Astrocytes as the site for bioactivation of neurotoxins

Evidence obtained from studies on the mechanisms of action of dopaminergic neurotoxins suggests that glial cells may play an important role in neurodegenerative processes. A possible link between the function of glial cells and nerve cell damage could relate to the ability of astrocytes 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 ultimate mediator of MPTP neurotoxicity and is apparently able to damage neuronal cells after being formed within and released from astrocytes. Dopaminergic neurons are particularly vulnerable to MPTP toxicity probably because of their ability to accumulate MPP+ and to retain it for a prolonged period of time. Two pathways of MPP+ formation have been identified in astrocytes, one dependent upon the activity of monoamine oxidase (MAO) and the other related to the presence of transition metals. Tetrahydroisoquinolines (TIQs) are neurotoxins similar to MPTP in chemical structure as well as in their requirement for metabolic activation. 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 the corresponding quinolinium metabolite.