Symposium overview: The role of glutathione in neuroprotection and neurotoxicity

Although the cytoprotective effects of glutathione (GSH) are well establish ed, additional roles for GSH in brain function are being identified that pr ovide a pharmacological basis for the relationship between alterations in G SH homeostasis and the development of certain neurodegenerative processes. Thus, GSH and glutathione disulfide (GSSG) appear to play important functio nal roles in the central nervous system (CNS), A symposium, focussing on th e emerging science of the roles of GSH in the brain, was held at the 37th a nnual meeting of the Society of Toxicology, with the emphasis on the role o f glutathione in neuroprotection and neurotoxicity, Jean Francois Ghersi-Eg ea 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 ch emical causes toxicity and at which sites such toxicity will occur. In this respect, it is becoming increasingly clear that GSH and its various conjug ation enzymes are not evenly distributed throughout the brain. Martin Philb ert discussed how this regional heterogeneity might provide a potential bas is 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 sensitivi ty of the cerebellum to CPA may also be linked to the ability of this compo und to activate a sub-type of the NMDA receptor. Thus, GSH and cysteine alo ne, or perhaps as conjugates with xenobiotics, may play a role in excitotox icity via NMDA receptor activation. In contrast, certain chemicals may be c onverted to neurotoxicants following conjugation with GSH, and Arthur Coope r described how the pyridoxal 5'-phosphate-dependent, cysteine conjugate be ta-lyases might predispose the brain to chemical injury in a GSH-dependent manner. The theme of GSH as a potential mediator of chemical-induced neurot oxicity was extended by Terrence Monks, who presented evidence for a role f or GSH conjugation in (+/-)-3,4-methylenedioxyamphetamine-mediated serotone rgic neurotoxicity.