The Nigrostriatal Dopaminergic System as a Preferential Target of Repeated Exposures to Combined Paraquat and Maneb: Implications for Parkinson's Disease

Abstract

Experimental evidence supporting 1,1Ј-dimethyl-4,4Ј-bipyridinium [paraquat (PQ)] as a risk factor for Parkinson's disease (PD) is equivocal. Other agricultural chemicals, including dithiocarbamate fungicides such as manganese ethylenebisdithiocarbamate [maneb (MB)], are widely used in the same geographical regions as paraquat and also impact dopamine systems, suggesting that mixtures may be more relevant etiological models. This study therefore proposed that combined PQ and MB exposures would produce greater effects on dopamine (DA) systems than would either compound administered alone. Male C57BL/6 mice were treated twice a week for 6 weeks with intraperitoneal saline, 10 mg/kg paraquat, 30 mg/kg maneb, or their combination (PQ ϩ MB). MB, but not PQ, reduced motor activity immediately after treatment, and this effect was potentiated by combined PQ ϩ MB treatment. As treatments progressed, only the combined PQ ϩ MB group evidenced a failure of motor activity levels to recover within 24 hr. Striatal DA and dihydroxyphenylacetic acid increased 1-3 d and decreased 7 d after injections. Only PQ ϩ MB reduced tyrosine hydroxylase (TH) and DA transporter immunoreactivity and did so in dorsal striatum but not nucleus accumbens. Correspondingly, striatal TH protein levels were decreased only by combined PQ ϩ MB 5 d after injection. Reactive gliosis occurred only in response to combined PQ ϩ MB in dorsal-medial but not ventral striatum. TH immunoreactivity and cell counts were reduced only by PQ ϩ MB and in the substantia nigra but not ventral tegmental area. These synergistic effects of combined PQ ϩ MB, preferentially expressed in the nigrostriatal DA system, suggest that such mixtures could play a role in the etiology of PD.

Apolipoprotein D mediates autocrine protection of astrocytes and controls their reactivity level, contributing to the functional maintenance of paraquat-challenged dopaminergic systems

“…It is known that alterations in DA levels in the striatum of WT animals require 12-18 doses of 10 mg kg 21 PQ (Prasad et al, 2009;Thiruchelvam et al, 2000), or combinations of PQ with MPTP or Maneb (Shepherd et al, 2006;Thiruchelvam et al, 2000). In our study, neither DA nor its metabolites change in the WT cohort after the 7th dose.…”

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

“…In another study, combined intraperitoneal administration of paraquat and maneb in mice, but not either alone, lead to degeneration of nigral dopaminergic neurons, loss of striatal dopamine and reduced motor activity [369]. In vitro, dieldrin (an organochlorine) caused increased α-Synuclein fibril formation [370] and in mice, dieldrin exposure lead to increased α-Synuclein expression and alterations in the dopaminergic system [371].…”

An In Vitro Model of Human Dopaminergic Neurons Derived from Embryonic Stem Cells: MPP+ Toxicity and GDNF Neuroprotection

“…Epidemiological data and twin studies suggest that environmental toxins may be important contributors to PD (Di Monte et al, 2002;Di Monte, 2003;Tanner et al, 1999). The dopaminergic neurons of the brain seem to be especially vulnerable to toxic events, as evidenced by their susceptibility to toxic insults, including rotenone, paraquat, and manganese (Betarbet et al, 2000;Thiruchelvam et al, 2000), lipopolysaccharides (Carvey et al, 2003;Gayle et al, 2002), diesel exhaust particles (Block et al, 2004) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Davis et al, 1979;Langston et al, 1983). Therefore, an in vitro system for studies of neurotoxicity and neuroprotection in normal human dopaminergic neurons may be especially valuable.…”