Prolonged Toxicokinetics and Toxicodynamics of Paraquat in Mouse Brain

Abstract

BackgroundParaquat (PQ) has been implicated as a risk factor for the Parkinson disease phenotype (PDP) in humans and mice using epidemiologic or experimental approaches. The toxicokinetics (TK) and toxicodynamics (TD) of PQ in the brain are not well understood.ObjectivesThe TK and TD of PQ in brain were measured after single or repeated doses.MethodsBrain regions were analyzed for PQ levels, amount of lipid peroxidation, and functional activity of the 20S proteasome.ResultsParaquat (10 mg/kg, ip) was found to be persistent in mouse ventral midbrain (VM) with an apparent half-life of approximately 28 days and was cumulative with a linear pattern between one and five doses. PQ was also absorbed orally with a concentration in brain rising linearly after single doses between 10 and 50 mg/kg. The level of tissue lipid peroxides (LPO) was differentially elevated in three regions, being highest in VM, lower in striatum (STR), and least in frontal cortex (FCtx), with the earliest significant elevation detected at 1 day. An elevated level of LPO was still present in VM after 28 days. Despite the cumulative tissue levels of PQ after one, three, and five doses, the level of LPO was not further increased. The activity of the 20S proteasome in the striatum was altered after a single dose and reduced after five doses.ConclusionsThese data have implications for PQ as a risk factor in humans and in rodent models of the PDP.

Absence of P-Glycoprotein Transport in the Pharmacokinetics and Toxicity of the Herbicide Paraquat

“…Although this is the first study to evaluate the role of P-gp in paraquat pharmacokinetics, there have been other studies to measure paraquat pharmacokinetics in chronic studies (Prasad et al, 2007(Prasad et al, , 2009Breckenridge et al, 2013). The paraquat plasma concentrations we observed following an oral dose in FVB mice were approximately a magnitude less than what has been observed following an intraperitoneal dose to C57BlJ/6 mice; correspondingly, the paraquat brain concentrations we observed were also lower (Prasad et al, 2007(Prasad et al, , 2009Breckenridge et al, 2013).…”

“…The paraquat plasma concentrations we observed following an oral dose in FVB mice were approximately a magnitude less than what has been observed following an intraperitoneal dose to C57BlJ/6 mice; correspondingly, the paraquat brain concentrations we observed were also lower (Prasad et al, 2007(Prasad et al, , 2009Breckenridge et al, 2013). Paraquat has highly variable bioavailability depending upon the route of administration, with the majority of an oral dose found in the feces, which may explain some of the differences in observed plasma concentrations in the different mouse strains (Daniel and Gage, 1966;Chui et al, 1988).…”

Parkinson's disease and pesticides: a toxicological perspective

“…In addition paraquat showed little penetration into the brain structures of rats with an intact blood-brain barrier [28,29]. More recent studies, however, have reported the ability of paraquat to cross the blood-brain barrier, possibly via the neutral amino acid transporter [30], and to accumulate in certain brain regions of the mouse [31].…”

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

“…PQ treatment elicits a selective and dose-dependent loss of nigral DA neurons with associated modest decreases in striatal dopamine nerve terminal density and mildly decreased motor behavior (9,64). Following sustained systemic intraperitoneal administration, PQ was found to have a very long half-life in the mouse brain (up to 28 days) and was associated with ongoing lipid peroxidation (77). Moreover, in a chronic rat PQ model, minor decreases in DA neurons and slight increases in DA neurotransmission were observed at 4 weeks; by 24 weeks significant DA neuron loss and DA neurotransmitter depletion were observed, indicating a potentially chronic neurodegenerative process induced by PQ treatment (74).…”