CDP-choline: neuroprotection in transient forebrain ischemia of gerbils.
CDP-choline is a rate-limiting intermediate in the biosynthesis of phosphatidylcholine (PtdCho), an important component of the neural cell membrane. The 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 acids (FFA), especially arachidonic acid (AA), after ischemia/reperfusion. Phase III clinical trials of CDP-choline in the treatment of stroke are currently underway. Here we report the neuroprotection by CDP-choline in transient forebrain ischemia of gerbils. CDP-choline significantly attenuated the blood-brain barrier (BBB) dysfunction after ischemia with 6-hr reperfusion, and considerably reduced the increase of AA in FFA and leukotriene C(4) (LTC(4)) synthesis at 1 day. Edema was significantly elevated after 1 and 2 days, but attained maximum at 3-day reperfusion. CDP-choline substantially attenuated edema at 3 days. Ischemia resulted in 80 +/- 8% CA(1) hippocampal neuronal death after 6-day reperfusion, and CDP-choline provided 65 +/- 6% neuroprotection. CDP-choline may act by increasing PtdCho synthesis via two pathways: (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 toxicity due to AA, leukotrienes, oxygen radicals, lipid peroxidation, and altered glutamate uptake, thus limiting BBB dysfunction, edema and providing neuroprotection.
Rao
A M
AM
Department of Neurological Surgery, University of Wisconsin, Madison, USA.
Hatcher
J F
JF
Dempsey
R J
RJ
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000502:physiology; D003566:Cytidine Diphosphate Choline / Q000494:pharmacology*; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000503:physiopathology; D017997:Leukotriene C4 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010713:Phosphatidylcholines / Q000378:metabolism; D016548:Prosencephalon / Q000503:physiopathology*
D018696:Neuroprotective Agents; D010713:Phosphatidylcholines; D016718:Arachidonic Acid; D017997:Leukotriene C4; D003566:Cytidine Diphosphate Choline