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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.
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Secades.
14
Citicoline in the Treatment of Cognitive Impairment
Review Article Open Access
https://doi.org/10.17756/jnen.2019-047
Julio J. Secades*
Scientic Department, Ferrer Group, Barcelona, Spain
*Correspondence to:
Dr. Julio J. Secades, MD, PhD
Scientic Department, Ferrer Group
Avda Diagonal 549 5th
08029 Barcelona, Spain
Tel: +34936003837
E-mail: jsecades@ferrer.com
Received: October 25, 2018
Accepted: January 24, 2019
Published: January 28, 2019
Citation: Secades JJ. 2019. Citicoline in the
Treatment of Cognitive Impairment. J Neurol Exp
Neurosci 5(1): 14-26.
Copyright: © 2019 Secades. is is an Open
Access article distributed under the terms of the
Creative Commons Attribution 4.0 International
License (CC-BY) (http://creativecommons.
org/licenses/by/4.0/) which permits commercial
use, including reproduction, adaptation, and
distribution of the article provided the original
author and source are credited.
Published by United Scientic Group
Abstract
Vascular cognitive impairment is a process which is more frequent in patients
with cardiovascular risk factors. e etiology of this kind of impairment could be
related to dierent 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. is
is an updated review of the possible use of citicoline in the treatment of cognitive
impairment.
Keywords
Mild cognitive impairment, Pharmacological treatment, Citicoline
Introduction
Phospholipids are essential constituents of cells, with a high turnover rate
to ensure adequate function of cell membranes, especially neuronal membranes
[1-3]. Among the main phospholipids in humans are phosphatidylcholine
[4]. e main function of the phospholipids is to be part of cell membrane
structures and ensure the functions of the membranes [1]. Additional specic
functions of the neuronal membrane include nerve impulse conduction and
neurotransmission [5]. In the Central Nervous System (CNS) there are various
conditions involving phospholipids that can lead to an impairment of functions
[6], such as brain maturation [7-10], neurite growth and neuronal regeneration
[11]. Impaired phospholipid metabolism has been implicated in the development
of traumatic brain injury (TBI) [12-21] and cerebral ischemia [22-37]. Also
the phospholipid metabolism has been involved in brain aging [38-40] and
certain neurodegenerative diseases [33, 41-53]. Phospholipids also participate
in neuroplasticity mechanisms [54], and in conditions involving changes in
neurotransmission [55-58], excitotoxic aggression [59, 60] and apoptosis [57-66].
In this context, there is a need to have drugs which act on the membrane structure
phospholipids in such situations [67-72].
Citicoline or cytidine-5’-diphosphocholine (CDP-choline) is an essential
intracellular precursor of phospholipid phosphatidylcholine [73-87]. e
endogenous formation of this compound from phosphorylcholine is the rate-
limiting step of this biosynthetic pathway [77, 88-100]. us CDP-choline is
considered an exogenous source of choline and cytidine, with relevant biochemical
actions [101, 102].
Journal of
Neurology & Experimental Neuroscience
Journal of Neurology & Experimental Neuroscience | Volume 5 Issue 1, 2019
15
Citicoline in the Treatment of Cognitive Impairment Secades.
eects of the drug in improving cognition in patients aected with
cognitive impairment of various causes. is also could be due to
the role of citicoline in augmenting the ecacy of endogenous
brain defense and neuronal repair mechanisms [131].
Clinical Studies
Various experimental investigations on the so-called brain
aging have led in recent years to give an increasing importance
to changes in cerebral metabolism as a crucial factor involved
in the pathophysiology of this processes. In the senile brain
there is a general decrease in energetic metabolism and changes
aecting lipid and nucleic acid metabolism. Changes in certain
neurotransmitters, especially acetylcholine, and hormones are
associated in brain aging processes [199], and more recently
there have been several publications showing an increasing
evidence of vascular risk factors as key mechanisms in the
development of cognitive impairment and dementia [200-202].
It has been demonstrated that a worse overall cardiovascular
risk prole is associated with poorer cognitive function and
this association could be present in young adults from 35
years old [203]. It is also known that these cardiovascular risk
factors are associated with smaller brain volumes, in regions
identied as early predictors of cognitive decline [204]. Both
microinfarcts and lacunar infarcts are associated with small
vessel disease of the brain, and this association makes the
patients more prone to develop cognitive impairment [205].
Both silent and clinically eloquent strokes are among the most
important determinants of dementia in the elderly [200]. But
in patients with cardiovascular risk factors without evidence of
an eloquent stroke, it is of interest to consider the possibility
of the presence of small vessel disease associated or not with
microinfarcts, which are normally silent, and their presence is
underestimated [206, 207].
Citicoline increases phospholipid synthesis and glucose
metabolism at brain level, and inuences the metabolism of
neurotransmitters. Accordingly, several clinical trials have
been carried out to evaluate the eects of CDP-choline in
the treatment of cognitive disorders [208, 209]. Citicoline
stimulates phosphatidylcholine synthesis in the brain [210-
213] and improves the energetic cerebral metabolism of elderly
subjects [214]; a fact that is correlated to an improvement
on cognitive capacities [215-219]. In healthy volunteers,
the administration of citicoline has been associated with
improvement in attention [220, 221], memory [222, 223] and
in some neurophysiological parameters [224-227].
Many studies have shown the eect of citicoline in the
treatment of the so-called senile cerebral involution, decreasing
its characteristic symptoms [228-240], especially on memory
evaluated by means of various cognitive scales. Other benets
reected in these studies include improvements in cooperation
and capacity of relationship to the environment, and reducing
dosage of psychoactive drugs routinely used in psychogeriatrics,
with an excellent safety prole. Patients were evaluated using
dierent scales, such as Fishback Mental Status Questionnaire,
SCAG, Mini Mental State Examination, Bender-Gestalt test,
Hamilton scale for depression, Parkside scale, neurological
assessment scale, and attention test.
Experimental Data
Citicoline has an extensive eect on the cholinergic system
and could act as a choline donor to increase the synthesis of
acetylcholine. e central cholinergic activating eect of
citicoline has been emphasized, with this eect explaining
the cardiovascular [103-110], metabolic [111-118], and
antinociceptive eects [119-121] of the drug, together with
eects on signaling systems [122-127].
Citicoline partially restored learning performance in
rats under hypobaric hypoxia [128] or chronic cerebral
hypoperfusion [129]; this suggests that citicoline could have a
cholinergic action on the mechanisms participating in cognition
[130]. Citicoline attenuates vascular cognitive impairment in
animal models of brain ischemia [131]. Citicoline also prevents
amnesia induced by scopolamine [132-134]. Citicoline acts as a
drug able to enhance memory in animals with memory decits
from dierent causes [135-140].
Citicoline improves phospholipid metabolism in
aging models [141-143], is able to restore the activity of
acetylcholinesterase and Na+/K+ pumps [144, 145], and controls
the levels of platelet activating factor in the brain [145-147].
Citicoline also oers benecial actions on brain metabolism
[143, 148-150] and on neuroendocrine functions [151-153]
in experimental models of brain aging, showing eects such as
neuroprotection [154-160], and sharing immunomodulatory
[161], and antiapoptotic eects [162, 163] in models of
neurodegeneration. Several studies corroborated the positive
eects of the drug on aged animals [137, 164, 165].
Another mechanism investigated has been the participation
of Sirtuin1 in the neuroprotective/neurorestorative actions
of CDP-choline [166]. Treatment with CDP-choline
increased Sirtuin1 protein levels in brain concomitantly to
neuroprotection. Treatment with sirtinol blocked the eect of
CDP-choline, whereas resveratrol elicited a strong synergistic
neuroprotective eect with CDP-choline. CDP-choline
failed to reduce infarct volume in Sirt1–/– mice. ese results
demonstrate a robust eect of CDP-choline like Sirtuin1
activator by up-regulating its expression.
It has been demonstrated that citicoline signicantly
increased dopamine levels and synthesis rate in the striate
[167], by means of an action on tyrosine hydroxylase activity,
leading to an inhibition of dopamine reuptake [168, 169]. e
eects of citicoline on dopamine levels have been shown by
other authors [170-173].
Eects on the levels of other neurotransmitters have been
reported by other authors [174-178]. e action of citicoline
upon the dopaminergic system has also been studied by
investigating its pharmacological actions in many experimental
models [179-193]. Citicoline increases norepinephrine release
[194], inuences the relationship between glutamate and
GABA [195], and increases the levels of vasopressin [196] and
other pituitary hormones [197, 198].
us the eects of citicoline on the cholinergic system,
together with the other actions on other neurotransmitters and
its neuroprotective/neurorestorative properties, could explain the
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Citicoline in the Treatment of Cognitive Impairment Secades.
e use of citicoline in healthy adult individuals induces
an increase of growth hormone secretion and a decrease on
prolactin secretion [241, 242].
Some positive eects in patients with chronic
cerebrovascular disease have also been demonstrated [243-
261]. However, in patients with vascular dementia according
to current diagnostic criteria, Cohen et al. [262] were not able
to show any benecial eect of citicoline in their pilot study.
Tanaka et al. [263] found a correlation between the
cognitive improvement and the increase in cerebral blood
ow in patients with vascular dementia treated with the drug.
Lozano [264] suggest that citicoline is a safe and eective
drug in the long-term course of dementia. Corona et al. [265]
concluded that the benecial eects of the drug in demented
patients will be partially explained by the action of the drug on
some neurotransmitters systems.
Cacabelos et al. have described several positive eects
of citicoline in dementia patients, with improvements on
cognitive scales, a signicant antidepressant eect, a certain
immunomodulatory action, and an increased cerebral blood
ow and improved bioelectric activity in the brain [266-269].
e same authors published the results of a double-blind,
randomized, placebo-controlled pilot study in patients with
mild to moderate senile dementia of the Alzheimer type
[270]. Citicoline showed a signicant improvement in the
cognitive capacity as assessed with the ADAS scale of patients
with a positive APOE ε4 genotype. Recently, Feng et al. [271]
found that treatment with citicoline may be benecial for the
improvement of network connectivity of the corpus callosum
in patients with leukoaraiosis.
Some authors advocate the use of multifactorial
treatments including citicoline in patients with degenerative
dementias [272, 273]. Zhuravin et al. [274] demonstrated
that the activities of blood serum acetylcholinesterase,
butyrylcholinesterase and neprilysin reect the level of
cognitive dysfunction in patients with Alzheimer’s disease and
can be used as prognostic biomarkers of the level of dementia
progression, and that the treatment with citicoline can modify
positively these levels.
Fioravanti and Yanagi [275] in their systematic review
examined the eects of citicoline in the treatment of cognitive,
emotional, and behavioral decits associated with chronic
brain disorders in the elderly. Fourteen studies were included
in this review. e type of participants varied over the years
and by type of disorders and severity, and ranged from aged
individuals with subjective memory disorders to patients
with vascular cognitive impairment (mild to moderate),
vascular dementia or senile dementia (mild to moderate). In
the studies included, the subjects were treated with citicoline
for a period of between 20 days and 3 months. e studies
were heterogeneous in dose, modalities of administration, and
inclusion criteria for subjects, and outcome measures. Results
were reported for attention, memory testing, behavioral rating
scales, global clinical impression and tolerability. Reaction
time was used as a measure of attention, and the results were
obtained from seven of the studies with a total of 790 subjects,
384 in the citicoline group and 406 in the placebo group.
Using the standardized mean dierence (SMD) and xed-
eect model, the summary eect size is -0.09 (-0.23 to 0.05),
meaning there was evidence of a small eect of CDP-choline
on attention. e meta-analysis of the memory tests from
ten studies included a total of 924 subjects, 456 in the
citicoline group and 468 in the placebo group. e eect
size on memory was 0.38 (0.11-0.65) which was statistically
signicant. Using the six studies which reported memory test
results in 675 participants with cognitive decits associated
with cerebrovascular disorders, the meta-analysis of memory
function revealed homogeneous results and there was
evidence of a statistically signicant positive eect on memory
(SMD = 0.22; 0.07-0.37). Behavior was measured using
ve dierent scales in eight studies with 844 subjects, 412
in the citicoline group and 432 in the placebo group. ere
was evidence of a positive eect of citicoline on behavior
(SMD = -0.60; -1.05 to -0.15) using the random eects model.
e evidence of a benet in global impression was stronger;
using a xed-eect model, the Peto OR for improvement in
the subjects treated with citicoline as opposed to the subjects
treated with placebo was 8.89 (95% CI: 5.19-15.22). Of
particular relevance was the nding that citicoline tended
to be associated with fewer adverse eects than placebo, but
this was not statistically signicant. According to the authors,
further research with citicoline should focus on longer term
studies in subjects who have been diagnosed with currently
accepted standardized criteria, especially mild vascular
cognitive impairment or vascular dementia.
Deutsch et al. [276, 277] studied the association of
citicoline and galantamine in schizophrenia. Also recently some
positive eects of citicoline in the prevention of postoperative
cognitive dysfunction during total intravenous anesthesia have
been reported [278-280]. In a recent study, Li et al. [281]
demonstrated the eect of citicoline as an adjuvant therapy for
mild cognitive impairment in Parkinsons disease. Kovalenko
and Lytvyn [282] demonstrated that citicoline treatment in
patients with hypertensive dyscirculatory encephalopathy
and concomitant hypothyroidism signicantly improves the
performance of brain electrogenesis. Putignano et al. published
the VITA study [283], a study performed to assess the ecacy
of citicoline in elderly patients suering from stupor related
to complex geriatric syndrome, showing that there was an
improvement in key measures of performance after the
treatment. In the IDEALE study [284] the eectiveness and
safety of citicoline in patients with mild vascular cognitive
impairment was assessed. e study group received oral
citicoline 1 g/d/9 m. MMSE scores improved slightly after the
treatment with citicoline, whereas a signicant dierence was
found between the study and control groups at 3 and 9 months
(Figure 1). No adverse events were recorded. In this study,
citicoline was eective and well tolerated in patients with mild
vascular cognitive impairment. e same team published the
CITIRIVAD Study [285], with the aim of demonstrating the
eectiveness of oral citicoline plus rivastigmine in patients with
Alzheimer’s disease and mixed dementia. e results show the
eectiveness and safety of combined administration versus
rivastigmine alone, mainly in slowing disease progression and
consequently in disease management, both in Alzheimer’s
disease and in mixed dementia. In the Citcholinage study
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Citicoline in the Treatment of Cognitive Impairment Secades.
[286] the association of citicoline with an acetylcholine
esterase inhibitor was more eective that the acetylcholine
esterase inhibitor alone in patients with Alzheimer’s disease.
ese results encourage further investigation of the combined
administration on demented patients and the eects on the
progression of the disease [287].
Cognitive disorders are common stroke sequelae [288].
Cerebral infarctions are a signicant risk factor for vascular
cognitive impairment and vascular dementia [289]. In this
context, Álvarez-Sabín et al. performed a study to assess the
safety and ecacy of long-term administration of citicoline
in reducing post-stroke cognitive decline in patients with
rst-ever ischemic stroke [290]. Cognitive functions
improved 6 and 12 months after stroke in the entire group
but in comparison with controls, citicoline-treated patients
showed better outcomes in attention-executive functions
and temporal orientation during the follow-up. e authors
concluded that citicoline treatment for one year in this kind of
patient is safe and eective in improving post-stroke cognitive
decline. ese authors published the follow-up to this study
after two years of treatment with citicoline [291], adding an
evaluation of the quality of life to the cognitive assessment.
Age and absence of citicoline treatment were associated with a
poorer quality of life. Citicoline treatment improved cognitive
status signicantly during follow-up (p = 0.005), showing a
gradual improvement over time. Other authors communicated
benecial eects of citicoline in the treatment of post-stroke
cognitive disturbances [292, 293].
León-Carrión et al. [294-296] demonstrated the positive
eects of citicoline in a series of studies on post-traumatic
memory disorders. Citicoline is considered a valid therapeutic
option for the treatment of post-traumatic cognitive
impairments [297], also improving the quality of survival
[298].
e drug may be more eective for mild cognitive disorders
[299-302] and cases related to vascular pathologies [303-306].
In addition, citicoline has been shown to have benecial eects
on some neurophysiological and neuroimmune changes.
Over time there has been an increase in the dosage of
the drug, with 1g/d as the recommended dose in recent years.
Also, as the bioavailability of the oral drug is almost the same
as that observed with parenteral administration [307], the
latest studies have used the oral administration of the drug,
which is more convenient for the patients
Conclusions
Cytidine 5’-diphosphocholine, CDP-choline, or
citicoline is an essential intermediate for the synthesis of
phosphatidylcholine. Citicoline activates the biosynthesis
of the structural phospholipids of neuronal membranes,
increases brain metabolism, and acts upon the levels of various
neurotransmitters. Citicoline improves learning and memory
performance in animal models of brain aging. Citicoline is a
safe drug without systemic cholinergic eects and is a well-
tolerated product. Citicoline protects the brain against ischemic
injury, due to its neuroprotective eects but also because the
drug can enhance neuroreparative mechanisms, as has been
extensively explained by various authors, who consider it to
be a suitable treatment for brain ischemia-related disorders
and cognitive impairment [304, 308]. ese pharmacological
characteristics and the pleiotropic mechanism of action of
citicoline suggest that it could be eective in the management
of cognitive disorders.
In patients with vascular cognitive impairment, citicoline
improves the cognitive function, while in patients with
degenerative dementias, it is able to stop the progression of
the disease.
No serious side eects have been reported related to
citicoline [309, 310], and this could be the basis for an
empirical (Figure 2) treatment of patients with MCI [311].
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Figure 1: Evolution of the MMSE scores between citicoline group and
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Figure 2: Algorithm for an empirical approach to mild cognitive
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https://doi.org/10.18103/mra.v1i4.370
... The drug may be more effective for mild cognitive disorders [728][729][730] and cases related with vascular pathologies [731][732][733][734]. In addition, citicoline has been shown to have beneficial effects on neurophysiological and neuroimmune changes [734]. ...
... The drug may be more effective for mild cognitive disorders [728][729][730] and cases related with vascular pathologies [731][732][733][734]. In addition, citicoline has been shown to have beneficial effects on neurophysiological and neuroimmune changes [734]. ...
Article
Full-text available
This review is based on the previous one published in 2016 (Secades JJ. Citicoline: pharmacological and clinical review, 2016 update. Rev Neurol 2016; 63 (Supl 3): S1-S73), incorporating 176 new references, having all the information available in the same document 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.
... The drug may be more effective for mild cognitive disorders [728][729][730] and cases related with vascular pathologies [731][732][733][734]. In addition, citicoline has been shown to have beneficial effects on neurophysiological and neuroimmune changes [734]. ...
... The drug may be more effective for mild cognitive disorders [728][729][730] and cases related with vascular pathologies [731][732][733][734]. In addition, citicoline has been shown to have beneficial effects on neurophysiological and neuroimmune changes [734]. ...
Article
Full-text available
This review is based on the previous one published in 2016 (Secades JJ. Citicoline: pharmacological and clinical review, 2016 update. Rev Neurol 2016; 63 (Supl 3): S1-S73), incorporating 176 new references, having all the information available in the same document 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.
... Furthermore, CTN activates synthesis and release of neurotransmitters like dopamine by stimulating tyrosine hydroxylase (Piamonte et al. 2020; 2019). In addition, CTN improves the release of Ach and noradrenalin, which increases vigilance, learning, and cognitive function (Secades 2019;Al-Kuraishy et al. 2021e). ...
... CTN improves cognitive function through improvement of cholinergic transmission and associated synaptic plasticity (Abdel-Aziz et al. 2021). Choline from CTN is essential for the synthesis of brain Ach and regulation of the neurochemical process of Ach neurotransmission (Secades 2019). In their study, Piamonte et al. found that CTN can be used as an adjuvant therapy with cholinesterase inhibitors in the management of cognitive dysfunction in patients with Alzheimer's disease (Piamonte et al. 2020). ...
Article
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Coronavirus disease 2019 (COVID-19) is a current pandemic disease caused by a novel severe acute respiratory syndrome coronavirus virus respiratory type 2 (SARS-CoV-2). SARS-CoV-2 infection is linked with various neurological manifestations due to cytokine-induced disruption of the blood brain barrier (BBB), neuroinflammation, and peripheral neuronal injury, or due to direct SARS-CoV-2 neurotropism. Of note, many repurposed agents were included in different therapeutic protocols in the management of COVID-19. These agents did not produce an effective therapeutic eradication of SARS-CoV-2, and continuing searching for novel anti-SARS-CoV-2 agents is a type of challenge nowadays. Therefore, this study aimed to review the potential anti-inflammatory and antioxidant effects of citicoline in the management of COVID-19.
... For example, buspirone and bupropion have both been shown to have cognitive-enhancing effects in patients with MDD [53,78] but not in healthy volunteers [54,79,80]. In contrast, modafinil and citicoline broadly improved cognition in neurological and nonclinical populations, but showed limited or no change in MDD [81,89,210]. Furthermore, fludrocortisone resulted in cognitive improvement young adults with MDD but impaired cognitive function in older adults with MDD [187,188]. ...
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Impaired cognition is often overlooked in the clinical management of depression, despite its association with poor psychosocial functioning and reduced clinical engagement. There is an outstanding need for new treatments to address this unmet clinical need, highlighted by our consultations with individuals with lived experience of depression. Here we consider the evidence to support different pharmacological approaches for the treatment of impaired cognition in individuals with depression, including treatments that influence primary neurotransmission directly as well as novel targets such as neurosteroid modulation. We also consider potential methodological challenges in establishing a strong evidence base in this area, including the need to disentangle direct effects of treatment on cognition from more generalised symptomatic improvement and the identification of sensitive, reliable and objective measures of cognition.
... In neuronal membranes, it facilitates the conduction of nerve impulses and neurotransmission. Neural growth and regeneration impairments in the CNS have been involved with the impaired metabolism of phospholipids, and this condition is also associated with neurodegenerative disease and neuroplasticity [19,146]. Membranes in patients with Alzheimer's Disease (AD) are significantly lower than in non-cognitive impaired patients. ...
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With growing concerns about COVID-19’s hyperinflammatory condition and its potentially damaging impact on the neurovascular system, there is a need to consider potential treatment options for managing short- and long-term effects on neurological complications, especially cognitive function. While maintaining adequate structure and function of phospholipid in brain cells, citicoline, identical to the natural metabolite phospholipid phosphatidylcholine precursor, can contribute to a variety of neurological diseases and hypothetically toward post-COVID-19 cognitive effects. In this review, we comprehensively describe in detail the potential citicoline mechanisms as adjunctive therapy and prevention of COVID-19-related cognitive decline and other neurologic complications through citicoline properties of anti-inflammation, anti-viral, neuroprotection, neurorestorative, and acetylcholine neurotransmitter synthesis, and provide a recommendation for future clinical trials.
... In addition to the observed effects on GPC, CAW also significantly increased the choline-containing metabolite CDP-choline (also known as citicoline) in the cortex of 5xFAD females. Similar to GPC, citicoline has demonstrated considerable potential as an adjunct therapy for AD in pre-clinical and clinical studies (Secades, 2019;Piamonte et al., 2020). ...
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Centella asiatica is an herb used in Ayurvedic and traditional Chinese medicine for its beneficial effects on brain health and cognition. Our group has previously shown that a water extract of Centella asiatica (CAW) elicits cognitive-enhancing effects in animal models of aging and Alzheimer’s disease, including a dose-related effect of CAW on memory in the 5xFAD mouse model of ß -amyloid accumulation. Here, we endeavor to elucidate the mechanisms underlying the effects of CAW in the brain by conducting a metabolomic analysis of cortical tissue from 5xFAD mice treated with increasing concentrations of CAW. Tissue was collected from 8-month-old male and female 5xFAD mice and their wild-type littermates treated with CAW (0, 200, 500, or 1,000 mg/kg/d) dissolved in their drinking water for 5 weeks. High-performance liquid chromatography coupled to high-resolution mass spectrometry analysis was performed and relative levels of 120 annotated metabolites were assessed in the treatment groups. Metabolomic analysis revealed sex differences in the effect of the 5xFAD genotype on metabolite levels compared to wild-type mice, and variations in the metabolomic response to CAW depending on sex, genotype, and CAW dose. In at least three of the four treated groups (5xFAD or wild-type, male or female), CAW (500 mg/kg/d) significantly altered metabolic pathways related to purine metabolism, nicotinate and nicotinamide metabolism, and glycerophospholipid metabolism. The results are in line with some of our previous findings regarding specific mechanisms of action of CAW (e.g., improving mitochondrial function, reducing oxidative stress, and increasing synaptic density). Furthermore, these findings provide new information about additional, potential mechanisms for the cognitive-enhancing effect of CAW, including upregulation of nicotinamide adenine dinucleotide in the brain and modulation of brain-derived neurotrophic factor. These metabolic pathways have been implicated in the pathophysiology of Alzheimer’s disease, highlighting the therapeutic potential of CAW in this neurodegenerative disease.
... Цитиколін -фармацевтична субстанція (цитидин-5'-дифосфохолін), ідентична до природного попередника фосфатидилхоліну, основного фосфоліпідного компонента клітинних мембран. Нейропротективні властивості цитиколіну досліджені в численних експериментах на моделях ішемії, травми головного мозку, а також нейродегенеративної патології [20]. Основним ефектом цитиколіну є стимуляція синтезу мозкових фосфоліпідів, що підтверджено методом магнітно-резонансної спектрометрії в дослідженнях за участю людей [21]. ...
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Генетические и биохимические исследования последних десятилетий выявили широкую сеть молекулярных и метаболических путей, вовлеченных в патогенез когнитивных нарушений, и стали основой для концепции мультитаргетного, или сетевого, подхода к терапии, который считается более перспективным, чем поиск фармакологического воздействия на отдельные мишени. В обзоре суммирована современная доказательная база множественных нейромолекулярних механизмов прокогнитивних эффектов аюрведического лекарственного растения бакопа монье, а также его возможные полезные взаимодействия с еще одним хорошо известным нейропротектором — цитиколином. По данным экспериментальных исследований, благоприятные эффекты бакопа монье опосредованы такими механизмами: антиоксидантная нейропротекция, улучшение мозгового кровообращения, редукция β-амилоида, ингибирование ацетилхолинэстеразы, активация ацетилтрансферазы, модуляция других нейротрансмиттерных систем (норадреналиновых, серотониновой, допаминовой). В ряде рандомизированных плацебо-контролируемых исследований с двойным ослеплением были подтверждены прокогнитивние эффекты бакопы у людей. Ноотропные свойства бакопы, по крайней мере частично, накладываются на механизмы нейропротекции цитиколина, что создает предпосылки для сетевого аддитивного эффекта в коррекции когнитивных нарушений разного (нейродегенеративного, сосудистого или смешанного) происхождения.
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Background: Alzheimer's disease (AD) is one of the furthermost advanced neurodegenerative disorders resulting in cognitive and behavioral impairment. Citicoline sodium (CIT) boosts the brain's secretion of acetylcholine, which aids in membrane regeneration and repair. However, it suffers from poor blood-brain barrier (BBB) permeation, which results in lower levels of CIT in the brain. Purpose: This study targeted to encapsulate CIT into novel nano-platform transbilosomes decorated with hyaluronic acid CIT-HA*TBLs to achieve enhanced drug delivery from the nose to the brain. Methods: A method of thin-film hydration was utilized to prepare different formulae of CIT-TBLs using the Box-Behnken design. The optimized formula was then hyuloranated via integration of HA to form the CIT-HA*TBLs formula. Furthermore, AD induction was performed by aluminum chloride (Alcl3), animals were allocated, and brain hippocampus tissue was isolated for ELISA and qRT-PCR analysis of malondialdehyde (MDA), nuclear factor kappa B (NF-kB), and microRNA-137 (miR-137) coupled with immunohistochemical amyloid-beta (Aβ1-42) expression and histopathological finding. Results: The hyuloranated CIT-HA*TBLs formula, which contained the following ingredients: PL (300 mg), Sp 60 (43.97 mg), and SDC (20 mg). They produced spherical droplets at the nanoscale (178.94 ±12.4 nm), had a high entrapment efficiency with 74.92± 5.54%, had a sustained release profile of CIT with 81.27 ±3.8% release, and had ex vivo permeation of CIT with 512.43±19.58 μg/cm2. In vivo tests showed that CIT-HA*TBL thermogel dramatically reduces the hippocampus expression of miR-137 and (Aβ1-42) expression, boosting cholinergic neurotransmission and decreasing MDA and NF-kB production. Furthermore, CIT-HA*TBLs thermogel mitigate histopathological damage in compared to the other groups. Conclusion: Succinctly, the innovative loading of CIT-HA*TBLs thermogel is a prospectively invaluable intranasal drug delivery system that can raise the efficacy of CIT in Alzheimer's management.