choline that is not used as a substrate by gut bacteria and does not result in fishy body odor (Zeisel et al., 1983). Most studies reviewed in this chapter used an intermediary in the synthesis of phosphatidylcholine, CDP-choline. CDP-choline is composed of cytidine and choline and is hydrolyzed in the small intestine before absorption as citidine and choline. After absorption, citidine and choline are rephosphorylated and then CDP-choline is resynthesized again. CDP-choline also serves as a donor of choline in the synthesis of acetylcholine. This chapter includes evidence for the potential use of CDP-choline in TBI.

CHOLINE AND THE BRAIN

Choline has a critical role in neurotransmitter function because of its impact on acetylcholine and dopaminergic function. Studies in animals suggest that CDP-choline supplements increase dopamine receptor densities and can ameliorate memory impairment. In Parkinson’s disease, for example, CDP-choline may increase the availability of dopamine. A Cochrane review of randomized trials testing the efficacy of CDP-choline in the treatment of cognitive, emotional, and behavioral deficits associated with chronic cerebral disorders in the elderly revealed no evidence of a beneficial effect on attention, but some evidence of benefit on memory function and behavior (Fioravanti and Yanagi, 2005). The brains of those with Alzheimer’s disease have decreased phosphatidylcholine and phosphatidylethanolamine, and it has been suggested that CDP-choline may provide benefit by repairing cell membrane damage and enhancing acetylcholine synthesis. Both sphingomyelin and phosphatidylcholine, major constituents of brain membranes, are synthesized from the precursor choline (Zeisel, 2005). The role of choline in regulating the synthesis of phospholipids (e.g., phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and sphingomyelin) as constituents of cell membranes is reviewed in Saver (2008). This review also includes a discussion of the evidence showing that choline promotes rapid repair of injured cell surfaces and mitochondrial membranes as well as maintenance of cell integrity and bioenergetic capacity. Increases in biomarkers representative of CDP-choline activity, such as phosphodiesters, were observed on proton magnetic resonance spectroscopy and were associated with improvements in verbal memory in humans (Babb et al., 2002; Fioravanti and Yanagi, 2005).

It is hypothesized that CDP-choline may exert neuroprotective effects in an injured brain through its ability to improve phosphatidylcholine synthesis (Adibhatla and Hatcher, 2002). In addition to its neuroprotective capability, CDP-choline potentiates neurorecovery, which has led to its evaluation as treatment for both stroke and TBI in animal models and in human clinical trials (Cohadon et al., 1982; Levin, 1991; Warach et al., 2000). The positive effects seen in models of ischemia and hypoxia may be explained by increased Bcl-2 expression, decreased apoptosis, and reduced expression of pro-caspase. Inhibiting caspase activity may decrease apoptotic activity and calcium-mediated cell death. Supporting these ideas, in vitro studies have also revealed that choline deficiency induces apoptosis in the liver by mechanisms independent of protein 53, which likely involve abnormal mitochondrial membrane phosphatidylcholine, leakage of oxygen radicals, and activation of caspases (Albright and Zeisel, 1997; Albright et al., 1996, 1998, 1999a, 199b, 2003; Chen et al., 2010). In humans, a choline-deficient diet also causes DNA damage and apoptosis (da Costa et al., 2006).

In addition, CDP-choline is hypothesized to attenuate the loss of phospholipid and increase in fatty acids after global and focal cerebral ischemia by preventing activation of phospholipase A2. CDP-choline may also act to protect against oxidative stress since it has



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