Citicoline: neuroprotective mechanisms in cerebral ischemia.
Cytidine-5'-diphosphocholine (citicoline or CDP-choline), an intermediate in the biosynthesis of phosphatidylcholine (PtdCho), has shown beneficial 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 citicoline that are responsible for its effectiveness. Our studies in transient cerebral ischemia suggest that citicoline might enhance reconstruction (synthesis) of PtdCho and sphingomyelin, 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 findings, a singular unifying mechanism has been hypothesized. Citicoline also provides choline for synthesis of neurotransmitter acetylcholine, stimulation of tyrosine hydroxylase activity and dopamine release.
Adibhatla
Rao Muralikrishna
RM
Department of Neurological Surgery and Cardiovascular Research Center, University of Wisconsin, Madison, Wisconsin 53792-3232, USA. adibhatl@neurosurg.wisc.edu
Hatcher
J F
JF
Dempsey
R J
RJ
D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D003566:Cytidine Diphosphate Choline / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*
D018696:Neuroprotective Agents; D003566:Cytidine Diphosphate Choline