Citicoline: Neuroprotective Mechanisms in Cerebral Ischemia

Cytidine-5¢-diphosphocholine (citicoline or CDP-choline), an intermediate in the biosynthesis of phosphatidylcholine (Ptd-Cho), has shown bene®cial effects in a number of CNS injury models and pathological conditions of the brain. Citicoline improved the outcome in several phase-III clinical trials of stroke, but provided inconclusive results in recent clinical trials. The therapeutic action of citicoline is thought to be caused by stimulation of PtdCho synthesis in the injured brain, although the experimental evidence for this is limited. This review attempts to shed some light on the properties of citico-line that are responsible for its effectiveness. 2 Our studies in transient cerebral ischemia suggest that citicoline might enhance reconstruction (synthesis) of PtdCho and sphingo-myelin, but could act by inhibiting the destructive processes (activation of phospholipases). Citicoline neuroprotection may include: (i) preserving cardiolipin (an exclusive inner mitochondrial membrane component) and sphingomyelin; (ii) preserving the arachidonic acid content of PtdCho and phosphatidylethanolamine; (iii) partially restoring PtdCho levels; (iv) stimulating glutathione synthesis and glutathione reductase activity; (v) attenuating lipid peroxidation; and (vi) restoring Na + /K +-ATPase activity. These observed effects of citicoline could be explained by the attenuation of phospholipase A 2 activation. Based on these ®ndings, a singular unifying mechanism has been hypothesized. 3 Citico-line also provides choline for synthesis of neurotransmitter acetylcholine, stimulation of tyrosine hydroxylase activity and dopamine release. Cytidine-5¢-diphosphocholine (citicoline or CDP-choline) was originally identi®ed as the intermediate in phosphat-idylcholine (PtdCho) synthesis by Eugene Kennedy in 1956 (Kennedy and Weiss 1956). In 1983 22 articles were published that described the physico-chemical properties, pharmacokinetics, toxicity and bioavailability of this agent (Anonymous 1983). In 1995 there were two review articles that discussed the bene®cial effects of this drug in CNS injury (Secades and Frontera 1995; Weiss 1995). Although much work has been carried out investigating citicoline absorption and metabolism, its mechanism of neuroprotec-tion has not been experimentally delineated in CNS injury models including cerebral ischemia. Citicoline has shown bene®cial effects in a variety of CNS injury models and neurodegenerative diseases, suggesting a common underlying mechanism associated with the loss of membrane integrity (Table 1). Citicoline neuroprotection is thought to be a result of increased PtdCho synthesis in the injured brain, but the experimental evidence is limited. The present review takes an overview of citicoline neuroprotective actions based on our recent ®ndings.