Molecules in focus
Citicoline (CDP-choline): What role in the treatment of complications of infectious diseases

https://doi.org/10.1016/j.biocel.2009.02.011Get rights and content

Abstract

A dysregulated host immune response, as opposed to the intrinsic virulence of a microbial pathogen induces a large part of the pathology seen in infectious diseases. However, current therapies are designed to target the pathogen rather than the underlying pathogenic mechanisms responsible for the manifestation of the pathology. Recent studies have highlighted the role of endothelial cell alteration in the pathology induced in sepsis and cerebral malaria. The endothelial onslaught described, is similar to that seen during ischemia reperfusion in stroke. Protecting endothelial cell membranes during sepsis and cerebral malaria, using citicoline in the same way as in stroke, has thus emerged as a new strategy that needs to be evaluated urgently. Citicoline is a natural compound that is registered for use in ischemic stroke, head trauma and neurological disorders. It enters the phosphatidylcholine synthesis pathway as a rate-limiting step and is involved in the modulation of a large number of metabolic pathways and neurotransmitter levels, and also in the biosynthesis of phospholipids in neuronal membranes. This short review highlights the potential role of citicoline as part of adjunct therapy in the treatment of infectious diseases.

Introduction

An overwhelming dysregulated host response induces a large part of the pathology seen in infectious disease. However, current therapies are designed to target the pathogen rather than the underlying pathogenic mechanisms responsible for the manifestation of the pathology. One such example is the current antibiotic treatment used for sepsis. Despite its wide implementation, bacterial infections still claim an unacceptably high mortality rate of 20–50 percent (review in Hodgin and Moss, 2008). Similarly, the antiparasitic treatment used for cerebral malaria (CM) has had a limited effect on post-neurological outcomes. Cerebral malaria is characterised by the cytoadhesion of parasites on host cells, leading to microcirculation impairment due to a cascade of host immune responses and consequently, unarousable coma or death (Gupta et al., 1994). This neurovascular pathology is a leading cause of death in African children with over two million deaths a year. Even with the best antiparasitic treatments, patients with CM have a similar outcome to sepsis, with 30–50 percent of cases moribund (WHO, 2008). Increasing evidence has accumulated to support a combination of contributing factors to the manifestation of CM. Numerous studies have highlighted cytokine-induced endothelial activation and the leakage of the blood-brain barrier as leading factors for the neurological signs and symptoms of CM (rev. Adibhatla et al., 2008). These studies strengthen the importance of treating the underlying pathophyisological mechanisms not just eradicating the infectious agent.

Ischemia-reperfusion (IR) seems to be a pivotal mechanism in both sepsis and CM. In stroke and myocardial infarction, the implementation of treatments managing IR, specifically citicoline, have proved their efficiency to reduce mortality (rev. Secades and Lorenzo, 2006). Citicoline is a membrane protector and it is registered for the treatment of brain stroke, head trauma and other neurological disorders such as dementia. It is naturally found in most cells as a rate-limiting step of the phosphatidylcholine synthesis, but its addition to diet activates its intervention in a large number of metabolic pathways. Citicoline is widely used to reduce IR induced pathology, but it is yet to be implemented as adjunct therapy in severe infectious diseases. By rethinking our strategies for the treatment of severe infections, we present citicoline as a potential therapeutic agent.

Section snippets

Structure

Citicoline (CDP-choline, cytidine diphosphate choline, cytidine 5′-diphosphocholine,) is a nucleotide composed of ribose, pyrophosphate, cytosine and choline. It is organized in two moieties, cytidine and choline, that are linked by a diphosphate bridge (Fig. 1). Citicoline was first identified by Kennedy et al., in 1955 and synthesized in 1956. In most cells, it is a rate-limiting intermediate in the biosynthesis of phosphatidylcholine (PC) and serves as the phosphocholine donor to

Synthesis and turnover

Regulation of PC is a central process for the cell and for membrane fluidity. It is mainly synthesized by the CDP-choline pathway (Fig. 2) (rev. van Meer et al., 2008). This pathway can be modulated by the level of ATP in the cells, tumor necrosis factor (TNF) which reduces CPT activity, and by lipopolysaccharide which stimulates phospholipid and PC synthesis. The phosphocholine-cytidylyltransferase can also be regulated in the nucleus by translocation from a soluble to a membranous form in

CDP-pathway is a central regulator of cell metabolism

The CDP pathway is a major target for drug development (rev. in Fioravanti and Yanagi, 2005), as it plays a central role in the regulation of PC-dependent pathways. It regulates the diacylglycerol pool which controls the secretory functions of the Golgi (rev. in Freyberg et al., 2003). Phosphocholine-cytidylyltransferase coordinates lipid synthesis and membrane deformation of the tubular nuclear network, which controls homeostasis in the nucleus (rev. in Martelli et al., 2004). It regulates the

CDP-choline is registered as a treatment for neurological disorders

Citicoline is registered in Europe for use in stroke, head trauma and neurological disorders, and in the USA for the treatment of ischemic stroke (rev. in Fioravanti and Yanagi, 2005, Secades and Lorenzo, 2006). It is also recommended as a nutritional supplement. In humans, 500–2000 mg are prescribed daily without side effects. Adverse reactions include minor epigastric pain, nausea, rash, headache and dizziness. Numerous studies report on efficacy of citicoline on damages after focal ischemia

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