Toxicokinetics and toxicodynamics of paraquat accumulation in mouse brain

Abstract

Paraquat (PQ) is a potential human neurotoxicant and is used in models of oxidative stress. We determined the toxicokinetics (TK) and toxicodynamics (TD) of PQ in adult mouse brain following repeated or prolonged PQ exposure. PQ accumulated in different brain regions and reached a plateau after ~18 i.p. (10 mg/kg) doses and resulted in modest morbidity and mortality unpredictably associated with dose interval and number. PQ had divergent effects on horizontal locomotor behavior depending on the number of doses. PQ decreased striatal dopamine levels after the 18th to 36th i.p. dose (10 mg/kg) and reduced the striatal level of tyrosine hydroxylase. Drinking water exposure to PQ (0.03– 0.05 mg/ml) did not result in any mortality and resulted in concentration and time dependent levels in the brain. The brain half-life of PQ varied with mouse strain. PQ accumulates and may saturate a site in mouse brain resulting in complex PQ level and duration-related consequences. These findings should alter our risk assessment of this compound and demonstrate a useful, but complex dynamic model for understanding the consequences of PQ in the brain.

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.…”

“…PQ and other neurotoxicants have been used as chemical models of Parkinson's disease. We used a paradigm of PQ injections (see Methods) that generates a mild OS and slow PQ accumulation in the brain (Prasad et al, 2009), but not systemically (Prasad et al, 2007). With this low-dose chronic PQ exposure, ApoD mRNA levels in the WT 1554 BAJO-GRAÑERAS ET AL.…”

“…We chose a PQ treatment that avoids systemic toxicity and maximizes the OS effects on sensitive brain regions (Prasad et al, 2009). The evident bradikynesia of ApoD-KO mice, even under a mild PQ paradigm, reflects an indispensable role of ApoD for establishing a proper antioxidant defense in the brain.…”

Neuroprotective Effect of Decalepis hamiltonii in Paraquat-Induced Neurotoxicity in Drosophila melanogaster: Biochemical and Behavioral Evidences

“…Paraquat (PQ) (1,1-dimethyl-4-4-bipyridynium dichloride) (PQ), is widely used as herbicide. In vivo studies employing Drosophila melanogaster [5], Rattus norvegicus [6] and Mus musculus [7] have revealed that PQ is neurotoxic which affects dopaminergic neurons. The toxicity of PQ is a consequence of generation of ROS mainly hydrogen peroxide and hydroxyl radical [8].…”

Investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson's disease and childhood leukaemia†

“…It is conceivable that compensatory/ buffer downstream processes provoked by soma loss, variations in experimental design (e.g. route of administration, dosing regimen, sacrifice interval, striatal subregions tested, age of mice) can possibly contribute to some of the inconsistency observed across studies (Rojo et al, 2007;Prasad et al, 2009;Kang et al, 2010;Rappold et al, 2010). …”