Glutamate-glutamine cycling in the epileptic human hippocampus.

Abstract

PURPOSE:

Several findings suggest that energy metabolism and the glutamate-glutamine cycle may be impaired in epilepsy. Positron emission tomography often shows interictal hypometabolism of the epileptogenic hippocampus. In vivo microdialysis studies show that seizure-associated glutamate release is doubled, and clearance is slowed. We hypothesized that the glutamate-glutamine cycle between neurons and glia may be decreased in the epileptic human hippocampus.

METHODS:

A 20% solution of 2-13C-glucose was infused before resection of the epileptogenic hippocampus. Blood glucose isotopic fractions were measured every 30 min. Blood and brain specimens were frozen quickly; perchloric acid extracts of the small metabolites were prepared and analyzed by proton and carbon magnetic resonance spectroscopy (MRS) at 11.75 Tesla.

RESULTS:

Standard histology showed 12 with hippocampal sclerosis and five with minimal neuron loss. The relative rates of glutamate-glutamine cycling with respect to glutamate synthesis were decreased in biopsies affected by hippocampal sclerosis (mean, 0.08; 95% confidence interval, 0.04-0.12) compared with those with minimal neuron loss (0.52; 95% CI, 0.30-0.75). Mean cellular glutamate concentrations were higher in minimal neuron loss (8.9 mM; 95% CI, 7.4-10.4) than hippocampal sclerosis (7.3 mM; 95% CI, 5.9-8.7). Cellular glutamine concentrations (mean, 2.8 mM; 95% CI, 2.4-3.2; n = 17) were the same in all groups.

CONCLUSIONS:

The epileptogenic, gliotic human hippocampus appears to be characterized metabolically by slow rates of glutamate-glutamine cycling, decreased glutamine content, and a relative increase in glutamate content. We hypothesize that the low rate of glutamate-glutamine cycling that results from a failure of glial glutamate detoxification could account for slow glutamate clearance from synapses and continuing low-grade excitotoxicity.

• Authors: Ognen A C Petroff, Laura D Errante, Douglas L Rothman, Jung H Kim, Dennis D Spencer
• Journal: Epilepsia (Epilepsia) Vol. 43 Issue 7 Pg. 703-10 (Jul 2002) ISSN: 0013-9580 [Print] United States
• PMID: 12102672 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carbon Isotopes
• Glutamine
• Glutamic Acid

Topics

• Adolescent
• Adult
• Carbon Isotopes
• Citric Acid Cycle (physiology)
• Energy Metabolism (physiology)
• Epilepsy (metabolism)
• Female
• Glutamic Acid (metabolism)
• Glutamine (metabolism)
• Hippocampus (cytology, metabolism, physiology)
• Humans
• Magnetic Resonance Spectroscopy (methods, statistics & numerical data)
• Male
• Middle Aged
• Neurons (metabolism)