CDP-choline: Neuroprotection in transient forebrain ischemia of gerbils

CDP-choline is a rate-limiting intermediate in the biosynthesis of phosphat idylcholine (PtdCho), an important component of the neural cell membrane, T he ability of CDP-choline to alter phospholipid metabolism is an important function in the treatment of ischemic injury. Exogenous treatment with CDP- choline stimulates PtdCho synthesis and prevents release of free fatty acid s (FFA), especially arachidonic acid (AA), after ischemia/reperfusion. Phas e III clinical trials of CDP-choline in the treatment of stroke are current ly underway, Here we report the neuroprotection by CDP-choline in transient forebrain ischemia of gerbils, CDP-choline significantly attenuated the bl ood-brain barrier (BBB) dysfunction after ischemia with 6-hr reperfusion, a nd considerably reduced the increase of AA in FFA and leukotriene C-4 (LTC4 ) synthesis at 1 day. Edema was significantly elevated after 1 and 2 days, but attained maximum at 3-day reperfusion, CDP-choline substantially attenu ated edema at 3 days, Ischemia resulted in 80 +/- 8% CA(1) hippocampal neur onal death after 6-day reperfusion, and CDP-choline provided 65 +/- 6% neur oprotection, CDP-choline may act by increasing PtdCho synthesis via two pat hways: (1) conversion of 1,2-diacylglycerol to PtdCho, and (2) biosynthesis of S-adenosyl-L-methionine, thus stabilizing the membrane and reducing AA release and metabolism to leukotriene C-4 This would result in decreased to xicity due to AA, leukotrienes, oxygen radicals, lipid peroxidation, and al tered glutamate uptake, thus limiting BBB dysfunction, edema and providing neuroprotection, (C) 1999 Wiley-Liss, Inc.