computerized tests (Cambridge Brain Sciences, Ontario, Canada). Safety measurements included adverse events query, body weight, blood pressure, and hematology and metabolic panel. Intent-to-treat analysis was conducted using ANCOVA for the primary and secondary outcome variables with Bonferroni correction for multiple comparisons. Results A total of 99 out of 100 participants completed the study in its entirety. After the 12-wk intervention, participants supplemented with citicoline showed significantly greater improvements in secondary outcomes of episodic memory (assessed by the Paired Associate test), compared with those on placebo (mean: 0.15 vs. 0.06, respectively, P = 0.0025). Composite memory (secondary outcome), calculated using the scores of 4 memory tests, also significantly improved to a greater extent following citicoline supplementation (mean: 3.78) compared with placebo (mean: 0.72, P = 0.0052). Conclusions Dietary supplementation of citicoline for 12 wk improved overall memory performance, especially episodic memory, in healthy older males and females with AAMI. The findings suggest that regular consumption of citicoline may be safe and potentially beneficial against memory loss due to aging. This trial was registered at clinicaltrials.gov as NCT03369925.
... Significant increases in phosphocreatine, ATP, the ratio of phosphocreatine to inorganic phosphate, and changes in membrane phospholipids were observed after 6 weeks of citicoline treatment, suggestive of that citicoline improves bioenergetics and phospholipid membrane turnover in a brain region critical for cognition and memory. Citicoline supplementation may therefore help to mitigate cognitive declines associated with aging by increasing energy reserves and utilization, as well as increasing the amount of essential phospholipid membrane components needed to synthesize and maintain cell membranes (Silveri et al., 2008). We may take it for granted that mitochondria are involved in these improvements. ...
Article
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Oral form of citicoline, a nootropic and neuroprotective drug in use for almost five decades, recently was pronounced a food supplement in both USA and EU. The idea of adding citicoline to topical treatment of primary open angle glaucoma (POAG) aimed at decreasing intraocular pressure appeared as a logical consequence of accepting neurodegenerative character of this disease. Experimental data, and also few clinical studies indicate that this substance has potential to counteract some important pathological mechanisms which seem to contribute to POAG initiation and progression, such as excitotoxicity and oxidative stress.
Article
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Citicoline, CDP Choline or Cytidine diphophocholine is a novel drug with a broad spectrum of benefits for condition associated with neurological dysfunction. Citicoline is an endogenous compound and an essential intermediate in the synthesis of phosphatidylcholine (cell membrane phopholipid). It is launched worldwide (outside of US and Canada only) as a drug for stroke and head injuries. It plays important roles in structural integrity, signaling of cell membrane and plays important role in human physiology. It supports the synthesis of Acetylcholine and Betaine, a methyl donor to generate phospholipids. Citicoline attenuates the production of free radicals in Ischemic condition and also stimulates the activity of glutathione reductase and has the ability to promote learning and improve cognitive impairment in Parkinson's and Alzheimer's disease. Citicoline administration reduces the severity of mental and motor deficits associated head injuries and supports eye health and mental health. Pharmacokinetics suggests that it is well absorbed and high bioavailable orally. A dose of 500mg to 2000 mg per day is an effective based on clinical trials and is safe for use in elderly population and pediatrics. It has the ability to improve phospholipid metabolism, with a consequent improvement in the deteriorated axonal flow of dopamine.
Article
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This review is based on the previous one published in 2006 -Secades JJ, Lorenzo JL. Citicoline: pharmacological and clinical review, 2006 update. Methods Find Exp Clin Pharmacol 2006; 28 (Suppl B): S1-56-, incorporating the new references until now, having all the information available to facilitate the access to the informacion in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
Article
The analysis of mechanisms of the neuroprotective effect of choline precursors reveals the primary effects of citicoline on the processes of repair of neuronal membranes, a decrease in the degeneration of free fatty acids, and choline alfoscerate, an increase in the production of the neurotransmitter acetylcholine. Although citicoline has a lesser effect on choline secretion than choline alfoscerate, the combination of choline and cytidine in its composition is a universal tool to reduce symptoms of cerebral ischemia, to stabilize cognitive status, superior to the standard benefits of choline. Various mechanisms of the action of citicoline enable to recommend it as a drug effective both in the acute phase of the disease and in the delayed period, giving it the status of a universal nootropic compound.
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Evidence suggests that mitochondria undergo functional and morphological changes with age. This study aimed to investigate the relationship of brain energy metabolism to healthy aging by assessing tissue specific differences in metabolites observable by phosphorus ((31)P) MRS. (31)P MRSI at 4 Tesla (T) was performed on 34 volunteers, aged 21-84, screened to exclude serious medical and psychiatric diagnoses. Linear mixed effects models were used to analyze the effects of age on phosphorus metabolite concentrations, intracellular magnesium and pH estimates in brain tissue. A significant age associated decrease in brain pH (-0.53% per decade), increase in PCr (1.1% per decade) and decrease in PME (1.7% per decade) were found in total tissue, with PCr effects localized to the gray matter. An increase in beta NTP as a function of age (1% per decade) approached significance (p = 0.052). There were no effects demonstrated with increasing age for intracellular magnesium, PDE or inorganic phosphate. This study reports the effects of healthy aging on brain chemistry in the gray matter versus white matter using (31)P MRS measures of high energy phosphates, pH and membrane metabolism. Increased PCr, increased beta NTP (reflecting ATP) and reduced pH may reflect altered energy production with healthy aging. Unlike some previous studies of aging and brain chemistry, this study examined healthy, non-demented and psychiatrically stable older adults and specifically analyzed gray-white matter differences in brain metabolism.
Article
Cytidine 5'-diphosphocholine (CDP-choline or citicoline) is a highly bioavailable compound with potential benefits for aiding neural repair and increasing acetylcholine levels in the central and peripheral nervous system. As a result, many researchers have investigated the use of CDP-choline for various types of neurological insult or conditions, including stroke, traumatic brain injury, and Alzheimer disease. Despite the fact that the safety of the compound has been verified across multiple international studies, evidence for efficacy remains less clear. This may be attributable, at least in part, to several issues, including a lack of randomized clinical trials, a lack of availability of the compound in the United States, and statistical power issues in reported trials. In addition, the fact that CDP-choline has multiple potential points of therapeutic impact makes it an exciting treatment option in theory but also complicates the analysis of efficacy in the sense that multiple mechanisms and time points must be evaluated. Although some clinical conditions do not appear to benefit from CDP-choline treatment, the majority of findings to date have suggested at least minor benefits of treatment. In this review we will examine the evidence in the published literature pertaining to use of CDP-choline in rehabilitation populations and briefly consider the work yet to be done.
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Brain health products are increasingly gaining popularity among consumers of all ages. These foods and beverages contain ingredients that aid in brain development, help mental performance, enhance memory, and prevent cognitive decline. Omega-3 fatty acids, specifically docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (ARA), have been associated with improving brain health in people of all ages. Omega-3 fatty acids are reported to promote brain development in children, as they play a key role in cognitive function from childhood to adulthood. These fatty acids are found to help in preventing cognitive decline and potentially Alzheimer's disease as the body ages. Phospholipids are some of the other brain health products that are natural building blocks of the human brain and help in improving memory skills.
Article
Considering the complex nature of alcohol use disorder (AUD) and the limitations of the three US Food and Drug Administration (FDA) approved medications, clinical trials for diverse treatment options are required. During the last decade, several interesting clinical trials with over‐the‐counter (OTC) supplements have been conducted for AUD by taking advantage of less vulnerable nature in regard to toxicity and side effects. In this commentary, we discuss the article describing “A randomized, double‐blind, placebo‐controlled trial of citicoline in patients with alcohol use disorder” (Brown et al., 2018). This article is protected by copyright. All rights reserved.
Article
BACKGROUND: Methamphetamine use disorders are common and severe problems. Persons with mood disorders, particularly bipolar disorder, have high rates of substance use disorders. We previously reported promising findings on drug use, memory and study retention in patients with a history of mania and cocaine dependence given the nutritional supplement citicoline. In the current proof-of-concept study, we examined citicoline in bipolar or unipolar depression and methamphetamine dependence. METHODS: Sixty adults with bipolar depression or major depressive disorder and methamphetamine dependence were randomized to citicoline (2000mg/day) or placebo for 12 weeks. Mood was assessed using Inventory of Depressive Symptomatology-Clinician Version (IDS-C), and cognition with the Hopkins Auditory Verbal Learning Test (HVLT). Drug use was assessed by urine drug screens. RESULTS: An ANCOVA of the intent-to-treat sample showed that those receiving citicoline (n=28) had a statistically significantly greater improvement in IDS-C scores than those receiving placebo (n=20). Survival in the study was significantly longer and completion rates significantly greater with citicoline than placebo. No significant differences were observed in memory or methamphetamine use. Citicoline was well tolerated. LIMITATIONS: Sample heterogeneity and small sample size were limitations. CONCLUSIONS: To our knowledge this is the first placebo-controlled trial in a dual diagnosis sample with methamphetamine use disorders. Findings suggest that citicoline may have antidepressant properties in this population. Greater treatment retention with citicoline is also noteworthy in a patient population with substance dependence. Larger trials targeting depressive symptoms and treatment retention seem warranted.
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Ischemic stroke is one of the leading causes of long-lasting disability and death. Two main strategies have been proposed for the treatment of ischemic stroke: restoration of blood flow by thrombolysis or mechanical thrombus extraction during the first few hours of ischemic stroke, which is one of the most effective treatments and leads to a better functional and clinical outcome. The other direction of treatment, which is potentially applicable to most of the patients with ischemic stroke, is neuroprotection. Initially, neuroprotection was mainly targeted at protecting gray matter, but during the past few years there has been a transition from a neuron-oriented approach toward salvaging the whole neurovascular unit using multimodal drugs. Citicoline is a multimodal drug that exhibits neuroprotective and neuroregenerative effects in a variety of experimental and clinical disorders of the central nervous system, including acute and chronic cerebral ischemia, intracerebral hemorrhage, and global cerebral hypoxia. Citicoline has a prolonged therapeutic window and is active at various temporal and biochemical stages of the ischemic cascade. In acute ischemic stroke, citicoline provides neuroprotection by attenuating glutamate exitotoxicity, oxidative stress, apoptosis, and blood–brain barrier dysfunction. In the subacute and chronic phases of ischemic stroke, citicoline exhibits neuroregenerative effects and activates neurogenesis, synaptogenesis, and angiogenesis and enhances neurotransmitter metabolism. Acute and long-term treatment with citicoline is safe and in most clinical studies is effective and improves functional outcome.
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In order to explain the insulin-like effect of exercise, it was proposed in 1951 that contracting muscle fibers liberate creatine, which acts to produce an acceptor effect--later called respiratory control--on the muscle mitochondria. The development of this notion paralleled the controversy between biochemists and physiologists over the delivery of energy for muscle contraction. With the demonstration of functional compartmentation of creatine kinase on the mitochondrion, it became clear that the actual form of energy transport in the muscle fiber is phosphorylcreatine. The finding of an isoenzyme of creatine phosphokinase attached to the M-line region of the myofibril revealed the peripheral receptor for the mitochondrially generated phosphorylcreatine. This established a molecular basis for a phosphorylcreatine-creatine shuttle for energy transport in heart and skeletal muscle and provided an explanation for the inability to demonstrate experimentally a direct relation between muscle activity and the concentrations of adenosine triphosphate and adenosine diphosphate.
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There are significant age and sex effects in cognitive ability and brain disease. However, sex differences in aging of human brain areas associated with nonreproductive behavior have not been extensively studied. We hypothesized that there would be significant sex differences in aging of brain areas that subserve speech, visuospatial, and memory function. We investigated sex differences in the effect of aging on human brain morphometry by means of volumetric magnetic resonance imaging and on regional cerebral metabolism for glucose by positron emission tomography. In the magnetic resonance imaging study, we examined 69 healthy right-handed subjects (34 women and 35 men), divided into young (age range, 20 to 35 years) and old (60 to 85 years) groups. In the positron emission tomography study, we investigated 120 healthy right-handed subjects (65 women and 55 men) aged 21 to 91 years. In the magnetic resonance imaging study, age-related volume loss was significantly greater in men than women in whole brain and frontal and temporal lobes, whereas it was greater in women than men in hippocampus and parietal lobes. In the positron emission tomography study, significant sex differences existed in the effect of age on regional brain metabolism, and asymmetry of metabolism, in the temporal and parietal lobes, Broca's area, thalamus, and hippocampus. We found significant sex differences in aging of brain areas that are essential to higher cognitive functioning. Thus, our findings may explain some of the age-sex differences in human cognition and response to brain injury and disease.
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Cytidine 5'-diphosphocholine, CDP-choline or citicoline, is an essential intermediate in the biosynthetic pathway of the structural phospholipids of cell membranes, especially in that of phosphatidylcholine. Upon oral or parenteral administration, CDP-choline releases its two principle components, cytidine and choline. When administered orally, it is absorbed almost completely, and its bioavailability is approximately the same as when administered intravenously. Once absorbed, the cytidine and choline disperse widely throughout the organism, cross the blood-brain barrier and reach the central nervous system (CNS), where they are incorporated into the phospholipid fraction of the membrane and microsomes. CDP-choline activates the biosynthesis of structural phospholipids in the neuronal membranes, increases cerebral metabolism and acts on the levels of various neurotransmitters. Thus, it has been experimentally proven that CDP-choline increases noradrenaline and dopamine levels in the CNS. Due to these pharmacological activities, CDP-choline has a neuroprotective effect in situations of hypoxia and ischemia, as well as improved learning and memory performance in animal models of brain aging. Furthermore, it has been demonstrated that CDP-choline restores the activity of mitochondrial ATPase and of membranal Na+/K+ ATPase, inhibits the activation of phospholipase A2 and accelerates the reabsorption of cerebral edema in various experimental models. CDP-choline is a safe drug, as toxicological tests have shown; it has no serious effects on the cholinergic system and it is perfectly tolerated. These pharmacological characteristics, combined with CDP-choline's mechanisms of action, suggest that this drug may be suitable for the treatment of cerebral vascular disease, head trauma of varying severity and cognitive disorders of diverse etiology. In studies carried out on the treatment of patients with head trauma, CDP-choline accelerated the recovery from post-traumatic coma and the recuperation of walking ability, achieved a better final functional result and reduced the hospital stay of these patients, in addition to improving the cognitive and memory disturbances which are observed after a head trauma of lesser severity and which constitute the disorder known as postconcussion syndrome. In the treatment of patients with acute cerebral vascular disease of the ischemic type, CDP-choline accelerated the recovery of consciousness and motor deficit, attaining a better final result and facilitating the rehabilitation of these patients. The other important use for CDP-choline is in the treatment of senile cognitive impairment, which is secondary to degenerative diseases (e.g., Alzheimer's disease) and to chronic cerebral vascular disease. In patients with chronic cerebral ischemia, CDP-choline improves scores on cognitive evaluation scales, while in patients with senile dementia of the Alzheimer's type, it slows the disease's evolution. Beneficial neuroendocrine, neuroimmunomodulatory and neurophysiological effects have been described. CDP-choline has also been shown to be effective as co-therapy for Parkinson's disease. No serious side effects have been found in any of the groups of patients treated with CDP-choline, which demonstrates the safety of the treatment.
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This report describes the implementation and application of a multicompartment analysis of ³¹P spectroscopic imaging data to determine the tissue-specific heterogeneities in metabolite content in the human brain and surrounding tissue. Using this information and a multicompartment regression analysis the phosphocreatine and ATP content of “pure” cerebral gray and white matter, the cerebellum, and skeletal muscle was determined in a group of 10 healthy volunteers. The data were converted to mM units using previously reported values for the T1s of phosphocreatine and ATP at 4 T, the water content of human brain, and an external reference for absolute quantification. The phosphocreatine concentration in cerebral gray and white matter, the cerebellum, and skeletal muscle was 3.53 ± 0.33, 3.33 ± 0.37, 3.75 ± 0.66, and 25.8 ± 2.3 mM, respectively. The ATP concentration in cerebral gray and white matter, the cerebellum, and skeletal muscle was 2.19 ± 0.33, 3.41 ± 0.33, 1.75 ± 0.58, and 8.5 ± 1.9 mM, respectively. Magn Reson Med 45:46–52, 2001. © 2001 Wiley-Liss, Inc.
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Mitochondria have been described as “the powerhouses of the cell” because they link the energy-releasing activities of electron transport and proton pumping with the energy conserving process of oxidative phosphorylation, to harness the value of foods in the form of ATP. Such energetic processes are not without dangers, however, and the electron transport chain has proved to be somewhat “leaky.” Such side reactions of the mitochondrial electron transport chain with molecular oxygen directly generate the superoxide anion radical (O2•−), which dismutates to form hydrogen peroxide (H2O2), which can further react to form the hydroxyl radical (HO). In addition to these toxic electron transport chain reactions of the inner mitochondrial membrane, the mitochondrial outer membrane enzyme monoamine oxidase catalyzes the oxidative deamination of biogenic amines and is a quantitatively large source of H2O2 that contributes to an increase in the steady state concentrations of reactive species within both the mitochondrial matrix and cytosol. In this article we review the mitochondrial rates of production and steady state levels of these reactive oxygen species. Reactive oxygen species generated by mitochondria, or from other sites within or outside the cell, cause damage to mitochondrial components and initiate degradative processes. Such toxic reactions contribute significantly to the aging process and form the central dogma of “The Free Radical Theory of Aging.” In this article we review current understandings of mitochondrial DNA, RNA, and protein modifications by oxidative stress and the enzymatic removal of oxidatively damaged products by nucleases and proteases. The possible contributions of mitochondrial oxidative polynucleotide and protein turnover to apoptosis and aging are explored.
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31P NMR is commonly used to study brain energetics in health and disease. Due to sensitivity constraints, the NMR measurements are typically made in volumes that do not contain pure gray or white matter. For accurate evaluation of abnormalities in brain metabolite levels, it is necessary to consider the differences in normal levels of 31P metabolites in gray and white matter. In this study, voxels from a three-dimensional spectroscopic image acquisition were analyzed for their dependence on tissue type to assess differences in metabolite levels between gray and white matter. Specifically, gray matter was found to have significantly higher ratios of phosphocreatine (PCr) to γ-ATP and PCr to the total 31P metabolite signal, whereas pH and the ratio of PCr to inorganic phosphate (P1) were found to differ insignificantly between gray and white matter. Thus, tissue type can be an important factor to consider for alterations in bioenergetics by 31P NMR spectroscopic studies of the brain.
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The mitochondrial respiratory chain is a powerful source of reactive oxygen species (ROS), considered as the pathogenic agent of many diseases and of aging. We have investigated the role of Complex I in superoxide radical production and found by combined use of specific inhibitors of Complex I that the one-electron donor in the Complex to oxygen is a redox center located prior to the sites where three different types of coenzyme Q (CoQ) competitors bind, to be identified with an Fe-S cluster, most probably N2, or possibly an ubisemiquinone intermediate insensitive to all the above inhibitors. Short-chain coenzyme Q analogues enhance superoxide formation, presumably by mediating electron transfer from N2 to oxygen. The clinically used CoQ analogue idebenone is particularly effective, raising doubts about its safety as a drug. The mitochondrial theory of aging considers somatic mutations of mitochondrial DNA induced by ROS as the primary cause of energy decline; in rat liver mitochondria, Complex I appears to be most affected by aging and to become strongly rate limiting for electron transfer. Mitochondrial energetics is also deranged in human platelets upon aging, as demonstrated by the decreased Pasteur effect (enhancement of lactate production by respiratory inhibitors). Cells counteract oxidative stress by antioxidants: CoQ is the only lipophilic antioxidant to be biosynthesized. Exogenous CoQ, however, protects cells from oxidative stress by conversion into its reduced antioxidant form by cellular reductases. The plasma membrane oxidoreductase and DT-diaphorase are two such systems: likewise, they are overexpressed under oxidative stress conditions.
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Interest in the role of mitochondria in aging has intensified in recent years. This focus on mitochondria originated in part from the free radical theory of aging, which argues that oxidative damage plays a key role in degenerative senescence. Among the numerous mechanisms known to generate oxidants, leakage of the superoxide anion and hydrogen peroxide from the mitochondrial electron transport chain are of particular interest, due to the correlation between species-specific metabolic rate (“rate of living”) and life span. Phenomenological studies of mitochondrial function long ago noted a decline in mitochondrial function with age, and on-going research continues to add to this body of knowledge. The extranuclear somatic mutation theory of aging proposes that the accumulation of mutations in the mitochondrial genome may be responsible in part for the mitochondrial phenomenology of aging. Recent studies of mitochondrial DNA (mtDNA) deletions have shown that they increase with age in humans and other mammals. Currently, there exist numerous important and fundamental questions surrounding mitochondria and aging. Among these are (1) How important are mitochondrial oxidants in determining overall cellular oxidative stress? (2) What are the mechanisms of mitochondrial oxidant generation? (3) How are lesions and mutations in mtDNA formed? (4) How important are mtDNA lesions and mutations in causing mitochondrial dysfunction? (5) How are mitochondria regulated, and how does this regulation change during aging? (6) What are the dynamics of mitochondrial turnover? (7) What is the relationship between mitochondrial damage and lipofuscinogenesis? (8) What are the relationships among mitochondria, apopotosis, and aging? and (9) How can mitochondrial function (ATP generation and the establishment of a membrane potential) and dysfunction (oxidant generation) be modulated and degenerative senescence thereby treated?
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We examined the effects of orally administered 5′-cytidinediphosphocholine (CDP-choline) on arterial plasma choline and cytidine levels and on brain phospholipid composition in rats. Animals receiving a single oral dose of 100, 250, or 500 mg/kg showed peak plasma choline levels 6–8 h after drug administration (from 12 ± 1 to 17 ± 2, 19 ± 2, and 24 ± 2 µM, respectively). The area under the plasma choline curve at >14 µM, i.e., at a concentration that induces a net influx of choline into the brain, was significantly correlated with CDP-choline dose. In rats receiving 500 mg/kg this area was 2.3 times that of animals consuming 250 mg/kg, which in turn was 1.8 times that of rats receiving 100 mg/kg. Plasma cytidine concentrations increased 5.4, 6.5, and 15.1 times baseline levels, respectively, 8 h after each of the three doses. When the oral CDP-choline treatment was prolonged for 42 and 90 days, brain phosphatidylcholine concentrations increased significantly (by 22–25%; p < 0.05) in rats consuming 500 mg/kg/day. Brain phosphatidylethanolamine and phosphatidylserine concentrations also increased significantly under some experimental conditions; levels of other phospholipids were unchanged.
Article
Functional magnetic resonance imaging (fMRI) was used to examine the pattern of activity of the prefrontal cortex during performance of subjects in a nonspatial working memory task. Subjects observed sequences of letters and responded whenever a letter repeated with exactly one nonidentical letter intervening. In a comparison task, subjects monitored similar sequences of letters for any occurrence of a single, prespecified target letter. Functional scanning was performed using a newly developed spiral scan image acquisition technique that provides high-resolution, multislice scanning at approximately five times the rate usually possible on conventional equipment (an average of one image per second). Using these methods, activation of the middle and inferior frontal gyri was reliably observed within individual subjects during performance of the working memory task relative to the comparison task. Effect sizes (2–4%) closely approximated those that have been observed within primary sensory and motor cortices using similar fMRI techniques. Furthermore, activation increased and decreased with a time course that was highly consistent with the task manipulations. These findings corroborate the results of positron emission tomography studies, which suggest that the prefrontal cortex is engaged by tasks that rely on working memory. Furthermore, they demonstrate the applicability of newly developed fMRI techniques using conventional scanners to study the associative cortex in individual subjects. © 1994 Wiley-Liss, Inc.
Article
Mitochondria have been described as “the powerhouses of the cell” because they link the energy-releasing activities of electron transport and proton pumping with the energy conserving process of oxidative phosphorylation, to harness the value of foods in the form of ATP. Such energetic processes are not without dangers, however, and the electron transport chain has proved to be somewhat “leaky.” Such side reactions of the mitochondrial electron transport chain with molecular oxygen directly generate the superoxide anion radical (O2•−), which dismutates to form hydrogen peroxide (H2O2), which can further react to form the hydroxyl radical (HO). In addition to these toxic electron transport chain reactions of the inner mitochondrial membrane, the mitochondrial outer membrane enzyme monoamine oxidase catalyzes the oxidative deamination of biogenic amines and is a quantitatively large source of H2O2 that contributes to an increase in the steady state concentrations of reactive species within both the mitochondrial matrix and cytosol. In this article we review the mitochondrial rates of production and steady state levels of these reactive oxygen species. Reactive oxygen species generated by mitochondria, or from other sites within or outside the cell, cause damage to mitochondrial components and initiate degradative processes. Such toxic reactions contribute significantly to the aging process and form the central dogma of “The Free Radical Theory of Aging.” In this article we review current understandings of mitochondrial DNA, RNA, and protein modifications by oxidative stress and the enzymatic removal of oxidatively damaged products by nucleases and proteases. The possible contributions of mitochondrial oxidative polynucleotide and protein turnover to apoptosis and aging are explored.
Article
Administered intravenously to rats, CDPcholine, significantly increases the level and the synthesis rate of dopamine, and the level of tyrosine in the corpus striatum (maximum effect for 50 mg/kg, one hour after administration). CDPcholine decreases the level of serotonin and tryptophan and the synthesis rate of serotonin in the midbrain + hypothalamus and in the brain stem. The increase of the striatum dopamine level and the decrease of the brain stem and midbrain serotonin level are correlated with the recognized antiparkinson and neurostimulant action of this nucleotide.
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The effect of hypoxia on the protein composition of mitochondria from cerebral cortex of rats at 4, 12, and 24 months of age was investigated. The proteins were separated by electrophoresis on SDS polyacrylamide gels and the percent content was evaluated by measuring the optical density of the stained gels. The results demonstrate that hypoxic treatment causes a decrease in the amount of some proteins as follows: the 90 and the 16 kDa Mw proteins at 4 months; the 82 and the 79 kDa Mw proteins at 24 months; the 52-49, 35 and 20 kDa at all ages investigated; the 44 kDa protein at 4 and 12 months and the 28 kDa protein at 4 and 24 months of age. Our results show that hypoxic conditions affect mitochondrial protein composition to a greater extent than aging alone.
Article
The synaptic energy state may be defined by the redox state of the intramitochondrial NAD-couple (delta Gox-red) and the phosphorylation state of adenine nucleotide system (delta GATP). The biological energy 'lost' by the system during the coupled reactions is calculated as delta delta G = delta Gox-red-delta GATP. These evaluations are performed in synaptosomes isolated from the forebrain of rats of different ages (20, 60 and 100 weeks of age) and incubated in Krebs-Henseleit-Hepes (pH 7.4) buffer, for 10 min at 24 degrees C. The animals are submitted for 10 min to different degrees of in vivo hypoxia. To better elucidate the mechanism of action, the effects of the pretreatment with agents inducing vasodilation (papaverine), or acting on cerebral carbohydrate metabolism (hopanthenate), or on neurotransmission and cerebral metabolism (theniloxazine) are tested. In synaptosomes isolated from the forebrain of animals submitted to moderate degree of hypoxia (PaO2 = 32-29 mmHg) the efficiency of the system is quite similar to that observed in normoxia, with the exception of the older rats. In synaptosomes isolated from the forebrain of rats submitted to severe degree of hypoxia (PaO2 = 20-18 mmHg) the efficiency is altered as a function of both aging and severity of hypoxemia. Drug pretreatment may partially interfere with the delta delta G by hypoxemia, the action being related to the rat age and hypoxic degrees. The age-related decrease in the efficiency of the coupled states seems to be related to alteration in the phosphorylation state of adenine nucleotides.
Article
The relationship between biochemical and physiological responses and tissue O2 during hypoxia was investigated in vivo in the dog brain by 31P nuclear magnetic resonance (NMR) spectroscopy. Our findings demonstrate how ATP synthesis in the brain can be maintained during hypoxia because of compensatory changes in NADH, ADP, and Pi. Eleven beagle dogs were anesthetized and mechanically ventilated, and a steady-state graded hypoxia was induced by decreasing the fraction of inspired O2 (FIO2) stepwise at 20-min intervals. Biochemical metabolites were measured using 31P-NMR and fluorescence spectroscopy. When sagittal sinus O2 partial pressure (PVO2) had decreased to 15 Torr, NADH increased by 30%, Pi increased by 50%, and phosphocreatine (PCr) decreased by 20%. In contrast, ATP remained constant. There was a 10% increase in ADP in dogs that maintained a steady temperature, but ADP decreased by as much as 30% in dogs in which body temperature decreased with the falling PVO2. PCr/Pi was logarithmically related to the phosphorylation potential during steady-state hypoxia. Compensation for the O2 lack is attributed to increases in ADP, Pi, and NADH as a result of the reciprocal relationship of the Michaelis-Menten equation. If the Michaelis-Menten constants (Km) of ADP, Pi, and O2 are the same as determined in vitro in mitochondria, the minimum brain cytosolic O2 capable of maintaining a steady-state ATP is near its Km (0.1 Torr) at a PVO2 of 7.5 Torr. At this critical O2 level, PCr/Pi is 0.9, intracellular pH is 6.75, phosphorylation potential is 38.5 mM-1, and the calculated maximum velocity of ATP formation by oxidative phosphorylation is 55% of normal.
Article
This article outlines a theoretical framework for the understanding of the neural basis of memory and consciousness, at systems level. It proposes an architecture constituted by: (1) neuron ensembles located in multiple and separate regions of primary and first-order sensory association cortices ("early cortices") and motor cortices; they contain representations of feature fragments inscribed as patterns of activity originally engaged by perceptuomotor interactions; (2) neuron ensembles located downstream from the former throughout single modality cortices (local convergence zones); they inscribe amodal records of the combinatorial arrangement of feature fragments that occurred synchronously during the experience of entities or events in sector (1); (3) neuron ensembles located downstream from the former throughout higher-order association cortices (non-local convergence zones), which inscribe amodal records of the synchronous combinatorial arrangements of local convergence zones during the experience of entities and events in sector (1); (4) feed-forward and feedback projections interlocking reciprocally the neuron ensembles in (1) with those in (2) according to a many-to-one (feed-forward) and one-to-many (feedback) principle. I propose that (a) recall of entities and events occurs when the neuron ensembles in (1) are activated in time-locked fashion; (b) the synchronous activations are directed from convergence zones in (2) and (3); and (c) the process of reactivation is triggered from firing in convergence zones and mediated by feedback projections. This proposal rejects a single anatomical site for the integration of memory and motor processes and a single store for the meaning of entities of events. Meaning is reached by time-locked multiregional retroactivation of widespread fragment records. Only the latter records can become contents of consciousness.
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Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, and ethanolamine plasmalogen represent the six most abundant phospholipids of brain cell membrane. The ratio of the phospholipid contents (phospholipid profile) of the brain is remarkably consistent under various metabolic conditions and alteration of the phospholipid profile is believed to reflect changes in the membrane system. We describe here a simple but sensitive method to analyze the phospholipid profile of the human brain utilizing the acidified chloroform-methanol lipid extraction method of Folch et al. and 31P nuclear magnetic resonance (NMR) spectroscopy. Unique regional phospholipid profiles were consistently obtained. Although the large chemical-shift anisotropy of the 31P confined to rigid structures such as the cell membrane precludes direct observation of phospholipid profiles in living tissue, a reflection of the membrane phospholipid profiles can nevertheless be obtained by studying "NMR visible" water soluble intermediate metabolites of membrane phospholipids in vivo.
Article
The incisive detection of bioenergetic insufficiency in an organ of known workload by P MRS is noninvasive and nondestructive, and in some cases the portion of the organ involved can be determined, particularly if both PCr and ATP are depleted. The fractional loss of ATP and hence the relative volumes of viable and "metabolically dead" tissue are thereby evaluated. In addition, the value of P MRS in following a therapy complements its value in diagnosis as this has been demonstrated in cases followed over 6 months to three years. The fact that deficiencies of the enzymes and substrates of oxidative metabolism can be detected by P MRS affords a global overview of energy metabolism that can be a key to rapid diagnosis. The distinction of the enzyme and/or substrate deficiency, while not directly indicated by steady state P MRS, can be identified by use of the "Crossover Theorem" and its impact upon blood and tissue levels of substrates (including oxygen). In the case of neonatal systemic hypoxia, there is no doubt about which of the equations applies, and similarly in metabolic disease, a glutaric acid urea is a direct consequence of the crossover response of metabolism and signifies that an enzyme deficiency may be involved. Furthermore, the clinical danger of a high Pi/PCr value is clarified by our observations, both from the animal models and from the theory, the high clues; i.e. 2 and over, suggest work stresses near the capability of oxidative metabolism and imminent failure of the negative feedback afforded by metabolic regulation, particularly ADP control of oxidative metabolism. This control is lost because of the fall of phosphocreatine to the point where creatine kinase is no longer in equilibrium, leading to the loss of ATP and its conversion to large amounts of ADP and its breakdown products. ATP then stimulates glycolysis and results in a massive lactic acidosis. At the same time, the low thermodynamic capability of glycolytic metabolism is unable to prevent irreversible ion disequilibration, water movements, edema, and eventually rupture of the cell membrane. The pathway of resynthesis of ATP is then tortuous, particularly as AMP is deaminated and adenosine is converted eventually to hypoxanthine. Thus, NMR reports that metabolic control is operating in the region where homeostasis of biochemical parameters is feasible. It further reports regions where the metabolic control is susceptible to failure and most aggressive clinical care is required.
Article
Cholinergic neurons are unique among cells since they alone utilize choline not only as a component of major membrane phospholipids, such as phosphatidylcholine (Ptd-Cho), but also as a precursor of their neurotransmitter acetylcholine (AcCho). It has been hypothesized that choline-phospholipids might serve as a storage pool of choline for AcCho synthesis. The selective vulnerability of cholinergic neurons in certain neurodegenerative diseases (e.g., Alzheimer disease, motor neuron disorders) might result from the abnormally accelerated liberation of choline (to be used as precursor of AcCho) from membrane phospholipids, resulting in altered membrane composition and function and compromised neuronal viability. However, the proposed metabolic link between membrane turnover and AcCho synthesis has been difficult to demonstrate because of the heterogeneity of the preparations used. Here we used a population of purely cholinergic cells (human neuroblastoma, LA-N-2), incubated in the presence of [methyl-3H]methionine to selectively label PtdCho synthesized by methylation of phosphatidylethanolamine, the only pathway of de novo choline synthesis. PtdCho, purified by thin-layer chromatography, contained 90% of the label incorporated into lipids, demonstrating that LA-N-2 cells contained phosphatidylethanolamine N-methyltransferase. Three peaks of radioactive material that cochromatographed with authentic Ac-Cho, choline, and phosphocholine were observed when the water-soluble metabolites of the [3H]PtdCho were purified by high-performance liquid chromatography. Their identities were ascertained by subjecting them to enzymatic modifications with acetylcholinesterase, choline oxidase, and alkaline phosphatase, respectively. The results demonstrate that AcCho can be synthesized from choline derived from the degradation of endogenous PtdCho formed de novo by methylation of phosphatidylethanolamine.
Article
The in vivo dog brain 31P NMR spectrum has a large peak in the phosphodiester region accounting for more than 35% of the total observable phosphorus metabolites. It is possible to reduce the intensity of this peak by off-resonance saturation. To characterize the nature of this peak, extracts of dog brain frozen in situ were analyzed by high resolution 31P NMR. ATP, phosphocreatine, inorganic phosphate, and phosphomonoesters were recovered in appropriate amounts in the methanol:HCl extract. However, acid soluble phosphodiesters accounted for only 8% of the observable phosphorus. More NMR observable phosphodiesters were selectively recovered following CHCl3:methanol extraction of phospholipids. These results suggest that the in vivo phosphodiester resonance has substantial contributions from a fraction of mobile brain phospholipids.
Article
:The author suggests that the maximal life span of a given mammalian species is largely an expression of genetic control over the rate of oxygen utilization. The latter determines the rate of accumulation of mitochondrial damage produced by free radical reactions, the rate increasing with the rate of oxygen consumption, which ultimately causes death.
Article
The effect of CDP-choline on the in vivo incorporation of labeled precursors into DNA, RNA, and proteins in cerebral hemispheres, cerebellum, and brainstem of guinea pigs after hypoxic treatment was studied. The labeling of macromolecules extracted from the various subcellular fractions of these brain regions was also determined. Hypoxic treatment affected macromolecular labeling to a different extent in the three brain regions examined. CDP-choline treatment was not able to reverse the effect of hypoxia on DNA labeling, but it was able to remove the effect of hypoxia on RNA and protein labeling. The action of CDP-choline was particularly evident on the labeling of RNA in nuclei and mitochondria of the cerebellum and on the labeling of proteins in microsomes of the three brain regions examined.
Article
Pulse-chase experiments with [3H]serine provide evidence that significant amounts of phosphatidylserine turn over to form phosphatidylethanolamine in mammalian cells in tissue culture. Phospholipase C hydrolysis of [3H]phosphatidylethanolamine synthesized from [3H]serine by baby hamster kidney (BHK-21) cells demonstrates that nearly all of the radiolabel remains in the ethanolamine moiety. Uniform labeling experiments with [3H]serine further demonstrate that the distribution of radiolabel in phosphatidylserine and phosphatidylethanolamine is nearly identical to the mass ratio of these lipids. Physiological concentrations of ethanolamine (20 microM) have only a marginal effect upon the ability of cells in culture to incorporate radiolabeled serine into either phosphatidylserine or phosphatidylethanolamine. These data provide compelling evidence that phosphatidylethanolamine synthesis via phosphatidylserine and phosphatidylserine decarboxylase contributes significantly to membrane biogenesis in mammalian cells.
Article
The maximal rate of some cerebral enzymatic activities related to energy transduction (hexokinase; phosphofructokinase; lactate dehydrogenase; citrate synthase; malate dehydrogenase; total NADH-cytochrome c reductase; cytochrome oxidase), amino acid metabolism (glutamate decarboxylase; glutamate dehydrogenase) and cholinergic metabolism (acetylcholine esterase) were tested in the cerebral cortex and in sub-cortical area of rats. The evaluations were performed both in the homogenate in toto and in the crude mitochondrial fraction, before and after a postdecapitative normothermic ischemia of 5, 10, 20, and 40 min duration. The results are discussed also with respect to the pharmacological pretreatment with two biological substances which may modulate amino acid (L-alanine) and phospholipid metabolism (CDP-choline). The analysis of the present data suggests the occurrence in brain tissue of a variety of interrelated factors implicated in the ischemia-induced changes of the maximal rate of the enzymatic activities related to the energy transduction. These include: (a) rearrangement of the enzymatic activities because of the changed metabolic and chemico-physical condition; (b) decrease in the activity of enzymes related to the electron transfer chain and glycolysis; (c) changes in enzymes related to mitochondrial membranes. The effects of in vivo administration of alanine or CDP-choline, even if significant, are not consistent throughout the time period studied.
Article
To demonstrate the feasibility of using NMR spectra of human limbs and larger animals for continuous, noninvasive, nondestructive evaluation of cell bioenergetics, we have constructed a relatively simple and inexpensive 31P NMR apparatus. This apparatus consists of an 18-cm (7-in.) bore superconducting magnet and appropriate transmit-receive components for Fourier transform NMR. The principal signals observed by this instrument in the tissues are due to phosphocreatine and inorganic phosphate. The apparatus can be used to detect tissue normoxia and hypoxia. The large phosphocreatine/phosphate ratio (greater than 10:1), and the low phosphate signal from normoxic tissue (approximately 10% of the phosphocreatine signal from brain and human skeletal tissue) make an increased phosphate peak a very sensitive indicator of tissue hypoxia. Direct experiments on the human forearm and leg and the brains of dog and rabbit suggest the applicability of 31P NMR to humans and animals. This method and optical methods can both be used for quantitative determination of oxygen delivery to tissue, function of mitochondria, and the coupling of bioenergetic processes to functional activity in skeletal tissue and brain.
Article
The [18F]fluorodeoxyglucose (FDG) scan method with positron emission computed tomography was used to determine patterns of local cerebral glucose utilization (LCMRglu) in 40 normal volunteer subjects aged 18 to 78 years. Throughout all the studies, each subject was quiet, without movement, with eyes open and ears unplugged, exposed only to ambient room light and sound. For the entire group, whole brain mean CMRglu was 26.1 +/- 6.1 mumol 100 g-1 min-1 (mean +/- SD, n = 40). At age 78, mean CMRglu was, on the average, 26% less than at age 18, an alteration of the same order as the variance among subjects at any age. The gradual decline of mean CMRglu with advancing age occurred at a faster rate than was reported for mean cerebral oxygen utilization, possibly due to increasingly altered pathways for glucose utilization, or to increasing oxidation of ketone bodies or other alternative substrates. Glucose utilization in the hemispheres was symmetrical and mean CMRglu of overall cortex, caudate, and thalamus was equal in individuals at all ages. The slopes of decline with age were similar when LCMRglu was averaged over zones corresponding to centrum semiovale, caudate, putamen, and frontal, temporal, parietal, occipital, and primary visual cortex. However, the metabolic ratio of superior frontal cortex to superior parietal cortex declined with age, possibly due to selective degeneration of superior frontal cortex or to differences between age groups in the sensory and cognitive response to the study. These results should be useful in distinguishing age from disease effects when the FDG scan method is used.
Article
The synaptosomal fractions obtained from the motor area of the cerebral cortex of normocapnic, normoxic, or hypoxic, untreated beagle dogs and of pentobarbital (Nembutal)- or cytidine diphosphate (CDP)-choline-treated dogs were incubated and analyzed for ATP, ADP, AMP, creatine phosphate, pyruvate, and lactate. The data were compared with data obtained by the surface freezing technique from the whole contralateral cortical area. The in vivo intracarotid perfusion of the drug differentially affected the content of the metabolites and their ratio. This occurred whether the evaluations were performed in the incubated synaptosomal preparations or in whole cerebral tissue, both during normoxia and after hypoxia (15 min; PaO2 = 17-19 mm Hg). Thus, intracarotid perfusion of nembutal increased the synaptosomal phosphorylation state both in normoxic and in hypoxic animals, whereas the effect on the metabolism of the contralateral cortical motor area as a whole was in all cases less than that observed in the synaptosomal fraction. Perfusion with CDP-choline increased synaptosomal phosphorylation after the hypoxic condition, but had no effect in normoxia or on the whole cortical tissue of the motor area. The possibility of obtaining a cerebral sparing action by utilizing molecules devoid of anesthetic action is suggested.
Article
The synthesis of sphingomyelin was studied in baby hamster kidney cells and in subcellular fractions derived from rat liver. During pulse-chase experiments with [3H]choline in tissue culture cells, the specific radioactivity of sphingomyelin continued to increase after the specific activities of phosphocholine and cytidine 5'-diphosphate choline (CDP-choline) had declined by a factor of 10. The addition of [3H]methionine to cells that were grown in 1 mM dimethylethanolamine efficiently radiolabeled phosphatidylcholine (by methylation of phosphatidyldimethylethanolamine) and sphingomyelin but not phosphocholine or CDP-choline. Thus, the proximal donor of the phosphocholine moiety of sphingomyelin was not CDP-choline but probably phosphatidylcholine. These in vivo results prompted investigation of the enzymic synthesis using phosphatidyl[3H]choline or [3H]ceramide as substrates. With both substrates the subcellular fraction with the highest specific enzyme activity was the plasma membrane. When phosphatidyl[3H]choline was used as the substrate, phospholipid exchange proteins were included in the reaction to effect the transfer of the labeled phospholipid from liposomes into the membrane bilayer in which the enzyme resided. Under these conditions the synthesis of sphingomyelin was almost completely dependent upon the addition of phospholipid exchange proteins. When [3H]ceramide was used as the substrate, the addition of detergents was necessary for sphingomyelin synthesis. The use of phospholipid exchange proteins to introduce lipid substrates to membrane-bound enzymes may have much broader applicability.