http://www3.interscience.wiley.com/cgi-bin/abstract/81502486/START
Annals of Neurology
Volume 50, Issue 2, 2001. Pages:
169-180
Peter Werner, PhD 1 2 4 *, David
Pitt, MD 2, Cedric S. Raine, PhD 1 2 3
1Department of Neurology, Albert
Einstein College of Medicine, Bronx, NY
2Department of Pathology, Albert
Einstein College of Medicine, Bronx, NY
3Department of Neuroscience, Albert
Einstein College of Medicine, Bronx, NY
4Department of Neurology, Beth Israel
Medical Center, New York, NY
email: Peter Werner (pwerner@aecom.yu.edu)
*Correspondence to Peter Werner,
Depts. of Neurology and Pathology (Neuropathology), Albert Einstein College
of Medicine, 1300 Morris Park Ave., F-121N Bronx, NY 10461
Abstract
Glutamate excitotoxicity, recently
demonstrated in an animal model of multiple sclerosis (MS), is evoked by
altered glutamate homeostasis.
In the present study, we investigated
the major regulating factors in glutamate excitotoxicity by immunohistochemistry
in MS and control white matter with markers for glutamate production (glutaminase),
glutamate transport (GLAST, GLT-1 and EAAT-1), glutamate metabolism (glutamate
dehydrogenase [GDH] and glutamine synthetase [GS]), axonal damage (SMI
32) and CNS cell types.
Active MS lesions showed high-level
glutaminase expression in macrophages and microglia in close proximity
to dystrophic axons.
Correlation between glutaminase expression
and axonal damage was confirmed experimentally in animals.
White matter from other inflammatory
neurologic diseases displayed glutaminase reactivity, whereas normals and
noninflammatory conditions showed none.
All three glutamate transporters
were expressed robustly, mainly on oligodendrocytes, in normal, control
and MS white matter, except for GLT-1, which showed low-level expression
around active MS lesions.
GS and GDH were present in oligodendrocytes
in normal and non-MS white matter but were absent from both active and
chronic silent MS lesions, suggesting lasting metabolic impediments.
Thus, imbalanced glutamate homeostasis
contributes to axonal and oligodendroglial pathology in MS.
Manipulation of this imbalance may
have therapeutic import.
Received: 1 December 2000; Revised:
18 January 2001; Accepted: 14 March 2001