Symposium overview: the role of glutathione in neuroprotection and neurotoxicity.

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.