Toxicological Sciences, Vol 51, 161-177, Copyright © 1999 by Society of Toxicology
TJ Monks, JF Ghersi-Egea, M Philbert, AJ Cooper and EA Lock
Although the cytoprotective effects of glutathione (GSH) are well
established, additional roles for GSH in brain function are being
identified that provide a pharmacological basis for the relationship
between alterations in GSH homeostasis and the development of certain
neurodegenerative processes. Thus, GSH and glutathione disulfide (GSSG)
appear to play important functional roles in the central nervous system
(CNS). A symposium, focussing on the emerging science of the roles of GSH
in the brain, was held at the 37th annual meeting of the Society of
Toxicology, with the emphasis on the role of glutathione in neuroprotection
and neurotoxicity. Jean Francois Ghersi-Egea opened the symposium by
describing the advances in our understanding of the role of the blood-brain
and blood-cerebral spinal fluid (CSF) barriers in either limiting or
facilitating the access of xenobiotics into the brain. Once within the
brain, a multitude of factors will determine whether a chemical causes
toxicity and at which sites such toxicity will occur. In this respect, it
is becoming increasingly clear that GSH and its various conjugation enzymes
are not evenly distributed throughout the brain. Martin Philbert discussed
how this regional heterogeneity might provide a potential basis for the
theory of differential sensitivity to neurotoxicants, in various regions of
the brain. For certain chemicals, GSH provides neuroprotection, and Edward
Lock discussed the selective toxicity of 2-chloropropionic acid (CPA) to
the cerebellum and how its modification by modulating brain thiol status
provides an example of GSH acting in neuroprotection. The sensitivity of
the cerebellum to CPA may also be linked to the ability of this compound to
activate a sub-type of the NMDA receptor. Thus, GSH and cysteine alone, or
perhaps as conjugates with xenobiotics, may play a role in excitotoxicity
via NMDA receptor activation. In contrast, certain chemicals may be
converted to neurotoxicants following conjugation with GSH, and Arthur
Cooper described how the pyridoxal 5'- phosphate-dependent, cysteine
conjugate beta-lyases might predispose the brain to chemical injury in a
GSH-dependent manner. The theme of GSH as a potential mediator of
chemical-induced neurotoxicity was extended by Terrence Monks, who
presented evidence for a role for GSH conjugation in (+/-)-3,4-
methylenedioxyamphetamine-mediated serotonergic neurotoxicity.
ARTICLES
Symposium overview: the role of glutathione in neuroprotection and neurotoxicity
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin 78712-1074, USA. scouser@mail.utexas.edu
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