Combination Of Citicoline Research Articles

The Combination of Citicoline and Nicotinamide Mononucleotide Induces Neurite Outgrowth and Mitigates Vascular Cognitive Impairment via SIRT1/CREB Pathway.

Vascular dementia (VD) is characterized with vascular cognitive impairment (VCI), which currently has few effective therapies in clinic. Neuronal damage and white matter injury are involved in the pathogenesis of VCI. Citicoline has been demonstrated to exhibit neuroprotection and neurorepair to improve cognition in cerebrovascular diseases. Nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin (SIRT) signaling pathway constitutes a strong intrinsic defense system against various stresses including neuroinflammation in VCI. Our hypothesis is that the combined use of citicoline and the precursor of NAD+, nicotinamide mononucleotide (NMN), could enhance action on cognitive function in VCI. We investigated the synergistic effect of these two drugs in the rat model of VCI by bilateral common carotid artery occlusion (BCCAO). Citicoline significantly enhanced neurite outgrowth in Neuro-2a cells, and the combination of citicoline and NMN remarkably induced neurite outgrowth in Neuro-2a cells and primary cortical neuronal cells with an optimal proportion of 4:1. In the rat model of BCCAO, when two drugs in combination of 160mg/kg citicoline and 40mg/kg NMN, this combination administrated at 7days post-BCCAO significantly improved the cognitive impairment in BCCAO rats compared with vehicle group by the analysis of the Morris water maze and the novel object recognition test. This combination also decreased microglial activation and neuroinflammation, and protected white matter integrity indicated by the increased myelin basic protein (MBP) expression through activation of SIRT1/TORC1/CREB signaling pathway. Our results suggest that the combination of citicoline and NMN has a synergistic effect for the treatment of VD associated with VCI.

Chronic Disorders of Cerebral Circulation: a Challenge for the Family Doctor

The article examines modern views on the pathogenesis and clinical manifestations of chronic cerebral ischemia (CCI) and the possibilities of their pharmacotherapy. From this point of view, the requirements for choosing the optimal pharmacological strategy for pathological changes in the brain during ischemia are analyzed. The main goals of the clinical application of the strategy of neuroprotection in general, and in particular the need for a simultaneous effect on the neuronal, neurotransmitter and vascular mechanisms of the development of cognitive and general brain symptoms are considered. The necessity of using membrane-protective, cholinergic and vasotropic type of action is well founded. In this regard, the risks of polypharmacy in such patients and the arguments in favor of prescribing combined drugs were analyzed. The advantages of the innovative domestic combination containing citicoline and ginkgo biloba extract are considered in detail. The mechanisms of action and clinical effects of these components are analyzed with an emphasis on the prospects of their use in general medical practice. Special attention is paid to the justification of new opportunities provided by the synergistic effect of citicoline and ginkgo biloba extract when they are used in the form of a combined dosage form in comparison with monotherapy with these agents. The data on the safety of the use of the specified combination, as well as the scheme of dosage and course regimens, are given. The combination of citicoline + ginkgo biloba extract opens up new opportunities for family doctors in the pharmacotherapy of early cerebral vascular insufficiency symptoms.

The Description Neurotherapy in Ischemic Stroke Patients

Introduction: Neuroprotectants are a therapy used to prevent the development of infarction in acute ischemic stroke patients. One approach to neuroprotective therapy is to start early administering neuroprotective agents to patients experiencing acute ischemic stroke. This study aims to describe the pattern of use of neuroprotectant drugs in ischemic stroke patients at RSUD Dr. Soegiri Lamongan.Methods: This research method is a descriptive observational method with a cross-sectional study design. Data collection was carried out retrospectively by searching patient medical records and pharmaceutical installation data for the period June-December 2019.Results: The majority of ischemic stroke patients were female (51.5%), the majority were aged 50-59 years (48.5%), had comorbid hypertension (79.4%) and comorbid DM and hypertension (20.6 %). The neuroprotective drug citicoline was prescribed in 32 patients (33%) and piracetam in 19 ischemic stroke patients (19.6%).Conclusion: The highest use of neuroprotective drugs in ischemic stroke patients at RSUD Dr. Soegiri is a combination of citicoline and piracetam (44.3%%).

Comparison of the Effects of Citicoline and Piracetam on Hypoxic-ischemic Brain Damage in Neonatal Rabbits.

Objectives Perinatal hypoxic-ischemic brain injuries have been a major cause of mortality and neurodevelopmental morbidities in newborns. Citicoline and Piracetam have been used as nootropic agents in a number of studies. In this investigation, we aimed to determine the effects of these agents solely and in combination in hypoxic-ischemic brain damage in rabbit neonates.Materials & Methods Hypoxic-ischemic brain damage was induced by the occlusion of both uterine arteries of dams for eight minutes. The subjects were randomly divided into five groups as follows (n=6 per group): control group without hypoxia (C1), control group with hypoxic-ischemic damage (C2), the third group (P) received Piracetam (100 mg/kg), the fourth group (T) administered with Citicoline (250 mg/kg), and the fifth (PT) received both. The preventive effects of the two drugs on hypoxic-ischemic brain damage were microscopically investigated by the rates of damage to the hippocampus.ResultsNeuronal destruction rates in C1, C2, P, T, and PT were 4%, 45%, 37.5%, 12.5% (P=0.01 vs. C2), and 20% (P=0.03 vs. C2), respectively. The total means of hypoxic-ischemic damage, cell edema, neuronal degeneration, and eosinophilic degeneration were lower in the T group compared to C2 (P<0.05). Conclusion According to our results and previous findings, Citicoline as a treatment for hypoxic-ischemic brain injuries could be beneficial, and it has priority over neuroprotective agents like Piracetam. Moreover, the combination of Citicoline and Piracetam showed no superior effect in contrast with Citicoline alone. However, experimental studies on larger populations and clinical trials are highly suggested.

Diabetic retinopathy: neurovascular disease requiring neuroprotective and regenerative therapies.

Diabetic retinopathy: neurovascular disease requiring neuroprotective and regenerative therapies.

Neuroprotection in Primary Open-Angle Glaucoma: The Role of a Fixed Citicoline-Homotaurine-Vitamin E Combination

Glaucomatous optic neuropathy is a chronic degenerative neuropathy characterized by progressive damage of the retinal ganglion cells despite good compensation of intraocular pressure. The purpose of this study was to assess the effect of oral administration of a fixed combination of citicoline 500 mg + homotaurine 50 mg + vitamin E 12 mg (CIT/HOMO) on retinal ganglion cell function as examined by pattern electroretinogram (PERG) in subjects with primary open-angle glaucoma. A prospective, randomized, single-blind, balanced, crossover study was performed on a population of 40 patients with POAG-HT and fully-compensated IOP with topical hypotensive therapy. Recruited patients were allocated by balancing randomization to two treatment groups: - group A: patients continued current hypotensive eye-drop for 4 months and subsequently took 1 tablet of CIT/HOMO each morning for 4 months; - group B: patients took 1 tablet of CIT/HOMO each morning for 4 months in addition to current hypotensive eye-drop and subsequently continued with current hypotensive eye-drop alone for 4 months. Patients were examined at baseline (T0), after 4 (T1) and 8 months (T2). At every single time was performed a whole eye examination, 3 IOP measurements, 30.2 SITA Standard Humphrey visual field test, OCT cup/disc ratio and PERG glaucoma Hemifield test with central amplitude analysis. 38 patients completed the study for a total of 76 eyes. In both groups of patients tonometry, cup/disc ratio and visual field did not reveal any statistically significant difference. In both groups, adding the CIT/HOMO at hypotensive eye-drop resulted in an improvement in PERG after 4 months of therapy that disappeared when CIT/HOMO was withdrawn. Four months supplementation with a fixed combination of citicoline, homotaurine and vitamin E was seen to significantly increase the amplitude of the PERG bioelectric potential transmitted by the optical pathway to the visual cortex in subjects with primary open-angle glaucoma with compensated IOP and initial damage of the visual field and optic disc. During this study, the IOP remained compensated with the current hypotensive therapy and no deterioration was observed in the visual field or the cup/disc ratio.

Possible Pharmacodynamic Interaction of Azelnidipine with Citicoline Against Ischemic Brain Injury: Behavioral, Biochemical and Histological Alterations

Background: Currently, no drug has been approved for the management of postischemic neuronal damage. Existing studies show that calcium channel blockers have neuroprotective properties, while citicoline is involved in maintaining neuronal integrity.Purpose: This study was envisaged to investigate the effect of azelnidipine (novel calcium channel blocker) alone and in combination with citicoline (phosphatidyl-choline analogue) against ischemic brain damage in Wistar rats.Methods: Previously standardized bilateral common carotid artery occlusion model was used to induce cerebral ischemic injury in Wistar rats. Pretreatment with azelnidipine (1.5 mg/Kg and 3 mg/Kg; p.o.) or citicoline (250 mg/Kg; i.p.) was done every 24 h starting 7 days before the bilateral common carotid artery occlusion surgery. Pharmacological assessments (behavioral, biochemical, mitochondrial, molecular, and histological) were done after 48 h of the reperfusion period.Results: Azelnidipine and citicoline were found to protect the brain from progressive neuronal damage as seen by improved sensorimotor behavior (locomotion, rota rod, and beam balance performance) and reduced oxidative stress (decreased malondialdehyde (MDA), nitrite, increased glutathione (GSH), superoxide dismutase (SOD)). Impairment of mitochondrial enzyme system and increase in the infarct area were found to be arrested by individual treatments with azelnidipine and citicoline. These effects were further potentiated synergistically as the combination of citicoline and azelnidipine was found to decrease glutamate levels, caspase-3 activity and histological alterations as compared to their individual effects.Conclusion: Azelnidipine and citicoline synergistically decrease excitotoxic and oxidative damage against ischemic brain injury in Wistar rats and, therefore, propose a clinically relevant combination for the prevention of postischemic neuronal damage.

Combined citicoline and docosahexaenoic acid treatment improves cognitive dysfunction following transient brain ischemia

Phospholipids are structural components of cellular membranes that play important roles as precursors for various signaling pathways in modulating neuronal membrane function and maintenance of the intracellular environment. Phosphatidylcholine (PtdCho) is the most abundant cellular phospholipid. Citicoline and docosahexaenoic acid (DHA) are essential intermediates in the synthesis of PtdCho. Both PtdCho intermediates have independently shown neuroprotective effects in cerebral ischemia, but their combined effect is unknown. This study aimed to investigate the combined effect of oral citicoline and DHA treatment on improvement of cognitive deficits following cerebral ischemia using a 20-min bilateral common carotid artery occlusion (BCCAO) mouse model. BCCAO ischemic mice were treated for a total of 11 days with a combination of citicoline (40 mg/kg body weight/day) and DHA (300 mg/kg body weight/day) or each alone. Combined citicoline and DHA synergistically and significantly improved learning and memory ability of ischemic mice compared with either alone. Further, citicoline and DHA treatment significantly prevented neuronal cell death, and slightly increased DHA-containing PtdCho in the hippocampus, albeit not significantly. Taken together, these findings suggest that combined citicoline and DHA treatment may have synergistic benefits for partially improving memory deficits following transient brain ischemia.

Влияние сочетанного применения цитиколина и антител к глутамату на развитие острых генерализованных судорог, вызванных пентилентетразолом у мышей

Цель исследования. На 2 моделях острых генерализованных судорог (ОГС), вызванных конвульсантом пентилентетразолом (ПТЗ), изучить эффективность сочетанного применения ноотропа цитиколина - препарата с противосудорожным действием, нейрорегенеративной, нейропротекторной активностью и антител (АТ) к глутамату, обладающих противосудорожной активностью. Методика. Эксперименты выполнены на мышах-самцах линии C57Bl/6 (n = 87) массой 22-28 г. Эффективность сочетанного применения цитиколина и АТ к глутамату изучали на двух моделях ОГС. Выполнено 2 серии экспериментов. В 1-й серии ОГС вызывали внутривенным введением 1% раствора ПТЗ со скоростью 0,01 мл/с. Для изучения эффективности сочетанного применения препаратов определяли минимальное противосудорожное действие цитиколина (Цераксон, «Nicomed Ferrer Internaсional, S.A.») и АТ к глутамату при их внутрибрюшинном введении. С этой целью цитиколин вводили в дозах 500 и 300 мг/кг за 1 ч до введения ПТЗ, АТ к глутамату - в дозах 5 и 2,5 мг/кг за 1 ч 30 мин до введения ПТЗ. АТ к глутамату получали путем гипериммунизации кроликов соответствующим конъюгированным антигеном. Во 2-й серии ОГС вызывали подкожным введением ПТЗ в дозе 85 мг/кг. Для изучения эффективности сочетанного действия изучаемых препаратов последние вводили в минимально действующих дозах, установленных в 1-й серии экспериментов. Контролем во всех сериях опытов служили животные, которым вводили в аналогичных условиях и в том же объеме физиологический раствор. Результаты. Показано, что сочетанное применение цитиколина и АТ к глутамату в минимально действующих дозах (300 и 2,5 мг/кг соответственно) при моделировании ОГС не вызывало повышения судорожной активности мозга и усиления противосудорожных свойств препаратов. Заключение. Cочетанное применение цитиколина и АТ к глутамату в минимально действующих дозах не вызывало повышения судорожной активности мозга, что свидетельствует о безопасности совместного применения препаратов. Проведенное исследование может служить также экспериментальным обоснованием возможности использования сочетанного применения данных препаратов при судорогах с целью замедления прогрессирования нейродегенеративных процессов и благоприятного влияния на когнитивные функции. Aim. To study the effectivity of a combination of citicoline, a nootropic substance with neuroregenerative, neuroprotective, and anticonvulsant actions, and glutamate antibodies (АB) with an anticonvulsant action in two models of acute generalized convulsions (AGC) caused by the convulsant pentylenetetrazole (PTZ). Methods. Experiments were conducted on C57Bl/6 mice (n = 87) weighing 22-28 g. Effects of combined citicoline and glutamate АB were studied on two models of AGС. In the first series of experiments, AGС was induced by intravenous infusion of a 1% PTZ solution at 0.01 ml/sec. In the second series, AGС was induced by a subcutaneous injection of PTZ 85 mg/kg. To evaluate efficacy of the drug combination minimum intraperitoneal anticonvulsant doses of citicoline (Tserakson, Nicomed Ferrer Internacional, S.A.) and glutamate АB were determined. To this purpose, citicoline was administered at 500 and 300 mg/kg 1 h prior to PTZ, and glutamate АB was administered at 5 and 2.5 mg/kg 90 min prior to PTZ. Glutamate АB was obtained by hyperimmunization of rabbits with a respective conjugated antigen. In the second series of experiments, AGС was induced by a subcutaneous injection of PTZ 85 mg/kg. To evaluate the effect of the drug combination, the drugs were administered at the minimum effective doses determined in the first series of experiment. Control animals were injected with the same volume of saline in the same experimental conditions. Results. The combination of citicoline and glutamate AB used at minimum effective doses of 300 and 2.5 mg/kg, respectively, did not increase the seizure activity in the brain and enhanced anticonvulsant properties of the drugs in two models of AGС. Conclusion. The combination of citicoline and glutamate AT at minimum effective doses did not increase the convulsive activity in the brain, which supported safety of the drug combination. Besides, this study can serve as an experimental justification for using the drug combination in convulsions to favorably influence cognitive functions and slow progression of neurodegenerative processes.

NEUROPROTECTIVE EFFECT OF CITICOLINE AND GLUCOCORTICOSTEROID COMBINATION UNDER CONDITIONS OF EXPERIMENTAL DEMYELINATING MODEL OF CENTRAL NERVOUS SYSTEM

Objective: Multiple sclerosis is a multifactorial, autoimmune, chronic inflammatory demyelinating disease of the central nervous system. Recent studies do not give possibility to estimate the contribution of neurodegenerative changes in neurological deficit of individual patient, to predict the disease development and the effectiveness of therapy. The goal of our research was to investigate methylprednisolone and citicoline co-administration effect to the processes of energy providing of the mitochondria of the cerebral cortex neurons in experimental allergic encephalomyelitis. Materials and Methods: Experiments were carried out on rats of both sexes weighing 150-180 g. Experimental allergic encephalomyelitis was induced by a single subcutaneous inoculation of encephalitogenic mixture in complete Freund's adjuvant. As material we used brains. We studied markers of mitochondrial dysfunction and content of adenine nucleotides, lactate, malate, isocitrate, aspartate, pyruvate. We also studied the state of neurons, their area, RNA-content and proportion of apoptotic cells. Results: Formation of experimental allergic encephalomyelitis (EAE) led to permanent disturbance of energy metabolism of brain. The administrations of methylprednisolone did not have a significant effect. Co-administration of methylprednisolone and citicoline exerted significant influence on some parameters of mitochondrial dysfunction and brain energy metabolism. We also found neuronal damage of sensorimotor cortex of experimental animals and to the neuroapoptosis activation. Administration of methylprednisolone resulted in direct neuroprotective effect. Conclusion: Combination of citicoline and methylprednisolone limit activity of unproductive anaerobic glycolysis and increases aerobic ATP synthesis reaction. Thus the combination of citicoline and methylprednisolone does not affect the activity of malate aspartatic shunt in EAE conditions.

The study of the membrane-protective potential of the combination of 2-ethyl-6-methyl-3-hydroxypyridine-succinate and citicoline

To assess the changes in the composition of plasma phospholipids in patients with chronic cerebrovascular disease treated with neuroprotectors 2-ethyl-6-methyl-3-hydroxypyridine succinate (neurox) and citicoline (neipilept), the natural metabolites involved in biochemical processes in the body, and their composition. The study included 40 patients, 18 men and 22 women, aged from 54 to 72 years, with chronic cerebrovascular disease at the decompensation stage complicated with the hypertensive crisis and/or arrhythmia. During extraction of phospholipids from blood cells, a significant decrease in the amount of total lipids was found to the end of treatment of patients who received neurox or neipilept or their combination. The study of quantitative composition of phospholipids showed no significant changes in patients treated with neurox, while the use of citicoline or combination of citicoline with 2-ethyl-6-methyl-3-hydroxypyridine succinate resulted in the increase of their total mass. There were no significant changes in the qualitative composition of phospholipid classes in blood plasma in patients treated with neurox. In patients treated with neipilept or with the combination of citicoline with 2-ethyl-6-methyl-3-hydroxypyridine succinate, plasma phosphatidylcholine was significantly increased. No significant changes in the content of phosphatidylinositol, phosphatidylserine and sphingomyelin were observed.

Cytoprotective Effects of Citicoline and Homotaurine against Glutamate and High Glucose Neurotoxicity in Primary Cultured Retinal Cells.

Citicoline and homotaurine are renowned compounds that exhibit potent neuroprotective activities through distinct molecular mechanisms. The present study was undertaken to demonstrate whether cotreatment with citicoline and homotaurine affects cell survival in primary retinal cultures under experimental conditions simulating retinal neurodegeneration. Primary cultures were obtained from the retina of fetal rats and exposed to citicoline plus homotaurine (100 μM). Subsequently, neurotoxicity was induced using excitotoxic levels of glutamate and high glucose concentrations. The effects on retinal cultures were assessed by cell viability and immunodetection of apoptotic oligonucleosomes. The results showed that a combination of citicoline and homotaurine synergistically decreases proapoptotic effects associated with glutamate- and high glucose-treated retinal cultures. This study provides an insight into the potential application of citicoline and homotaurine as a valuable tool to exert neuroprotective effects against retinal damage.

Combination of Citicoline and L-NAME Restores Neurological Functions, Reverts Biochemical Alterations and Reduces Neuronal Damage in Transient Focal Cerebral Ischemic Rats

Objectives: To investigate the neuroprotective effect of combination of Citicoline (membrane stabilizer) and L-NAME (NOS inhibitor) in middle cerebral artery occluded/reperfused rats (MCAO/R). Methods: Citicoline (250 mg/kg b.w.) followed by L-NAME (3 mg/kg b.w.) was administered 30 minutes before (Pre) performing middle cerebral artery occlusion/reperfusion (MCAO/R) in Sprague Dawley rats. Parameters such as Glutamate, Aspartate, Nitrite/Nitrate, Sodium potassium ATPase (Na + K + ATPase) content, expression of TNF-α and IL-10, and histopathology was studied. Neurological scoring was also performed in the MCAO/R rats. Findings: Pre ischemic administration of citicoline and L-NAME has improved neurological deficit (p<0.001). Combination treatment has also ameliorated the glutamate level in MCAO/R rats (p<0.05). Combination of these drugs has also reduced the nitrate/nitrite content (p<0.001) and also sodium potassium ATPase (Na + K + ATPase) (p<0.001) significantly. Citicoline and L-NAME combination treatment has also down regulated the expression of TNF-α and up regulated the expression of IL-10 in middle cerebral artery occlusion/reperfusion rats. Citicoline and L-NAME combination was also observed to reduce the neuronal damage which is evident from the histopathology (H and E) of brain sections of MCAO/R rats. Novelty of the Study: Though Citicoline and L-NAME has been evaluated and proven for their neuroprotection separately, the effect of these two drugs when administered together as a combination has not been studied. This study is first of its kind to determine the neuroprotective effect of combination of citicoline and L-NAME. Conclusion/Application: Combination of citicoline and L-NAME has profoundly improved neuroprotection and ameliorated excitotoxicity when administered 30 minutes before ischemia.