CITICOLINE

Cytidine-5′-diphosphate choline (CDP-choline) is an endogenous compound normally produced by the body. When it was introduced as a drug, it was called citicoline. Both in animals and in humans, citicoline has been shown to possess proved neuroprotective properties (1-3). In clinical practice, a number of different studies have clearly shown that citicoline is effective in cognitive impairment of diverse aetiology, cerebrovascular disease, head trauma, glaucoma, amblyopia, and Parkinson’s disease (PD). 6 months is the reported recommendation for getting the best outcomes. Citicoline has been widely prescribed for cognitive impairment in several European countries (4).

Citicoline is also able to potentiate neuroplasticity and is a natural precursor of phospholipid synthesis, chiefly phosphatidylcholine, or rather serves as a choline source in the metabolic pathways for biosynthesis of acetylcholine (1-3). On a molecular basis, CDP-choline activates the biosynthesis of structural phospholipids in the neuronal membranes and increases cerebral metabolism, noradrenaline, and dopamine levels in the central nervous system (CNS) (1). Furthermore, it is able to prevent the loss of cardiolipin, an exclusive inner mitochondrial phospholipid enriched with unsaturated fatty acids, which is essential for mitochondrial electron transport (1). Animal studies suggest that exogenously administered CDP-choline may protect cell membranes by accelerating re-synthesis of phospholipids, thus resulting in rapid repair of injured cell surfaces and mitochondrial membranes. Several studies have shown that it can have beneficial effects both in degenerative and in vascular cognitive decline (5-10)

 

Evidence on the effectiveness of citicoline

Overall evidence of benefit of CDP-choline on memory function and behaviour in the short-to-medium term was reviewed by Fioravanti and Yanagi, where the drug was well-tolerated (2). Fourteen studies were included in this review; seven of the included studies observed the subjects for a period between 20 and 30 days, one study was of 6 weeks duration, five studies over 2 months and 3 months, and one study was prolonged up to 12 months of observation (2). Citicoline appears to deliver “safe” neuroprotection, capable of enhancing endogenous protective pathways and plasticity with cellular functions mainly aimed to preserve membrane function and integrity. This may be due to control of excitotoxicity and maintaining cellular adenosine 5′-triphosphate levels (3).

Citicoline has been shown to be of benefit in vascular cognitive impairment, vascular dementia, and AD, especially when associated with significant cerebrovascular disease (6). Stroke can double the risk of dementia; a trial lasting 12 months in patients with first-ever ischemic stroke showed that citicoline prevented cognitive decline after stroke, with significant improvements in temporal orientation, attention, and executive functions (6).

The VITA study and the IDEALE study also showed substantial benefits in vascular cognitive impairment (11-12) The IDEALE study was one of the few trials conducted for a period longer than 6 months. A number of studies have shown that citicoline’s bioavailability is very good following oral administration (26,27). The authors suggest the most pronounced benefits of treatment with citicoline are probably due to the activation of biosynthesis of phospholipids in neuronal membranes, the increase in brain metabolism, and the neuroprotective effects during hypoxia and ischemia. Furthermore, they are most likely to be accrued with prolonged use. This is confirmed by the positive results in the treated group and by the decrease in MMSE scores in the control group at only 9 months, after starting the study.

 

Memory and recall

Other studies have clearly demonstrated citicoline’s effects on several cognitive domains (9). Citicholine has been shown to:

• improve both immediate and delayed recall of words and objects;

• ameliorate short- and long-term memory, attention, and perceptual-motor ability, as well as behavioral and emotional control;

• improve verbal memory functioning in older individuals with relatively inefficient memory.

The effect of CDP-choline was studied in 19 AD patients (mean age 66.21±1.48 years) for 30 days and was effective in significantly improving cognitive functions, in particular in early-onset AD patients (EOAD) (13). The authors concluded that the therapeutic effects of CDP-choline may be mediated by the enhancement of cholinergic neural transmission, activation of repair mechanism, regulation of several immunological responses, and attenuation of hypoperfusion patterns in cerebral blood flow (13).

Caamaño et al (14) investigated the effects of CDP-choline on cognition for 1 month in 20 patients, mean age 66.7±6.73 years. Cognition was assessed by the Mini-Mental State Examination (MMSE), and blood flow velocities were measured by transcranial Doppler ultrasonography. Increased cranial blood flow velocity was registered, and the authors postulated that citicoline’s cholinergic effects influence cytokine production, and immunogenic and/or neurotrophic effects at the microvascular niche may partially account for its benefits in these individuals (14).

It is known that excess of histamine may affect the pathological development of AD and CDP-choline is able to reduce the basal levels of blood histamine in both early and late-onset Alzheimer’s disease (LOAD) (15).

Cacabelos et al (16) showed that the administration of CDP-choline for 3 months in AD and multi-infarct dementia improved mental performance (assessed by MMSE and Hamilton Rating Scale for Depression). The possible explanations given by the authors were that CDP-choline can improve vascular risk factors and stabilize immune function.

CDP-choline was also studied in a double-blind, placebo-controlled, randomized trial involving 30 patients with apolipoprotein E (APOE) genotyped AD. Improvement in cognitive performance and cerebral blood perfusion in these patients was found, and the drug was quite well-tolerated (17).

 

Neuroprotection

One of the more recent findings of citicoline relates to its neuroprotective effect linked to sirtuins. Sirtuins are highly conserved NAD-dependent protein deacetylases that are able to regulate aging in lower organisms and possess important roles in centenarians (18) and in age-related diseases in higher organisms (19,20) Activating SIRT1 appears to be beneficial in protecting against cognitive decline. On the other hand, deletion of SIRT2 seems to be protective against PD (21).

Hurtado et al recently showed that CDP-choline increases SIRT1 protein expression in animal models, in cultured neurons, and in circulating blood mononuclear cells, an effect that is strongly involved in the neuroprotective actions of this drug (22).

Moreover, CDP-choline and the SIRT1 activator resveratrol have a potent synergistic effect leading up to 60% reductions in the infarct volume after middle cerebral artery occlusion (MCAO), when used together at doses individually sub-effective of these compounds (22). In experimental models of stroke, sirtinol, a specific inhibitor of SIRT1, was shown to abolish the neuroprotective effect of CDP-choline at a concentration previously shown to be effective (23) furthermore, it does not have any effect on infarct volume in the absence of CDP-choline. To emphasize its neuroprotective effects, CDP-choline-induced reduction in infarct volume is totally abolished in the absence of SIRT1. Sirt1-/- mice display larger infarct volumes than their wild-type counterparts after being subjected to brain ischemia, thus suggesting the neuroprotective action of endogenous SIRT1 in stroke (24).

Other possible neuroprotective effects are linked to citicoline’s possible modulation of activity/expression of some protein kinases involved in neuronal death (25).

The IDEALE study was one of the few trials conducted for a period longer than 6 months. A number of studies have shown that citicoline’s bioavailability is very good following oral administration (26,27). The authors suggest the most pronounced benefits of treatment with citicoline are probably due to the activation of biosynthesis of phospholipids in neuronal membranes, the increase in brain metabolism, and the neuroprotective effects during hypoxia and ischemia. Furthermore, they are most likely to be accrued with prolonged use. This is confirmed by the positive results in the treated group and by the decrease in MMSE scores in the control group at only 9 months, after starting the study.

 

Conclusion

CDP-choline has been shown to possess beneficial physiological actions on cellular function. CDP-choline and its hydrolysis products play important roles in phospholipid synthesis and neuronal repair. The wealth of data from published studies suggest it to be to be effective in cognitive impairment of any kind, especially of vascular origin, a result widely demonstrated in the VITA study and the IDEALE studies. Importantly, citicoline has been recently shown to increase SIRT1 protein expression and this is strongly involved in its neuroprotective actions. Some studies have shown poor results following citicoline administration, even if this could be due to its short time of administration. Also, it would be interesting to study whether the use of citicoline in association with cholinesterase inhibitors may help in delaying the progression of AD. It might be the possible target of future studies.

 

References

1. Secades JJ, Frontera G. CDP-choline: pharmacological and clinical review. Methods Find Exp Clin Pharmacol. 1995;17(suppl B):1–54.

2. Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev. 2005;18(2):CD000269.

3. Hurtado O, Lizasoain I, Moro MÁ. Neuroprotection and recovery: recent data at the bench on citicoline. Stroke. 2011;42(suppl1):S33–S35.

4. Franco-Maside A, Caamaño J, Gómez MJ, Cacabelos R. Brain mapping activity and mental performance after chronic treatment with CDP-choline in Alzheimer’s disease. Methods Find Exp Clin Pharmacol. 1994;16(8):597–607.

5. Grieb P. Neuroprotective properties of citicoline: facts, doubts and unresolved issues. CNS Drugs. 2014;28(3):185–193.

6. Alvarez-Sabín J, Ortega G, Jacas C, et al. Long-term treatment with citicoline may improve poststroke vascular cognitive impairment. Cerebrovasc Dis. 2013;35(2):146–154.

7. Secades JJ. Citicoline: pharmacological and clinical review, 2010 update. Rev Neurol. 2011;52(suppl 2):S1–S62.

8. Alvarez-Sabin J, Roman GC. Citicoline in vascular cognitive impairment and vascular dementia after stroke. Stroke. 2011;42:S40–S43.

9. García-Cobos R, Frank-García A, Gutiérrez-Fernández M, Díez-Tejedor E. Citicoline, use in cognitive decline: vascular and degenerative. J Neurol Sci. 2010;299(1–2):188–192.

10. Fioravanti M, Buckley AE. Citicoline (Cognizin) in the treatment of cognitive impairment. Clin Interv Aging. 2006;1(3):247–251.

11. Putignano S, Gareri P, Castagna A, et al. Retrospective and observational study to assess the efficacy of citicoline in elderly patients suffering from stupor related to complex geriatric syndrome. Clin Interv Aging. 2012;7:113–118.

12. Cotroneo AM, Castagna A, Putignano S, et al. Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study. Clin Interv Aging. 2013;8:131–137.

13. Franco-Maside A, Caamaño J, Gómez MJ, Cacabelos R. Brain mapping activity and mental performance after chronic treatment with CDP-choline in Alzheimer’s disease. Methods Find Exp Clin Pharmacol. 1994;16(8):597–607.

14. Caamaño J, Gómez MJ, Franco A, Cacabelos R. Effects of CDP-choline on cognition and cerebral hemodynamics in patients with Alzheimer’s disease. Methods Find Exp Clin Pharmacol. 1994;16(3):211–218.

15. Fernández-Novoa L, Alvarez XA, Franco-Maside A, Caamaño J, Cacabelos R. CDP-choline-induced blood histamine changes in Alzheimer’s disease. Methods Find Exp Clin Pharmacol. 1994;16(4):279–284.

16. Cacabelos R, Alvarez XA, Franco-Maside A, Fernández-Novoa L, Caamaño J. Effect of CDP-choline on cognition and immune function in Alzheimer’s disease and multi-infarct dementia. Ann N Y Acad Sci. 1993;695:321–323.

17. Alvarez XA, Mouzo R, Pichel V, et al. Double-blind placebo-controlled study with citicoline in APOE genotyped Alzheimer’s disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion. Methods Find Exp Clin Pharmacol. 1999;21(9):633–644.

18. Bellizzi D, Dato S, Cavalcante P, et al. Characterization of a bidirectional promoter shared between two human genes related to aging: SIRT3 and PSMD13. Genomics. 2007;89(1):143–150.

19. Donmez G. Sirtuins as possible targets in neurodegenerative diseases. Curr Drug Targets. 2013;14:644–647.

20. Donmez G, Guarente L. Aging and disease: connections to sirtuins. Aging Cell. 2010;9:285–290.

21. Donmez G, Outeiro TF. SIRT1 and SIRT2: emerging targets in neurodegeneration. EMBO Mol Med. 2013;5:344–352.

22. Hurtado O, Hernández-Jiménez M, Zarruk JG, et al. Citicoline (CDP-choline) increases Sirtuin1 expression concomitant to neuroprotection in experimental stroke. J Neurochem. 2013;126:816–819.

23. Grozinger CM, Chao ED, Blackwell HE, Moazed D, Schreiber SL. Identification of a class of small molecule inhibitors of the sirtuin family and NAD-dependent deacetylases by phenotypic screening. J Biol Chem. 2001;276:38837–38843.

24. Hernández-Jiménez M, Hurtado O, Cuartero MI, et al. Silent information regulator 1 (SIRT1) protects the brain against cerebral ischemic damage. Stroke. 2013;44(8):2333–2337.

25. Krupinski J, Slevin M, Badimon L. Citicoline inhibits MAP kinase signalling pathways after focal cerebral ischaemia. Neurochem Res. 2005;30(8):1067–1073.

26. Lozano-Fernandez R. Efficacy and safety of oral CDP-choline. Drug surveillance study in 2,817 cases. Arzneimittelforschung. 1983;33(7A):1073–1080.

27. Secades JJ. CDP-choline: update and review of its pharmacology and clinical use. Methods Find Exp Clin Pharmacol. 2002; 24(suppl B):1–53.