Pharmacology: Pharmacodynamics: Mechanisms of Action: Phospholipid Precursor: Evidence of citicoline's role as a phosphatidylcholine precursor has been found in animal studies.
The brain uses choline preferentially for acetylcholine synthesis, which can limit the amount of choline available for phosphatidylcholine production.
When the demand for acetylcholine increases or choline stores in the brain are low, phospholipids in the neuronal membrane can be catabolized to supply the needed choline.
Exogenous citicoline thus helps preserve the structural and functional integrity of the neuronal membrane.
In an in vitro study, citicoline at high concentrations stimulated brain acetylcholinesterase (AChE) along with Na+K+-ATPase.
The postulated mechanism involves bioconversion of citicoline to phosphatidylcholine.
Neuronal Membrane Repair: Citicoline has been investigated as a therapy for stroke patients. Three mechanisms are postulated: repair of neuronal membranes via increased synthesis of phosphatidylcholine; repair of damaged cholinergic neurons via potentiation of acetylcholine production; and reduction of free fatty acid buildup at the site of stroke-induced nerve damage.
In addition to phosphatidylcholine, citicoline serves as an intermediate in the synthesis of sphingomyelin, another neuronal membrane phospholipid component. Citicoline has shown the potential to restore post-ischemic sphingomyelin levels.
Citicoline also restores levels of cardiolipin, a phospholipid component of the inner mitochondrial membrane. The mechanism for this is unknown, but data suggest citicoline inhibits enzymatic hydrolysis of cardiolipin by phospholipase A2.
In an animal study, citicoline decreased the formation of hydroxl radicals following ischemia and perfusion, again suggesting citicoline acts to decrease phospholipase stimulation.
Effect on beta-Amyloid: Evidence has surfaced that citicoline counteracts the deposition of beta-amyloid, a neurotoxic protein believed to play a central role in the pathophysiology of Alzheimer's disease (AD). The characteristic lesion in AD is the formation of plaques and neurofibrillary tangles in the hippocampus. The degree of cognitive dysfunction and neurodegeneration in AD is proportional to the build-up of beta-amyloid.
Citicoline counteracted neuronal degeneration in the rat hippocampus induced by intrahippocampal injection of beta-amyloid protein. The number of apoptotic cells was also reduced. Memory retention as measured by a passive-avoidance learning task improved in the rats.
Effect on Neurotransmitters: Evidence of citicoline's ability to enhance norepinephrine release in humans was found in a study showing citicoline raised urinary levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), a norepinephrine metabolite.
Citicoline increased brain levels of neurotransmitters in rats at a dose of 100 mg/kg, administered daily for seven days. Norepinephrine increased in the cerebral cortex and hypothalamus, dopamine increased in the corpus striatum, and serotonin increased in the cerebral cortex, striatum, and hypothalamus. Rat studies have found evidence that citicoline potentiates dopamine release in the brain, presumably by stimulating release of acetylcholine.
Pharmacokinetics: Citicoline is a water-soluble compound with greater than 90-percent bioavailability. Pharmacokinetic studies on healthy adults show oral doses of citicoline are rapidly absorbed, with less than one percent excreted in feces. Plasma levels peak in a biphasic manner, at one hour after ingestion followed by a second larger peak at 24 hours post-dosing. Citicoline is metabolized in the gut wall and liver. The byproducts of exogenous citicoline formed by hydrolysis in the intestinal wall are choline and cytidine. Following absorption, choline and cytidine are dispersed throughout the body, enter systemic circulation for utilization in various biosynthetic pathways, and cross the blood-brain barrier for resynthesis into citicoline in the brain.
Pharmacokinetic studies using citicoline show citicoline elimination occurs in two phases mirroring the biphasic plasma peaks, mainly via respiratory and urinary excretion. The initial peak in plasma concentration is followed by a sharp decline, which then slows over the next 4-10 hours. In the second phase, an initially rapid decline after the 24-hour plasma peak is similarly followed by a slower elimination rate. The elimination half-life is 5-6 hours for respiratory CO2 and 71 hours for urinary excretion.