-- (Medical News Today: Possible new
treatment target for epilepsy. Article Date: 03 Jul 2005 - 15:00pm
(UK):
"CURRENT LITERATURE IN BASIC SCIENCE
EXCITABLE BUT LACKING IN ENERGY: CONTRADICTIONS IN THE HUMAN EPILEPTIC
HIPPOCAMPUS
"Extracellular Metabolites in the Cortex and Hippocampus of Epileptic
Patients
Cavus I, Kasoff WS, Cassaday MP, Jacob R, Gueorguieva R, Sherwin RS,
Krystal JH, Spencer DD, Abi-Saab WM
Ann Neurol 2005 Feb;57(2):226–235
"Interictal brain energy metabolism and glutamate– glutamine cycling
are impaired in epilepsy and may contribute to seizure generation. We
used the zero-flow mi-
crodialysis method to measure the extracellular levels of
glutamate, glutamine, and the major energy substrates glucose and
lactate in the epileptogenic and the nonepilep-togenic cortex and
hippocampus of 38 awake epileptic patients during the interictal
period. Depth electrodes attached to microdialysis probes were used to
identify the epileptogenic and the nonepileptogenic sites. The
epileptogenic hippocampus had surprisingly high basal glutamate levels,
low glutamine/glutamate ratio, high lactate levels, and indication for
poor glucose utilization.
"The epileptogenic cortex had only marginally increased glutamate
levels. We propose that interictal energy deficiency in the
epileptogenic hippocampus could contribute to impaired glutamate
reuptake and glutamate-glutamine cycling, resulting in persistently
increased extracellular glutamate, glial and neuronal toxicity,
increased lactate production together with poor lactate and glucose
utilization, and ultimately worsening energy metabolism. Our data
suggest that a different neurometabolic process underlies the
neocortical epilepsies.
COMMENTARY
"Glutamate is the principal excitatory neurotransmitter in mammalian
brain and has long been implicated in the generation of epileptic
discharges. Administration of glutamate or glutamate analogues to
experimental animals can elicit seizures, whereas glutamate antagonists
are both anticonvulsant and neuroprotective (1). Glutamate receptor
sub-units are upregulated in hippocampal tissue resected from patients
with chronic temporal lobe epilepsies; electrophysiological recordings
from human epileptic hippocampal slice preparations demonstrate a
glutamate-dependent hyperexcitability; and in vivo microdialysis
studies show an elevation in extracellular glutamate during seizures
(2). These observations point to glutamate as potentially crucial in
the generation and maintenance of seizures in localization-related
epilepsies.
"Glutamate is synthesized from glutamine in glutamatergic neurons via
the action of the enzyme glutaminase and, following synaptic release,
is removed into both nerve terminals and glial cells by selective
energy-dependent transporters. Glial cells subsequently reconvert
glutamate into glutamine, via the enzyme glutamine synthetase, and
glutamine is finally transferred to glutamatergic neurons, completing
the so-called glutamate–glutamine cycle (3). Glutamate homeostasis is
critical to the
normal functioning of the nervous system, and in this regard, glial
glutamate uptake is believed to be of principal importance (4).
Glutamate is not only a neurotransmitter but also an excitotoxic agent
that, in high concentrations, has the potential to cause cell death. As
a result, it is maintained at low levels in the "extracellular
fluid of the brain by efficient, but energetically expensive uptake
into glial cells.
"The evidence to support glutamatergic dysfunction in temporal lobe
epilepsies is compelling and yet, until recently, has been largely
circumstantial. Although seizures are almost certainly associated with
increased extracellular glutamate concentrations, with the potential
for localized glial and neuronal damage, the source of elevated
glutamate and the distinction between cause and effect have proved
elusive. Much of the understanding to date has come from animal models,
which may not adequately mirror the human situation, or from the ex
vivo analysis of surgical and postmortem tissue, which is subject to a
multitude of confounding factors. However, recent advances in brain
imaging and the ongoing development of intracerebral microdialysis for
human use, pioneered by During and Spencer in the 1990s (5), have
significantly improved the ability to perform real-time investigations
of brain neurochemistry in disease states.
"A recent study by Cavus and colleagues employed intracerebral
microdialysis to investigate extracellular concentrations of glutamate,
glutamine, and the major energy substrates, glucose and lactate, in
epileptogenic and nonepileptogenic regions of the hippocampus and
cortex in conscious epilepsy patients during the interictal period. The
investigators reported elevated glutamate levels in the epileptogenic
hippocampus, together with a low glutamine/glutamate ratio, increased
lactate, and evidence of reduced glucose utilization. Interestingly,
these phenomena did not extend to epileptogenic regions of the cortex.
This is the first study to report concentrations of multiple
seizure-related neurometabolites in conscious epilepsy patients and
serves to confirm many previously held suspicions. The authors hypoth-
esized that an unspecified energy deprivation, possibly related to
mitochondrial injury, could be responsible for the neurochemical
profile observed. Energy deficiency could, in theory, lead to
functional impairment of both glutamate transporters and glutamine
synthetase, which could in turn result in poor glutamate clearance from
the synapse and an increase in the nonvesicular release of glutamate
from the glial compartment,
leadingtoneurotoxicityandpoorutilizationofavailableglucose and lactate.
"This hypothesis is supported by previous observations of
hypometabolism in the epileptic focus (6) and reduced activity of
glutamine synthetase in surgically excised epileptic tissue (7).
However, several questions remain to be answered. Because glutamate is
causal to the generation of seizures and is chronically elevated in the
epileptogenic hippocampus, one would expect seizures and neurotoxicity
to propagate uninterrupted—unless some type of protective mechanism is
equally upregulated. Similarly, the suggestion that energy deprivation
leads to glutamatergic dysfunction, and thereby impaired glucose
utilization, would appear to be a circular argument and difficult to
reconcile in the absence of evidence to support ever-worsening energy
metabolism and the catastrophic failure of local neuronal function. The
10-fold variation in basal glutamate concentrations in the
epileptogenic hippocampus, from low normal values to neurotoxic levels,
would suggest considerable heterogeneity in the study population,
sufficient to question the experimental design and statistical power of
the investigation. Finally, the
potentially confounding influence of antiepileptic drug treatment
cannot be taken lightly. Although the authors did not observe any
specific drug-related effects, possibly as a result of the low number
of patients analyzed and the use of combination therapy, subanalyses
based on principal drug mechanisms or comparison with untreated
individuals may have been more revealing.
"Intracerebral microdialysis may offer significan tadvantages over
previous investigational approaches by providing a direct measure of
brain metabolite concentrations in living subjects, without the
confounding influence of general anesthesia or the inherent limitations
of ex vivo tissue analysis. The differences in hippocampal and cortical
neurochemistry reported in this study are intriguing and not only merit
further investigation but also may, in time, encourage consideration of
focal epilepsies in terms of their distinctive neurobiology rather than
just their anatomical localization. If nothing else, the use of
microdialysis in conscious epilepsy patients should begin to offer
unprecedented insights into the neurochemistry of the epileptic focus."
by Graeme J. Sills, PhD
Epilepsy Currents, Vol. 6, No. 1 (January/February) 2006 pp. 6–7
Blackwell Publishing, Inc.
c American Epilepsy Society
References
1. Chapman AG. Glutamate receptors in epilepsy.
Prog Brain Res 1998;116:371–383.
2. Scheyer RD. Involvement of glutamate in human epileptic activities.
Prog Brain Res 1998;116:359–369.
3. Petroff OAC, Errante LD, Rothman DL, Kim JH, Spencer DD.
Glutamate-glutaminecyclingintheepileptichumanhippocampus.
Epilepsia 2002;43:703–710.
4. Anderson CM, Swanson RA. Astrocyte glutamate transport: review of
properties, regulation and physiological function.
Glia 2000;32:1–14.
5. During MJ, Spencer DD. Extracellular hippocampal glutamate and
spontaneous seizure in the conscious human brain.
Lancet 1993;341:1607–1610.
6. Lamusuo S, Jutila L, Ylinen A, Kalviainen R, Mervaala E, Haaparanta
M, Jaaskelainen S, Partanen K, Vapalahti M, Rinne J. [
18
F]FDG-PET reveals temporal hypometabolism in patients with temporal
lobe epilepsy even when quantitative MRI and histopathological analysis
show only mild hippocampal damage.
Arch
Neurol 2001;58:933–939.
7. Eid T, Thomas MJ, Spencer DD, Runden-Pran E, Lai JCK, Malthankar GV,
Kim JH, Danbolt NC, Ottersen OP, de Lanerolle NC. Loss of glutamine
synthetase in the human epileptogenic hippocampus: Possible mechanism
for raised extracellular glutamate in mesial temporal lobe epilepsy.
Lancet 2004;363:28–37.