Effect Of CDP-choline Research Articles

Effects of CDP-Choline and Choline on COX Pathway in LPS-Induced Inflammatory Response in Rats

Effects of CDP-Choline and Choline on COX Pathway in LPS-Induced Inflammatory Response in Rats

Cytidine 5'-diphosphocholine differentially affects hemostatic parameters in diverse conditions in rats: an investigation via thromboelastography.

Cytidine 5'-diphosphocholine (CDP-choline) has several physiological and pharmacological effects on various bodily functions, including hemostasis. This study determined the impact of CDP-choline on hemostasis in a trauma-hemorrhage (T-H) model in rats or under in vitro conditions or after chronic treatment via thromboelastography. Trauma-hemorrhage resuscitation was induced, and either saline (1 mL/kg) or CDP-choline (50 mg/kg) was injected intravenously just prior to resuscitation in the T-H group and at the same time point in the sham-control group. The effects of CDP-choline on thromboelastogram parameters, coagulation markers, and platelet aggregation were investigated under in vitro conditions (1.5 mM, 30- or 3-min incubation in blood or plasma) and after chronic use (50 mg/kg, i.p., 10 days). Acute CDP-choline treatment was shown to decrease the initial and maximum clot formation time, accelerate clotting rapidity, reduce the lysis percentage, and increase the coagulation index in the T-H resuscitation group, whereas the same treatment in the sham-control rats did not alter any of the thromboelastogram parameters. However, the incubation of whole blood with CDP-choline prolonged the initial and maximum clot formation time, and CDP-choline treatment significantly decreased the slopes of the disaggregation and aggregation curves when platelets were stimulated with ADP and collagen, respectively. Interestingly, the chronic use of this drug did not influence any of these hemostatic parameters. These data implicate that acute but not chronic CDP-choline administration may differentially alter the hemostatic parameters under diverse conditions. The drug may produce a hypercoagulable state in activated situations but cause opposite effects under normal in vitro conditions.

The choline pathway as a strategy to promote central nervous system (CNS) remyelination.

The choline pathway as a strategy to promote central nervous system (CNS) remyelination.

Role of central arginine vasopressin receptors in the analgesic effect of CDP-choline on acute and neuropathic pain

Recent studies have demonstrated that arginine vasopressin (AVP) plays a crucial role in pain modulation. In addition, our previous studies have proven that centrally administered cytidine-5'-diphosphate-choline (CDP-choline; citicoline) elicits an analgesic effect in different pain models in rats. Given that CDP-choline enhances central and peripheral vasopressin levels, the present study was designed to investigate the role of central AVP receptors in the analgesic effect of CDP-choline in acute and chronic constriction injury-induced neuropathic pain models. For this purpose, rats were pretreated intracerebroventricularly with the AVP V1 or AVP V2 receptor antagonist 15 min before intracerebroventricular injection of CDP-choline or saline, and pain threshold was determined using the Randall-Selitto test. AVP V1 and AVP V2 receptor antagonist blocked the CDP-choline-induced analgesic effect either in acute or neuropathic models of pain in rats. These results suggest, for the first time, that central AVP receptors are involved in the CDP-choline-elicited analgesic effect.

耳鳴, 難聴, めまいなどに対するCDP-choline (Nicholin) の効果

耳鳴, 難聴, めまいなどに対するCDP-choline (Nicholin) の効果

Effect of cdp-choline on microcirculatory alterations during endotoxemia

The cholinergic anti-inflammatory pathway (CAP) is a physiological mechanism that inhibits cytokine production and minimizes tissue injury during inflammation. CAP-mediated anti-inflammatory signals in vagal efferent nerve fibers result in the release of acetylcholine, which interacts with innate immune cells that express the nicotinic acetylcholine receptor subunit α7 (α7nAChR). Endothelial dysfunction during sepsis is responsible for increased endothelial permeability, leukocyte-endothelial interaction and functional breakdown of microvascular perfusion. Endotoxemia-induced endothelial dysfunction can be reduced by cholinergic CAP activation [1]. The aim of this study was to determine the effects of the α7nAChR-agonist cdp-choline on microcirculatory alterations during experimental endotoxemia.

Effect of CDP-choline on age-dependent modifications of energy- and glutamate-linked enzyme activities in synaptic and non-synaptic mitochondria from rat cerebral cortex

The effect of aging and CDP-choline treatment (20mgkg−1 body weight i.p. for 28days) on the maximal rates (Vmax) 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 24months.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 18months, 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.

Effect of CDP-choline and erythropoietin on ultrastructural characteristics of neurodegeneration in a model of slow glutamate excitotoxicity in vitro

Effect of CDP-choline and erythropoietin on ultrastructural characteristics of neurodegeneration in a model of slow glutamate excitotoxicity in vitro

Effects of cytidine 5′-diphosphocholine (CDP-choline) on the thermal nociceptive threshold in streptozotocin-induced diabetic mice

Neuropathy accompanied by abnormal sensory perception is the most common complication in insulin-dependent and -independent diabetes mellitus. Since there are very few effective therapeutic regimens for sensory abnormalities in diabetes, we examined the effect of cytidine 5′-diphosphocholine (CDP)-choline on the thermal nociceptive threshold in streptozotocin-induced diabetic mice using the tail-flick test. Diabetic mice showed a shorter tail-flick latency at 1–4 weeks after streptozotocin treatment and a longer tail-flick latency after 8–12 weeks. This hyper- and hypoalgesia in diabetic mice was almost completely inhibited by daily treatment with CDP-choline (100mg/kg/day, p.o.) beginning on the day of streptozotocin treatment. Daily treatment with CDP-choline beginning 5 weeks after streptozotocin treatment attenuated the development of hypoalgesia. Diabetic mice showed a significant increase in Na +-K +-ATPase activity at 3 weeks after streptozotocin treatment, whereas Na +-K +-ATPase activity was decreased at 12 weeks after treatment. These alterations were normalized by daily treatment with CDP-choline (100mg/kg/day, p.o.) beginning the day of streptozotocin treatment. These results provide evidence to support the therapeutic potency of CDP-choline on the development of thermal hyper- and hypoalgesia and the progression of thermal hypoalgesia in diabetic mice. Moreover, these effects of CDP-choline may result from the normalization of Na +-K +-ATPase activity.

Cytidine-5-diphosphocholine supplement in early life induces stable increase in dendritic complexity of neurons in the somatosensory cortex of adult rats

Cytidine-5-diphosphocholine (CDP-choline or citicholine) is an essential molecule that is required for biosynthesis of cell membranes. In adult humans it is used as a memory-enhancing drug for treatment of age-related dementia and cerebrovascular conditions. However the effect of CDP-choline on perinatal brain is not known. We administered CDP-choline to Long Evans rats each day from conception (maternal ingestion) to postnatal day 60 (P60). Pyramidal neurons from supragranular layers 2/3, granular layer 4 and infragranular layer 5 of somatosensory cortex were examined with Golgi–Cox staining at P240. CDP-choline treatment significantly increased length and branch points of apical and basal dendrites. Sholl analysis shows that the complexity of apical and basal dendrites of neurons is maximal in layers 2/3 and layer 5. In layer 4 significant increases were seen in basilar dendritic arborization. CDP-choline did not increase the number of primary basal dendrites on neurons in the somatosensory cortex. Primary cultures from somatosensory cortex were treated with CDP-choline to test its effect on neuronal survival. CDP-choline treatment neither enhanced the survival of neurons in culture nor increased the number of neurites. However significant increases in neurite length, branch points and total area occupied by the neurons were observed. We conclude that exogenous supplementation of CDP-choline during development causes stable changes in neuronal morphology. Significant increase in dendritic growth and branching of pyramidal neurons from the somatosensory cortex resulted in enlarging the surface area occupied by the neurons which we speculate will augment processing of sensory information.

Citicoline Inhibits MAP Kinase Signalling Pathways after Focal Cerebral Ischaemia

The link between membrane phospholipids and different intracellular signal transduction pathways affected by cerebral ischaemia is unclear. CDP-choline, a major neuronal membrane lipid precursor and its intracellular target proteins and transcription factors were studied to further understand its role in ischaemic stroke. Cerebral ischaemia was produced by distal, permanent occlusion of the middle cerebral artery (MCAO) in the rat. Animals receiving 500 mg/kg of CDP-choline in 0.5 ml of 0.9% saline, intraperitoneally, 24 h and 1 h before MCAO and 23 h after MCAO demonstrated a notable reduction in the phosphorylation of MAP-kinase family members, ERK1/2 and MEK1/2, as well as Elk-1 transcription factor, compared with control animals treated with 0.5 ml of 0.9% saline. Immunohistochemistry showed a particular reduction in immunoreactivity in glia. The effects of CDP-choline on intracellular mechanisms of signal transduction, suggests that this molecule may play a key role in recovery after ischaemic stroke.

Effect of CDP-choline on brain acetylcholinesterase and Na +,K +-ATPase in adult rats

Objective: The aim of this work was to investigate the effect of different cytidine-5′-diphosphocholine (CDP-choline) concentrations (0.1–1 mM) on acetylcholinesterase (AChE), (Na +,K +)-ATPase and Mg 2+-ATPase activities in homogenates of adult rat whole brain and in pure (nonmembrane bound) enzymes. Design and Methods: Tissues were homogenized, centrifuged at 1000 ×g for 10 min, and in the supernatant AChE activity and Na +,K +-ATPase, Mg 2+-ATPase activities were determined according to Ellman’s method and Bowler’s and Tirri’s, respectively. Results: After a 1–3 h CDP-choline preincubation, this substance induced a maximal stimulation of 20%–25% (p < 0.001) for AChE and 50-55% ( p < 0.001) for Na +,K +-ATPase, but it did not influence Mg 2+-ATPase activity. One mM acetylcholine (ACh) resulted in an approximately 18% ( p < 0.001) AChE inhibition by excess substrate in the brain homogenate, while 0.01 mM noradrenaline did not influence Na +,K +-ATPase activity. Conclusions: CDP-choline can stimulate brain AChE and Na +,K +-ATPase independently of ACh and noradrenaline. This enzymatic stimulation may be due to the transformation of CDP-choline to membrane phophatidylcholine. The above data could explain in part the clinical effects of this substance in some neuronal disturbances.

Effects of CDP-Choline on acetylcholine-induced relaxation of the perfused carotid vascular beds of the rat

1. The effects of an infusion of cytidine-5′-diphosphocholine (CDP-choline) on the relaxation induced by exogenous acetylcholine (ACh) was studied in the isolated and perfuded external (ECB) and internal (ICB) carotid vascular beds of the rat. Changes in perfusion pressure were recorded during a dose-response curve to ACh and after a 30 min perfusion with CDP-choline (1 mg/min). 2. ACh induced a dose-dependent relaxation in both vascular beds, indicating the presence of muscarinic receptors. The affinity of the receptors for ACh in the ICB was significantly lower than in the ECB (ED 50: 120 ± 21.4 ng and 69 ± 10.3 ng, respectively). 3. In the ICB the infusion of CDP-choline for 30 min significantly shifted the dose-response curve to ACh to the left, potentiating the relaxation. This effect was not seen in the ECB. 4. The infusion of hemicholinium (4 μM) for 30 min together with CDP-choline completely prevented the potentiation of exogenous ACh-induced relaxation in the ICB. 5. The results of the present work suggest that CDP-choline is acting by increasing choline levels in the cholinergic nerve terminals of the ICB, increasing the synthesis and/or release of ACh.

Effect of CDP-choline on cognition and immune function in Alzheimer's disease and multi-infarct dementia

The present study aimed to investigate the metabolic profile, as well as the antioxidant and anti-ageing activities of twenty propolis samples from different regions of Greece. Chemical profiling of methanolic extracts was investigated using HPTLC and 1H-NMR techniques. Their antioxidant activity was evaluated by free radical scavenging methods (DPPH and ABTS), whereas anti-ageing properties were assessed as anti-collagenase activity. Extracts were also investigated in vitro for their ability to inhibit tyrosinase, which is responsible for the oxidation of L-DOPA to dopachrome and the production of melanin. The HPTLC and NMR analysis revealed high variability in the phytochemical profile of the methanolic extracts, with three major groups to be observed: a) Group I, consisting of samples rich in terpenoids, which present low antioxidant but high anti-tyrosinase activity, b) Group II, consisting of samples rich in flavonoids, which form a broad cluster with major similarities at the aromatic region and showed the highest anti-oxidant and anti-collagenase activities and c) Group III, consisting of samples with lower flavonoid content than the samples of Group II, which exhibited moderate antioxidant, anti-collagenase and anti-tyrosinase activities.In conclusion, this study has shown high differentiation on the chromatographic and spectroscopic metabolic profile of Greek propolis samples of different geographical origin, which is also reflected in their biological properties. Their important effects as antioxidant, anti-tyrosinase and anti-collagenase agents make propolis an important potent ingredient in the industry of food supplements and cosmeceuticals. Moreover, a correlation of a particular chemical propolis type to a specific type of biological activity will allow to prepare standardized extracts and develop food supplements and cosmeceuticals possessing the desired pharmacological properties.

Effects of CDP-choline on the recovery of patients with head injury

A single blind randomized study has been conducted in 216 patients with severe or moderate head injury, with the aim of comparing the evolution of those that received only conventional treatment with the evolution of those treated with CDP-choline. Our results indicate that CDP-choline improves the global outcome of patients. We have found a trend towards a greater improvement in motor, cognitive and psychic alterations in the patients treated with CDP-choline, as well as a shortening of the stay in the hospital ward in the patients receiving this drug that initially presented with severe head injuries.

Effect of CDP-choline on age-related changes of non-synaptic mitochondrial enzyme systems of cerebral cortex

Effect of CDP-choline on age-related changes of non-synaptic mitochondrial enzyme systems of cerebral cortex

Circling behaviour in rats with unilateral lesions of the nigrostriatum induced by 6-hydroxydopamine: changes induced by oral administration of cytidine-5'-diphosphocholine.

A unilateral administration of 6-hydroxydopamine into the nigrostriatal system of the rat was responsible for ipsiversive circling behaviour in response to administration and, in time, of contraversive circling behaviour in response to L-DOPA and apomorphine. This contraversive circling behaviour appears to be mediated by the development, on the lesioned side, of supersensitivity of postsynaptic dopamine receptors. Subchronic treatment with cytidine-5'-diphosphocholine (p.o.) by itself was devoid of behavioural effects. The CDP-choline did not modify the apomorphine-induced stimulant effect but potentiated the circling behaviour produced by L-DOPA and amphetamine. The data show that the effects of CDP-choline were mediated by a presynaptic mechanism: the potentiation of the effects of L-DOPA cannot be explained by an activation of tyrosine hydroxylase, but seems to be related to an improvement of release of newly synthesized dopamine from exogenous L-DOPA.

Effects of CDP-choline on platelet aggregation and the antiaggregatory activity of arterial wall in the rat

The effects of the acute (250 mg/kg) and chronic (250 mg/kg for two weeks) treatments with CDP-choline on platelet aggregation and thromboxane formation and on the platelet antiaggregatory activity of thoracic aorta, have been studied in the rat. The acute administration resulted mainly in reduced platelet reactivity to aggregating agents, with no change of platelet thromboxane formation. The antiaggregatory activity of aortic walls was also concomitantly reduced. After chronic treatment, the major effect was a greater antiaggregatory activity of the vessel wall in respect of the control values, whereas platelet function was not affected. CDP-choline treatment, thus exerts favourable effects especially in the acute treatment, by reducing platelet reactivity.

Effects of CDPcholine and CDPethanolamine on the alterations in rat brain lipid metabolism induced by global ischemia.

The fast turnover pool of rat brain lipids was labeled by intracerebral injection of [3H]acetate. Cerebral ischemia for a duration of 5 min after decapitation caused a 2.2-fold increase in radioactivity in the free fatty acids and loss of more than 20% of the radioactivity from choline and ethanolamine glycerophospholipids. An intracerebral injection of 0.6 mumol each of cytidine diphosphocholine (CDPcholine) and cytidine diphosphoethanolamine (CDPethanolamine) prevented the loss of radioactivity from the glycerophospholipids and decreased the amount of radioactivity in the free fatty acids by 59% as compared with control values and 82% as compared with ischemia values. By GLC assays of the mass of the free fatty acids there was a threefold increase of free fatty acids in ischemic brains. Pretreatment of ischemic brains with CDPcholine and CDPethanolamine reduced the levels of unesterified fatty acids to 60% of the control values. Thus, a prior injection of cytidine nucleotides prevented the release of free fatty acids observed in ischemic brains.

New strategies in the management of Parkinson's disease: a biological approach using a phospholipid precursor (CDP-choline).

CDP-choline, an intermediate in the phospholipid metabolic pathway supposed to improve the functionality of the dopamine (DA) system, was administered to parkinsonian patients in a double-blind cross-over study versus placebo. All patients were already treated with L-dopa + dopa decarboxylase inhibitor. Clinical evaluations were carried out using the Webster Rating Scale (WRS), the Northwestern University Disability Scale (NUDS) and a semiquantitative rating scale for tremor, rigidity and bradykinesia. CDP-choline treatment showed a significant improvement of rigidity and bradykinesia and a less important amelioration of tremor. NUDS and WRS showed a similar positive result. Comparing the results obtained by placebo, we found that the actual clinical efficacy of CDP-choline regards mainly bradykinesia and rigidity (23 and 33% improvement, respectively). The positive effect of CDP-choline on parkinsonian patients already treated with L-dopa + dopa decarboxylase inhibitor stands for a possible action on the DA receptor through an activation of the phospholipid metabolism.