Ahstruct; 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.Paraquat ( 1,l '-dimethyl-4,4'-bipyridinium dichloride) is a potent non-selective contact herbicide. It was introduced in agriculture in 1962 and since then widely used in many countries for chemical weed control due to its speed of action, lack of selectivity and of biologically active residues (Sagar 1987). However, since its marketing, hundreds of cases of poisoning have been reported due to accidental or suicidal ingestion of the herbicide (Onyon & Volans 1987), although there are some reports of deaths caused by dermal exposure (see Smith 1988). The herbicide is extremely toxic to the pulmonary system where it is highly concentrated in an energy-dependent manner by an uptake system shared by polyamines, inducing acute alveolitis, widespread fibrosis and fatal hypoxia (Smith &Heath 1974;Smith 19...

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1 The role of the pro-in¯ammatory cytokine interleukin-1b in the mechanism of cell death induced by the human immunode®ciency virus type 1 (HIV-1) recombinant coat glycoprotein, gp120 IIIB, has been studied in the human CHP100 neuroblastoma cell line maintained in culture. 2 Death of neuroblastoma cells typically elicited by 10 pM gp120 or by human recombinant IL-1b (10 ng ml 71 ) has been minimized by the antagonist of IL-1 receptor, i.e. IL-1ra (0.5 and 50 ng ml 71 , respectively), an endogenous molecule that antagonizes most of the biological actions of IL-1b, or by an antibody (5 and 50 ng ml 71 ) which blocks the human IL-1 receptor type I (IL-1RI).3 ELISA experiments have established that gp120 enhances immunoreactive IL-1b levels in the culture medium and this is prevented by exposure to the IL-1 converting enzyme (ICE) inhibitor t-butoxycarbonyl-L-aspartic acid benzyl ester-chloromethylketone [Boc-Asp(OBzl)-CMK] used at a concentration (2.5 mM) which signi®cantly (P50.001) reduces cell death. 4 Death of CHP100 cells induced by gp120 is also prevented by acetyl-Tyr-Val-Ala-Aspchloromethylketone (Ac-YVAD-CMK; 10 ± 100 mM), a second inhibitor of ICE, supporting the concept that the viral protein stimulates the conversion of the 31 kDa pro-IL-1b in to the 17 kDa mature cytokine which is then secreted to cause death. 5 In conclusion, our present data demonstrate that gp120 stimulates the secretion of IL-1b which then triggers CHP100 neuroblastoma cell death via stimulation of IL-1 receptor type I.

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