Neuroprotective Properties of Citicoline: Facts, Doubts and Unresolved Issues

Grieb, Pawel

P. Grieb Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego str., 02–106 Warsaw, Poland e-mail: [email protected]

Published online: 7 February 2014

Acknowledgements Dr Grieb has no conflicts of interest that are directly relevant to the content of this review. No sources of funding were used in the preparation of the review.

Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

CNS Drugs 28(3):p 185-193, March 2014. | DOI: 10.1007/s40263-014-0144-8

Abstract

Citicoline is the generic name of the pharmaceutical substance that chemically is cytidine-5′-diphosphocholine (CDP-choline), which is identical to the natural intracellular precursor of phospholipid phosphatidylcholine. Following injection or ingestion, citicoline is believed to undergo quick hydrolysis and dephosphorylation to yield cytidine and choline, which then enter the brain separately and are used to resynthesize CDP-choline inside brain cells. Neuroprotective activity of citicoline has been repeatedly shown in preclinical models of brain ischaemia and trauma, but two recent, large, pivotal clinical trials have revealed no benefits in ischaemic stroke and traumatic brain injury. However, the substance seems to be beneficial in some slowly advancing neurodegenerative disorders such as glaucoma and mild vascular cognitive impairment. This paper critically discusses issues related to the clinical pharmacology of citicoline, including its pharmacokinetics/biotransformation and pharmacodynamics/mode of action. It is concluded that at present, there is no adequate description of the mechanism(s) of the pharmacological actions of this substance. The possibility should be considered and tested that, in spite of apparently fast catabolism, the intact citicoline molecule or the phosphorylated intermediate products of its hydrolysis, cytidine monophosphate and phosphocholine, are pharmacologically active.

Key Points for Decision Makers

Citicoline is chemically identical to CDP-choline, the natural precursor of the major cell membrane phospholipid phosphatidylcholine.

Given orally or by injection, citicoline is non-toxic and very well tolerated.

Preclinical experiments with various models of central neurodegenerative diseases have shown that citicoline displays significant neuroprotective properties.

However, recent large and well-controlled data have shown no benefit from citicoline in acute ischaemic stroke and traumatic brain injury.

The pharmacological actions of citicoline in the central nervous system seem to be pleiotropic and involve, amongst other things, modulation of some kinases and sirtuin-1. However, our understanding of the mechanisms involved is, at most, fragmentary.