Formation of Free Choline in Brain Tissue during in vitro Energy Deprivation

Abstract

Summary: Free choline and ATP contents were mea sured in Mongolian gerbil hippocampal slices (tissue) and incubation media (media) during exposure to 30 min of aglycemia, high potassium, anoxia, or ischemia. Changes in choline levels reflected the degree of energy reduction, lower ATP levels being associated with high choline (4-fold increase during exposure to high potassium and an oxia, and II-fold increase during ischemia). Media (ex tracellular) choline was particularly affected and in creased about twofold during relatively mild energy depletion (e.g., aglycemia), but tissue choline content was less sensitive to energy reduction. A plot of choline vs. ATP levels indicated a nonlinear correlation, and the sharp increase in choline occurred when ATP values fell Choline is a precursor not only for acetylcholine, but also for phospholipids (phosphatidylcholine) and sphingomyelin in the brain. Thus, choline is involved in two important aspects of brain function: neurotransmission and the maintenance of cell membrane integrity. Both aspects are affected by a decrease in energy reserves. Synthesis and storage of acetylcholine are glucose and energy dependent (Gibson and Blass, 1976;Yamagata and Parsons, 1989) 308to about 2.5 nmollmg of protein. Inhibition of acetylcho line sterase by \0 fLM physostigmine during ischemia did not prevent an increase in choline contents but rather enhanced them, indicating that acetylcholine hydrolysis was not the source of free choline. Formation of free choline was Ca 2 + independent. These findings suggest the involvement of phospholipase D and phosphatidyl choline hydrolysis in free choline formation during energy stress. The extent of choline formation may be an indi cator of the degree of membranal damage, which in turn reflects damage to the metabolic machinery of the cell.

Region-Specific and Calcium-Dependent Increase in Dialysate Choline Levels by NMDA

“…9) indicates that NMDA evokes a direct release of Cho from the phospholipid pool that is followed by cell death. Consistent with these results is the finding that extracellular Cho levels are increased by treatments that produce glutamate release and subsequent excitotoxic cell death, such as seizures induced by different convulsant treatments (Jope and Gu, 1991), energy deprivation (Djuricic et al, 1991), or hypoxia (K lein et al, 1993).…”

Proton magnetic resonance spectroscopy of late delayed radiation-induced injury of the brain

“…A late primary radiation-induced apoptosis of the glial cells is possible but not supported by the absence of Cho/Cr ratio elevation in milder cases. It may be due to a raised Cho secondary to cell membrane or myelin breakdown due to a critical ischemic episode with cell breakdown (29). Glial cells are relatively resistant to anoxia and ischemia, but oligodendrocytes and related myelin sheaths are more vulnerable to anoxia and ischemia because of their susceptibility to free radical damage, sensitivity to glutamate toxicity, and greater dependence on oxidative phosphorylation (30).…”

Proton magnetic resonance spectroscopy of cerebral lactate and other metabolites in stroke patients.

“…46 A recent in vitro experiment found that choline levels were not decreased by treatment with an acetylcholinesterase inhibitor during ischemia, implying that phospholipid membrane breakdown and not acetylcholine metabolism was responsible for the rise in choline. 48 These studies suggest that increases in trimethylamine signal may arise from cell membrane breakdown. However, as the magnitude of the trimethylamine resonance varied greatly from patient to patient, better understanding of this phenomenon will require more data.…”