Paraquat: A useful tool for the in vivo study of mechanisms of neuronal cell death

The present article reviews the results of experimental studies on paraquat neurotoxicity, started by our group several years ago - when clinical and experimental reports had increased the interest for the possibility that environmental chemicals, including paraquat, may be related to the development of Parkinson's disease -, and which are still continuing since paraquat appears to be a promising tool to study the mechanisms of neuronal cell death in vivo. Our observations have demonstrated that paraquat causes evident neurotoxic effects after intracerebroventricular or intracerebral injection in experimental animals; however, it seems that the herbicide does not exibit a selective neurotoxicity towards the dopaminergic nigro-striatal system since potent behavioural and electrocortical changes are induced by paraquat after injection in brain areas other than the substantia nigra and caudate nucleus. By studying the mechanisms through which paraquat induces neurotoxic effects in vivo, it was shown that either free radical production and activation of cholinergic and glutamatergic transmission may be regarded as related events which play a crucial role in paraquat-induced neurotoxicity. In addition, it was observed that in rats paraquat penetrates the blood-brain barrier following systemic administration to give rise to a differential brain regional distribution; the latter observation rises some concern over the hazard of paraquat as a potential environmental neurotoxin. Indeed, paraquat, administered systemically in rats produces behavioural excitation and brain damage. The brain damage appears to be selective for the pyriform cortex and this does not seem to be strictly related to the high concentrations reached by the herbicide in this area but to the higher vulnerability of this cortical area to the enhanced cholinergic transmission. The recent observation that paraquat, injected into the rat hippocampus, induces the expression of apoptotic neuronal cell death, appears of valuable interest also with a view to paraquat as an useful experimental model in the development of neuroprotective drugs able to block the molecular events which, once activated, are responsible for the induction of neuronal cell death.