Citicoline: A Potential Breakthrough in Cerebrovascular Disorder

Abstract

Citicoline, CDP Choline or Cytidine diphophocholine is a novel drug with a broad spectrum of benefits for condition associated with neurological dysfunction. Citicoline is an endogenous compound and an essential intermediate in the synthesis of phosphatidylcholine (cell membrane phopholipid). It is launched worldwide (outside of US and Canada only) as a drug for stroke and head injuries. It plays important roles in structural integrity, signaling of cell membrane and plays important role in human physiology. It supports the synthesis of Acetylcholine and Betaine, a methyl donor to generate phospholipids. Citicoline attenuates the production of free radicals in Ischemic condition and also stimulates the activity of glutathione reductase and has the ability to promote learning and improve cognitive impairment in Parkinson’s and Alzheimer’s disease. Citicoline administration reduces the severity of mental and motor deficits associated head injuries and supports eye health and mental health. Pharmacokinetics suggests that it is well absorbed and high bioavailable orally. A dose of 500mg to 2000 mg per day is an effective based on clinical trials and is safe for use in elderly population and pediatrics. It has the ability to improve phospholipid metabolism, with a consequent improvement in the deteriorated axonal flow of dopamine.

Keywords: Citicoline; Phosphatidylcholine; Betaine; Choline; Neurological dysfunction

Abbreviations

CDP: Cytidine Diphosphocholine; US: United States; GABA: Gamma Amino Butyric Acid; ATP: Adenosine Tri Phosphate; BBB: Blood Brain Barrier; NE: Nor Epinephrine; IM: Intra Muscular

Introduction

Citicoline is a mononucleotide which is composed of choline, cytosine, pyrophosphate and ribose. It is an essential intermediate in the synthesis of cell membrane phospholipids i.e. Phosphatidylcholine and Acetylcholine, a key neurotransmitter. Phospholipids are essential constituents of cell and have a high turnover rate, which requires a continuous synthesis of these compounds to ensure the adequate function of cell membrane [1,2]. Citicoline first identified in 1955 by Kennedy et al. and was synthesized in 1956. Initially it was developed in Japan to treat stroke patients. Later, Interneuron obtained its marketing and manufacturing license for Canada and US in 1993. By September 1997, a patent application had been filed by Interneuron worldwide, for the use of Citicoline [3]. It is widely available as an approved drug for the treatment of neurological disorder. When administered, Citicoline is hydrolyzed in the intestinal tract and in circulation to form choline and cytidine. Choline is a component of the diet and is produced in the brain in small amount. It plays several essential roles in human physiology, including signaling of cell membrane, support synthesis of betaine, a methyl donor and Acetylcholine. Studies in neuronally related cell lines have also shown that Cytidine administration increased the incorporation of choline into membrane phosphatidylcholine. Citicoline lowers the toxicity index an additional 20 fold and has low level of toxicological index [4,5]. It prevents the accumulation of free fatty acids and generation of free radicals at the site of ischemia, thereby prevents the initiation of proinflammatory cascade of events. Citicoline has been shown to act as a dopaminergic agonist. In addition, it also has some effects upon the other monoamines, serotonin and nor epinephrine, muscarinic receptors, and glutamate and GABA [6]. It inhibit catabolism of cerebral phospholipids and has a protective effect upon membrane ATPase and enzymes involved in brain energy metabolism, particularly succinyl dehydrogenase and citrate synthetase [7-9].

Bioavailability / Pharmacokinetics

Administration of 300mg dose to healthy adults shows nearly complete absorption, with less than 1% of excretion in feces [10]. The main route of excretion was found to be via a respiratory route, with significant excretion occurring through urine. A confirmatory study, using radioactive Citicoline in rats, found 62.8% of total radioactivity distributed in brain tissues as phospholipids, including phosphatidylcholine and sphingomyelin. Metabolites of orally administered Citicoline resynthesize endogenous Citicoline, which yields beneficial effects for the synthesis and incorporation of neuronal phospholipids [11-13]. Only a small percentage of total Citicoline crosses the BBB as choline and Cytidine, the utilization of these precursors is extremely efficient [14].

Mechanism of Action

Citicoline has beneficial effects on neurological functions; it acts by increasing the synthesis of phosphatidylcholine, the primary neuronal phospholipid and enhancing the production of acetylcholine [15]. Brain phospholipid synthesis is impaired following stroke and ischemic events. Oral citicoline administration increases the plasma levels of choline and cytidine, building blocks used to restore neuronal membrane integrity. Citicoline seems to have different effects on phosphatidylcholine synthesis in younger versus older adults. Phosphatidylcholine is an essential compound for cell membrane integrity and reduces in brain as a result of aging. Clinical data suggest that uridine and choline are the circulating substrates through which citicoline facilitates an increase in brain membrane phospholipid synthesis. Uridine crosses the blood-brain barrier and is converted to uridine triphosphate. Uridine directly gets converted to cytidine triphosphate intracellularly. The frontal lobe is the preferred site for the deposition of Citicoline [16-19].

This area of the brain contributes to memory function by supporting attention, memory capacity, and by reducing mental fatigue. Citicoline has benefit in patients experiencing ischemia by decreasing the accumulation of free fatty acids at the site of the lesion, which occurs as a result of neuronal cell damage and death. After the initiation of ischemia, there is a significant increase in arachidonic acid, glycerols, and free fatty acids caused by the breakdown of neuronal membranes (Figure 1) [20-22].

    

    

    Figure 1: Major metabolic pathway of citicoline.