Effects of Citicoline on Phospholipid and Glutathione Levels in Transient Cerebral Ischemia

Abstract

Background and Purpose-Cytidine-5Ј-diphosphocholine (citicoline or CDP-choline) is an essential intermediate in the biosynthesis of phosphatidylcholine, an important component of the neural cell membrane. Citicoline provided significant neuroprotection after transient forebrain ischemia in gerbils. This study was undertaken to examine changes and effects of citicoline on phospholipids and glutathione synthesis after transient cerebral ischemia and reperfusion. Methods-Ten-minute transient forebrain ischemia was induced by bilateral carotid artery occlusion in male Mongolian gerbils with reperfusion up to 6 days. Citicoline (500 mg/kg IP in saline) was given to gerbils just after the end of ischemia, at 3-hour reperfusion, and daily thereafter until 1 day before euthanasia. Hippocampal lipids were extracted and analyzed by thin-layer and gas chromatography. Glutathione was measured by using an enzymatic recycling assay. Glutathione reductase activity was determined by measuring NADPH oxidation. Results-Significant decreases in phospholipids occurred at 1-day reperfusion. Citicoline significantly restored the phosphatidylcholine, sphingomyelin, and cardiolipin levels but did not affect phosphatidylinositol and phosphatidylserine at 1 day. The phospholipids returned to sham levels over days 2 to 6 and were unaffected by citicoline. Ceramide levels significantly increased by 3 and 6 days of reperfusion and were unaltered by citicoline. Ischemia resulted in significant decreases in glutathione and glutathione reductase activity over 3 days of reperfusion. Citicoline significantly increased total glutathione and glutathione reductase activity and decreased the glutathione oxidation ratio, an indicator of glutathione redox status. Conclusions-Our data indicated that the effects of citicoline on phospholipids occurred primarily during the first day of reperfusion, with effects on glutathione being important over the 3-day reperfusion period.

Multifunctional Actions of Approved and Candidate Stroke Drugs

“…127 Similar mechanisms were suggested for the preserving effects of citicoline on sphingomyelin and cardiolipin. 128 Excessive neuronal stimulation with acetylcholine release after cerebral ischemia leads to choline depletion, which in turn induces apoptosis. 129 Citicoline provides choline for the synthesis of acetylcholine and may thereby prevent apoptotic cell death in cholinergic neurons.…”

Lipids and lipidomics in brain injury and diseases

“…Altered lipid metabolism is believed to contribute to cerebral ischemic injury. [21][22][23][24][25][26][27][28][29][30][31][32] Lipidomics holds the promise of characterizing complex mixtures of lipids, identifying previously unknown changes in lipid metabolism, and opening new opportunities for drug development. 33 …”

Loss of miR-29b following Acute Ischemic Stroke Contributes to Neural Cell Death and Infarct Size

“…3 Acute ischemic stroke is known to be associated with glutathione depletion and metabolism of membrane-bound arachidonic acid. [4][5][6] Under these conditions, 12-lipoxygenase has been recognized as a key pathway of arachidonic acid metabolism, which has been directly implicated in middle-cerebral artery occlusion (MCAO)-induced injury of the brain. 7,8 In this work, we report the loss of miR-29b at the infarct site after stroke by a 12-lipoxygenase-dependent mechanism.…”