Significance and goal: CDP-choline (citicoline) stroke clinical trials in Europe and Japan showed significant improvement, while US studies provided ambiguous results. The route of administration (oral in USA vs iv in non-USA) and 24-hr time window may have hindered its effectiveness in the USA trials. It has now been realized that oral administration in USA trials was inappropriate and new Phase III trials will soon be undertaken. Our studies show that CDP-choline treatment delayed by 3-hr did not offer any neuroprotection. CDP-choline mode of action has not been clearly identified, and understanding its mechanism(s) should lead to more effective treatment of ischemic brain injury. The efficacy of CDP-choline in stroke therapy might still be achieved. Rationale: Phospholipid degradation is a significant promoter of neuronal death after transient cerebral ischemia. CDP-choline neuroprotection is thought to be due to increased phosphatidyl-choline (PtdCho) synthesis in the injured brain, although the evidence is limited. We showed in gerbil transient forebrain ischemia that CDP-choline: (a) provided significant neuroprotection (b) significantly restored PtdCho, cardioliPin and sphingomyelin, (c) attenuated arachidonic acid release and metabolism, and (d) increased glutathione levels. Our preliminary results show that CDP-choline affects activation of membrane and mitochondrial phospholipase A2 (PLA2) that is raM-Ca 2+ dependent (characteristic of secretory PLA2; sPLA2), supporting the hypothesis and Aim 1. In vitro, CDP-choline and its components (cytidine and choline) did not inhibit PLA2 activity, and thus as such CDP-choline is not a """"""""direct PLA2 inhibitor"""""""". Instead CDP-choline in vivo likely affects PLA2 activation. Hypothesis: CDP-choline attenuates phospholipid hydrolysis by preventing activation of PLA2. To test this hypothesis in transient cerebral ischemia, we propose the following specific aims:
Aim 1 : Determine whether CDP-choline inhibits PLA2 activation and protein expression. Since this aim is central to our hypothesis, it will be tested both in gerbil transient forebrain ischemia and transient focal cerebral ischemia of spontaneously hypertensive rat.
Aim 2 : Determine whether CDP-choline alters cytidine triphosphate phosphocholine cytidylyltransferase (PCCT) and sphingomyelinase activities mediated through PLA2. PCCT makes endogenous CDP-choline and is the rate-limiting enzyme in PtdCho synthesis. Exogenous CDP-choline is hydrolyzed, absorbed as cytidine and choline, and has to be re-synthesized by PCCT. PtdCho hydrolysis by PLA2 results in lyso-PtdCho and arachidonic acid. Lyso-PtdCho inhibits PCCT activity resulting in impaired PtdCho synthesis. Arachidonic acid activates neutral sphingomyelinase, resulting in membrane disintegration. PCCT activity was stimulated by exogenous CDP-choline.
Aim 2 will be tested in gerbil transient forebrain ischemia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Brain Disorders and Clinical Neuroscience 5 (BDCN)
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Golanov, Eugene V
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University of Wisconsin Madison
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Adibhatla, Rao Muralikrishna; Hatcher, J F (2008) Altered lipid metabolism in brain injury and disorders. Subcell Biochem 49:241-68
Adibhatla, Rao Muralikrishna; Dempsy, Robert; Hatcher, James Franklin (2008) Integration of cytokine biology and lipid metabolism in stroke. Front Biosci 13:1250-70
Adibhatla, Rao Muralikrishna; Hatcher, James F (2008) Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies. CNS Neurol Disord Drug Targets 7:243-53
Adibhatla, Rao Muralikrishna; Hatcher, J F (2008) Phospholipase A(2), reactive oxygen species, and lipid peroxidation in CNS pathologies. BMB Rep 41:560-7
Adibhatla, Rao Muralikrishna; Hatcher, J F (2007) Role of Lipids in Brain Injury and Diseases. Future Lipidol 2:403-422
Larsen, E C; Hatcher, J F; Adibhatla, R M (2007) Effect of tricyclodecan-9-yl potassium xanthate (D609) on phospholipid metabolism and cell death during oxygen-glucose deprivation in PC12 cells. Neuroscience 146:946-61
Adibhatla, Rao Muralikrishna; Hatcher, J F (2007) Secretory phospholipase A2 IIA is up-regulated by TNF-alpha and IL-1alpha/beta after transient focal cerebral ischemia in rat. Brain Res 1134:199-205
Muralikrishna Adibhatla, Rao; Hatcher, J F (2006) Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic Biol Med 40:376-87
Adibhatla, Rao Muralikrishna; Hatcher, James F; Larsen, Eric C et al. (2006) CDP-choline significantly restores phosphatidylcholine levels by differentially affecting phospholipase A2 and CTP: phosphocholine cytidylyltransferase after stroke. J Biol Chem 281:6718-25
Adibhatla, Rao Muralikrishna; Hatcher, J F; Dempsey, R J (2006) Lipids and lipidomics in brain injury and diseases. AAPS J 8:E314-21

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