Citicoline – a Neuroprotector with Proven Effects on Glaucomatous Disease

Romanian Journal of Ophthalmology, Volume 61, Issue 3, July-September 2017. pp:152-158

REVIEW

Citicoline – a neuroprotector with proven effects on glaucomatous disease

Iulia Chitu, Ruxandra Tudosescu, Costin Leasu-Branet, Liliana-Mary Voinea Department of Ophthalmology, University Emergency Hospital, Bucharest, Romania

Correspondence to: Department of Ophthalmology, University Emergency Hospital, Bucharest, Iulia Chițu Bucharest, Romania E-mail: [email protected] 169 Splaiul Independenței Street, Code 050098, Accepted:Mobile phone: September +40746 0109th, 314,2017

Abstract Citicoline is the generic name of cytidine- -diphosphocholine (CDP-choline), an endogenous compound that is able to increase the levels of neurotransmitters in the central nervous system by interacting with 5’the synthesis of cellular membranes phospholipids, especially phosphatidylcholine. Exogenous Citicoline, administered by ingestion or injection, is hydrolyzed and dephosphorylated in order to form cytidine and choline, which resynthesize CDP-choline inside brain cells. It has proven neuroprotective

amblyopia. Citicoline acts as a neuroprotector for those patients with progressive glaucomatouseffects in Alzheimer disease disease, in spite stroke, of well and-controlled Parkinson’s intraocular disease, as pressure. well as inThe glaucoma purpose and of this review was to outline the main features of Citicoline and the evidences of its effect in glaucoma. Keywords: Citicoline, neuroprotection, glaucoma

Pharmacology and effects

Cytidine- -diphosphocholine (CDP- choline, CDPCho) or Citicoline is a pharmaceutical5’ substance identical with the natural compound, and has an important role in and collaborators showed that Citicoline is a theprecursor phospholipid of phosphatidylcholine synthesis. In 1050s, (PC), Kennedy one of the most important phospholipid of the cell membrane [1]. Phospholipids are major constituents of cell membrane, with a high turnover rate, thus the continuous synthesis of these substances Fig. 1 Chemical structure of Citicoline ensure the optimal structure and function of the cell. The CDP-choline pathway is the pathway of CDP-Choline is a mononucleotide made of the novo synthesis of phosphatidylcholine and ribose, pyrophosphate, cytosine and choline, and its chemical structure is illustrated in Fig. 1 [2]. choline phosphate cytidilyltransferase (CCT) and includes the enzymes cytidine kinase (CK), 152 Romanian Society of Ophthalmology © 2017 doi:10.22336/rjo.2017.29 Romanian Journal of Ophthalmology 2017; 61(3): 152-158

CDP-choline:1,2-diacylglicerol choline uridine phosphate inside the brain. At neuronal phosphotransferase (CTP). In this pathway, level, this is transformed to cytidine choline is provided by PC turnover and transport triphosphate. After administration, Citicoline into the cell (Fig. 2) [1]. rapidly diffuses to the tissues and is actively used. It can be found in liver, brain, and kidney. The excretion of CDP-choline is by urinary or fecal route and in expired CO2. Citicoline provides neuroprotection by few mechanisms such as the following: maintains sphingomyelin and cardiolipin levels (constituent of inner mitochondrial membrane),

restores the phosphatidylcholine (PtdCho) levels, increases the activity of glutathione Fig. 2 The CDP-choline pathway reductase activity and the glutathione synthesis,

decreases lipid peroxidation, and restores the + + The term “Citicoline” was first introduced activity of Na ATPase. It is also involved in acetylcholine synthesis, providing choline [3]. drug. Manaka et al. from Japan administered Cytidine and/K choline are the two parts of in the 1970s when the substance was used as a Citicoline connected by a diphosphate bridge. After being absorbed, cytidine and choline are CiticolineWhen for administered the first time in(orally 1974 foror re-phosphorylated, and Citicoline is recreated Parkinson’sparenterally), disease. Citicoline is quickly metabolized from choline monophosphate and cytidine (minutes) and transformed in pyrimidinergic triphosphate. and cholinergic catabolites. It is a safe molecule, In the course of PtdCho synthesis, choline with only few adverse effects, such as digestive monophosphate is added to PtdCho, releasing intolerance after oral administration. The -monophosphate (CMP). CMP can be - used for DNA or RNA synthesis. The acetylation cytidine 5’ - 1]. of choline part of Citicoline leads to therapeuticThe most dosage important in humans phospholipids is 500 2000 are mg acetylcholine. phosphatidylinositol,Citicoline daily (7 28 mg/phosphatidylethanolamine, kg) [ Studies have shown that Citicoline is almost phosphatidylcholine, and sphingomyelin. They completely absorbed when it is orally are part of cell membrane and ensure its administered and only a small part of it is function, like enzymatic processes of membrane, excreted. Citicoline metabolites reach the brain linking receptors and intracellular signals, and maintaining the cell homeostasis. The blood level has a slow increase, with a peak at 6 mechanism of some neurodegenerative diseases, hoursin about after 30 theminutes oral intake. after administration, but the such as vascular dementia, Alzheimer disease, The choline is used by cholinergic neurons and cognitive impairment involve specific in two metabolic pathways: synthesis of PtdCho changes in neuronal membrane and metabolism and the neurotransmitter acetylcholine. The two of structural phospholipids. The apoptotic pathways compete for the available choline, cascade is triggered by phosphatidylcholine which is used preferentially for acetylation. metabolism changes. CDP-choline is also linked When choline is depleted, phospholipids to acetylcholine metabolism. Thus, exogenous (PtdCho) are hydrolyzed in order to restore Citicoline administration provides choline for choline levels. Acetylcholine synthesis is favored acetylcholine synthesis [2]. when the available amount of choline is limited. Therefore, Citicoline is a source of choline, Pharmacokinetics avoiding PtdCho hydrolysis and cholinergic When administered orally or intravenous, neurons death. Citicoline is converted to cytidine and choline, its Choline liberated from Citicoline can be main circulating metabolites. Plasmatic cytidine metabolized to glutathione, one of the most is then converted to uridine, and, this results in important endogenous antioxidant defense systems in the brain. Glutathione has a

153 Romanian Society of Ophthalmology © 2017 Romanian Journal of Ophthalmology 2017; 61(3): 152-158 neuroprotective role by decreasing lipid improvement of bradykinesia and rigidity. peroxidation. Citicoline has proven effects in Citicoline could decrease the incidence of side cerebral edema reduction by restoring Na+ +- effects and slow down the loss of efficacy of ATPase activity in traumatic brain injury and levodopa in the long-term treatment [9]. transient focal or global ischemia [3]. /K Having these properties, Citicoline has been Use of Citicoline in Amblyopia and Non- studied as a promising therapeutic agent in brain arteritic Ischemic Optic Neuropathy In amblyopia, Citicoline may improve the disease and ocular diseases such as glaucoma, retinal and postretinal visual pathways by ischemia,non-arteritic Parkinson’s ischemic disease,neuropathy Alzheimer’s and stimulating the dopaminergic system. It has been amblyopia. proven that it enhances contrast sensitivity, visual acuity, visual evoked responses and the Use of Citicoline in neurological diseases – effect of part-time occlusion. evidence Campos et al. [11] treated children with Many experimental studies have proven the amblyopia (anisometropic or strabismic protective effects of Citicoline in stroke models amblyopia) with oral Citicoline in addition to by reducing the infarct volume and brain edema, leading to improvement of neurological deficits. conclusion was that Citicoline was not more In these studies, Citicoline was used as a single effectivepatching. than After patching 30 days alone of but treatment, was able theto therapy or in combination with others agents stabilize the effect obtained during the [4]. Moreover, the benefic role of Citicoline was treatment. They maintained the same visual reported in clinical stroke trials when administered soon after ischemia. only patching and who showed a decrease of visualacuity acuityafter 90 [12,13 days]. compared to those who had inhibit the deposition of beta-amyloid, a Another study made by Porciatti et al. [14] neurotoxicIn Alzheimer’s protein disease,involved Citicoline in maythe also showed the benefic role of Citicoline in pathophysiology of the disease [5]. It is believed to be an interaction between the formation of with in amyloid peptides and membrane phospholipids visualamblyopia. acuity He improved treaded in 10 both amblyopic eyes with patients 1.4- disintegration. tramuscular Citicoline for 15 days. The Alvarez et al. [6] revealed in a study contrast sensitivity and the visual evoked1.5 potentiallines and alsowith improved. 0.4 lines in the control group. The disease that after 12 weeks of treatment with [15] proved the Citicoline,performed the on cognitive 30 patients performance with Alzheimer’s increased, positive role of Citicoline treatment on patients and this was more pronounced in patients with with nonIn - 2008,arteritic Parisi ischemic et al.optic neuropathy. He mild dementia. It was also an increase of evaluated the visual function before and after a cerebral blood flow velocity and of brain bioelectrical activity. was an improvement of visual acuity, Pattern The improvement in mental performance Electroretinogram60 days treatment with(PERG), oral Citicoline.visual evoked There and brain electrical activity was also proven by potential (VEP) parameters, compared with pre- Franco et al. [7] after one month of treatment treatment values. The results persisted after the with Citicoline in patients with an early onset of wash out period, compared to baseline.

Many authors have studied the role of Neuroprotective role of Citicoline in Alzheimer’s disease. 8-10] and glaucoma – Current Evidence concluded that the basis of symptoms Physiopathology of glaucoma and Citicolineimprovement in Parkinson’sis the stimulation disease [ of the neuroprotection dopaminergic system. Glaucoma is a group of optic neuropathies Agnoli et al. [8] administered Citicoline to characterized by death of retinal ganglionar cells patients with Parkinson disease already treated (RGC), which leads to structural and functional with L-dopa + dopa decarboxylase inhibitor and abnormalities of the optic nerve. It is the second revealed that Citicoline determined an important

154 cause of blindness in the world with 111.8 Romanian Society of Ophthalmology © 2017 Romanian Journal of Ophthalmology 2017; 61(3): 152-158 million peop Citicoline could also have an anti-apoptotic The most important factor is an elevated effect in the mitochondria-dependent cell death intraocular lepressure estimated (IOP), to be butaffected hypotensive in 2040. mechanism and could help the axon therapy alone is not sufficient in some cases to regeneration. Shuettauf et al. [18] studied the preserve the visual function, and the disease anti-apoptotic effect of Citicoline in adult rats by continues to progress despite a well-controlled treating them with lithium, Citicoline or a IOP. It is currently recognized as a chronic mixture of lithium and Citicoline by neurodegenerative disease, which alters the intraperitoneal injections. The results indicated a whole visual pathways running from the eye to higher density or RGC connected with the the visual cortex. This suggests that the superior colliculus in those treated with pharmacological approach used in different Citicoline compared with the others. degenerative brain disorders can also be useful Some authors demonstrated the in glaucoma. neuroprotective role of Citicoline in glutamate- first demonstrated the presence of degenerative changes in lateral -induced retinal damage in rats, which geniculateIn 2006, nucleus Gupta and visual cortex in glaucoma mediated cell death by using a model of Kainic patients. The eye could be part of the central theacid (KA)vitreous space and Citicoline nervous system and glaucoma could be a intrais an peritoneallyanalogue of inglutamate. some of Theythe rats. injected Compared KA in neurodegenerative disease. There are also common cell death mechanisms of glaucoma and which a reduction of retinal thickness was neurological progressive diseases [16]. noticedto the control gradually, group thethat groupreceived treated only KA,with in The death of RGC is the main Citicoline showed an attenuated reduction (Fig. pathophysiological event in glaucoma and 3) [19]. neuroprotection has the aim to prevent, delay, or reduce the cell death by targeting the neurons. One of the mechanisms involved is the deprivation of neurotrophins. Acute or chronic IOP elevation can cause a blockade of the axonal transport of neurotrophins from the superior colliculus to the optic nerve head. Apoptosis can be the result of neurotrophic factors deprivation, such as brain derived neurotrophic factor (BDNF), which are important for cell survival and growth. Glutamate-mediated toxicity is Fig. 3 -E staining. In control another mechanism that has been investigated; retina, Transversefive, well organized sections retinalin rat retina layers at are 7 daysseen blocking glutamate cascade could represent a after KA injection-injected using group, H the thickness of neuroprotective strategy. retina is markedly reduced due to loss of internal (A). In the KA nuclear (INL) and internal plexiform layers (IPL) -injected group Experimental studies treated with Citicoline (C) (B). Conserved retinal layers in KA In recent years, experimental studies have proven the protective role of Citicoline on RGCs. The neuroprotective effect of Citicoline on 17] showed the retinal nerve fibers in hyperglycemia conditions impact of Citicoline on retinal catecholamine has also been proven by using Citicoline eye levels.In He 2002, injected Rejadak intraperitoneally et al. [ adult male drops in a mouse model of diabetes [20]. Albino rabbits and measured the concentration of catecholamines in the retina, showing a higher level of dopamine in the animal treated with Clinical studies Citicoline, a slightly higher adrenaline concentration, while noradrenaline was Many studies have investigated the unmodified. neurotrophic effect of Citicoline in glaucoma. The

155 Romanian Society of Ophthalmology © 2017 Romanian Journal of Ophthalmology 2017; 61(3): 152-158 effects of Citicoline treatment in glaucoma were Citicoline can also be administered as eye analyzed by perimetry using Humphrey Field drops in order to increase the patient Analyzer and electrophysiological methods. The compliance and adherence. In an experimental last can describe the structures that contribute study, Citicoline has been detected in the to the visual function. The function or retinal vitreous when administered topically [25]. In ganglionar cells are analyzed by pattern this study, five mice were treated with Citicoline electroretinogram (ERGp). Visual evoked eye drops 1% and 2%, two drops per day. The potentials (VEP) describe the whole visual molecule was detected in vitreous at the end of pathways. the treatment. When 2% Citicoline was In 1999, Parisi et al. [21] investigated the administered, a systemic absorption was also effect of Citicoline by using electrofunctional noted. This study had a clinical part too. The tests (VEP and ERGp) in order to assess the authors added Citicoline eye drops to the retinal and cortical response in patients with hypotensive therapy of glaucoma patients for 2 glaucoma. The intramuscular dose of Citicoline months followed by one month of washout. After or placebo was added to their hypotensive the first 2 months of treatment, an improvement treatment, followed by a washout period. The in RGC function was noted on electrofunctional Citicoline-treated group showed an improvement of VEP and ERGp parameters when compared to placebo that was treatment- tests, but regressed after 30 days of washout. dependent. 22] evaluated the long-term treatment effect of Citicoline In 2005, Parisi et al. [ the hypotensive therapy followed by a washout periodtreatment and in repeated a 8 years the study protocol adding for Citicoline the whole to period. The results obtained at the end of each period were compared to baseline. Citicoline improved the VEP and ERGp parameters compared to pre-treatment conditions and to placebo patients. An increase in the visual field mean deviation was also observed at the end of the follow up, and this was linked to the electrofunctional results. This improvement could be determined by dopamine increase in the central nervous system. All the above studies refer to Citicoline administered by intramuscular injection. In [23] made the first clinical

2003, Rejadak et al. mg of active ingredient, given twice a day. VEP measurementstudy by using Citicolineshowed tabletsan improvement containing 500of conduction along the visual pathways. Electrophysiological examination at 24] studied the effect Fig. 4 of oral suspension of Citicoline versus the intramuscularIn 2008, Parisiadministration et al. [ over visual and after the last washout period. Improvement of visualbaseline, field after and 60 electrophysiolodays of treatmentgical with parameters Citicoline function in patients with moderate visual field after treatment followed by regression or defects. They noticed an improvement of VEP stabilization after washout [24] and ERGp parameters after both treatments, with no difference between the two The positive effects of Citicoline on the administration routes. After washout, a partial retinal function and neural conduction in regression was noticed ( ). Fig. 4 glaucoma patients was also reported by Parisi et

156 Romanian Society of Ophthalmology © 2017 Romanian Journal of Ophthalmology 2017; 61(3): 152-158 al. [26]. They treated a group of patients with Disclosures beta-blocker monotherapy and Citicoline eye None

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