ASTROCYTES AS THE SITE FOR BIOACTIVATION OF NEUROTOXINS

Evidence obtained from studies on the mechanisms of action of dopamine rgic neurotoxins suggests that glial cells may play an important role in neurodegenerative processes. A possible link between the function o f glial cells and nerve cell damage could relate to the ability of ast rocytes to convert innocuous compounds into toxic metabolites. Indeed, a mechanism of metabolic activation has been demonstrated in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of dopaminergic toxicity. The fully oxidized pyridinium metabolite (MPP+) is the ultim ate mediator of MPTP neurotoxicity and is apparently able to damage ne uronal cells after being formed within and released from astrocytes. D opaminergic neurons are particularly vulnerable to MPTP toxicity proba bly because of their ability to accumulate MPP+ and to retain it for a prolonged period of time. Two pathways of MPP+ formation have been id entified in astrocytes, one dependent upon the activity of monoamine o xidase (MAO) and the other related to the presence of transition metal s. Tetrahydroisoquinolines (TIQs) are neurotoxins similar to MPTP in c hemical structure as well as in their requirement for metabolic activa tion. Original data presented in this study do not support, however, a role of astrocytic MAO in the conversion of N-methyl-1,2,3,4-TIQ to t he corresponding quinolinium metabolite. (C) 1996 Inter Press, Inc.