Cytidine 5′-Diphosphocholine (CDP-Choline) in Stroke and Other CNS Disorders

Citicoline is a brain chemical that occurs naturally in the body. As a medicine, it is taken by mouth as a supplement or given as an injection into the vein (by IV) or as a shot into the muscle.

In Japan and Europe, Citicoline was originally used as a prescription drug to help improve memory, thinking, and brain function in people who are healing from a stroke. It is primarily used as a dietary supplement in the U.S. Citicoline is taken by mouth or given as an injection to help memory loss due to aging, improve vision in people with glaucoma, and help with recovery in stroke patients. It is also used for Alzheimer disease, Parkinson disease, bipolar disorder, lazy eye, and other conditions of the brain. But there is no good scientific research to support these other uses.

Mechanism of Action

Citicoline is regarded to increase a brain chemical called phosphatidylcholine. This brain chemical is important for brain function. Citicoline might also increase the amounts of other chemicals that send messages in the brain.

Biological Effects

Stroke or “brain attack” is the first leading cause of long-lasting disability, third leading cause of death and continues to be a problem of vast clinical significance. Approximately 3.9 million Americans are stroke survivors, and the after-effects of stroke require more than $51 billion in healthcare costs annually. Presently, tissue plasminogen activator (tPA) is the only FDA approved drug for the treatment of acute ischemic stroke but needs to be administered within 3 h (1). However, there are some concerns that tPA has neurotoxic side effects in addition to its beneficial (thrombolytic) actions (2). Many neuroprotective agents have undergone phase III clinical trials for stroke; most of the trials were abandoned due to ineffectiveness or toxicity of the drug.

Cytidine-5′-diphosphocholine (CDP-choline or Citicoline) is composed of cytidine and choline linked by a diphosphate bridge and is an essential intermediate in the synthesis of phosphatidylcholine (PC), a major brain phospholipid, via Kennedy pathway. Exogenous CDP-choline is hydrolyzed and absorbed as cytidine and choline (3), and CDP-choline is re-synthesized from cytidine triphosphate (CTP) and phosphocholine by CTP-phosphocholine cytidylyltransferase (CCT), the rate-limiting enzyme in PC synthesis. CDP-choline also serves as a choline donor in the biosynthesis of the neurotransmitter acetylcholine. As the intermediate in PC biosynthesis, it was believed that CDP-choline would rectify membrane damage and provide benefit in CNS disorders and injury (including stroke).

Parkinson’s Disease

CDP-choline stimulates tyrosine hydroxylase activity and dopamine release (3), which may be due to increases in brain acetylcholine since choline administration produced the same effects. Parkinson’s disease is characterized by a selective degeneration of the dopaminergic neurons of the substantia nigra, however the phospholipid abnormalities present in Alzheimer’s brains were not observed. Levodopa is the main therapeutic option for treatment of Parkinson’s disease; its main disadvantage is progressive loss of efficacy. CDP-choline has been tested in treatment of Parkinson’s disease because of its ability to increase the availability of dopamine (3). Combination treatment of Parkinson’s patients with CDP-choline and levodopa allowed significant reduction of the levodopa dose, thus minimizing side effects of levodopa therapy (3).

Alzheimer’s Disease and Other Memory Disorders

Clinical studies have demonstrated that CDP-choline improves cognitive performance in elderly subjects. Blocking synthesis of PC is sufficient in itself to cause cell death, and a 10% loss of cellular membrane is a threatening situation for neuronal viability. Alzheimer’s brains have shown loss of PC and phosphatidylethanolamine and CDP-choline may rectify the membrane damage in these brains (36). Additionally, the cholinergic system is dysfunctional in Alzheimer’s brain (50), and CDP-choline may provide benefit by enhancing acetylcholine synthesis (Fig. 1A).

Fig. 1 CDP-choline: (A) possible neuroprotective pathways based on the published reports, (B) effects mediated by attenuating PLA2 stimulation (based on authors’ work). ↑ indicates increase; ↓ indicates decrease.

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