Neuroprotective Properties of Citicoline

Citicoline is the name of the pharmaceutical product that chemically is cytidine-50-diphosphocholine (CDP-choline), which is identical to the natural precursor of phospholipid phosphatidylcholine. After administration, CDP-choline undergos quick hydrolysis and dephosphorylation to produce cytidine and choline, which then enter the brain separately and then are used to restore CDP-choline inside neurons. This, in turn, is believed to result in inhibition of phospholipid breakdown and acceleration of phospholipid resynthesis cruitial for membrane repair. Neuroprotective properties of CDP-choline has been reported in many preclinical models of brain ischaemia and trauma. The compound has offered marked neuroprotection in many in vitro and in vivo models of brain ischaemic and neurodegenerative diseases, including brain hypoxia, ischaemia and intracerebral haemorrhage, brain and spinal cord trauma, in vitro glutamate excitotoxicity and also in vivo amyloid toxicity. However, the mechanisms of this neuroprotection are still unknown. One major effect of citicoline is believed to be stimulation of the synthesis and increase in the level of phospholipids. The other mechanisms suggested to be involved in the neuroprotective effects of CDP-choline include inhibition of activation of phospholipase A2. The related effects comprise attenuation of the increase in hydroxyl radical synthesis, preventing loss of cardiolipin (an exclusive inner mitochondrial membrane phospholipid essential for electron transport, which is degraded in response to cellular insults and disrupts the mitochondrial respiratory chain). In aged rats, an increase in the brain level of platelet-activating factor (a bioactive phospholipid implicated in neuronal excitotoxic death) has also been noted. In rats, attenuation of mitogen-activated protein kinases and caspase activation have been observed after CDP-choline administration. Last, but not least, according to the most recent report, treatment with CDP-choline has been found to stimulate sirtuin-1 (SIRT1) protein levels in neurons, in circulating blood mononuclear cells and in the neurons. This effect seems to be of critical importance for neuroprotection in experimental stroke because sirtinol, a specific inhibitor of SIRT1 which, by itself, does not influence infarct volume, has been shown to abolish the neuroprotection offered by citicoline. Citicoline showed a potent synergistic effect with resveratrol (which is known to be a SIRT1 activator).