Elsevier

Brain Research

Volume 1259, 9 March 2009, Pages 74-79
Brain Research

Research Report
Paraquat is excluded by the blood brain barrier in rhesus macaque: An in vivo pet study

https://doi.org/10.1016/j.brainres.2008.12.033Get rights and content

Abstract

Environmental factors have long been thought to have a role in the etiology of idiopathic Parkinson's disease (PD). Since the discovery of the selective neurotoxicity of MPTP to dopamine cells, suspicion has focused on paraquat, a common herbicide with chemical structure similar to 1-methyl-4-phenylpyridinium (MPP+), the MPTP metabolite responsible for its neurotoxicity. Although in vitro evidence for paraquat neurotoxicity to dopamine cells is well established, its in vivo effects have been ambiguous because paraquat is di-cationic in plasma, which raises questions about its ability to cross the blood brain barrier. This study assessed the brain uptake of [11C]-paraquat in adult male rhesus macaques using quantitative PET imaging. Results showed minimal uptake of [11C]-paraquat in the macaque brain. The highest concentrations of paraquat were seen in the pineal gland and the lateral ventricles. Global brain concentrations including those in known dopamine areas were consistent with the blood volume in those structures. This acute exposure study found that paraquat is excluded from the brain by the blood brain barrier and thus does not readily support the causative role of paraquat exposure in idiopathic Parkinson's disease.

Introduction

Paraquat (1,1′-dimethyl-4,4′-bipyridium dichloride) (Fig. 1) is a common herbicide with close chemical structural resemblance to MPP+ (1-methyl-4-phenylpyridium), the toxic metabolite of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a well-established selective toxin for dopamine cells (Javitch et al., 1985). Numerous studies have reported on the possible causative role of paraquat in Parkinson's disease (PD) based on this chemical homology. Since paraquat dichloride is a di-cation in blood, doubts regarding its neurotoxicity were raised early on (Koller, 1986) and again recently (Miller, 2007) because of the blood brain barrier (BBB). While it is clear from in vitro studies that paraquat is toxic to dopamine cells (McCormack et al., 2005, Fei et al., 2008), achieving in vivo brain concentrations required for toxicity has been questioned (Miller 2007). The confusion regarding the role of paraquat in PD has been exacerbated by ambiguity of data on the ability of paraquat to cross the blood brain barrier. Many rodent studies have reported the ability of systemic paraquat administration to induce parkinsonism (Corasaniti et al., 1992a, Shimizu et al., 2001, Li et al., 2005, Prasad et al., 2007). But others (Naylor et al., 1995, Widdowson et al., 1996) find the contrary, including a recent study on chronic inhalation of paraquat in rodents which was found not to induce dopaminergic neurotoxicity (Rojo et al., 2007). To clarify the issue of blood brain barrier penetration of systemic paraquat, this study was undertaken to assess the uptake of [11C]paraquat in the non-human primate brain in vivo using quantitative PET imaging.

Section snippets

Results

Fig. 2 displays both axial and sagittal views of one monkey brain at early, mid, and late time points after [11C]paraquat injection, providing visualization of the pharmacokinetics of the radiotracer. The early image set is the first frame of the study collected over the first 60 s after injection, reflects the blood delivery of paraquat to all cerebral and extracerebral regions and [11C]-intensity is related to perfusion. The second image set is an average of frames corresponding to 3–8 min

Discussion

The finding that MPTP caused parkinsonism (Langston et al., 1983) and the subsequent identification of its metabolite MPP+ as the selective toxin for dopamine neurons (Javitch et al., 1985) buttressed the idea that environmental chemicals have a role in idiopathic PD. Paraquat was first suggested as an environmental agent with potential causative role in PD because of the similarity of its chemical structure to MPTP and MPP+ (Barbeau et al., 1985) (Fig. 1). Since then, many studies have either

Chemicals and materials

Paraquat dichloride and 4,4′-bipyridine (dipyridyl) were purchased from Sigma-Aldrich Chemicals Inc. (St. Louis, MO). The precursor to prepare [11C-methyl]-paraquat, des-methyl-paraquat (1-methyl-4,4′-bipyridium dichloride) was prepared by mono-methylating 4,4′-bipyridine (dipyridyl) by treatment with methyl iodide in methylene chloride. The pale yellow quaternary ammonium iodide salt of 1-methyl-4,4′-bipyridine was then converted using aqueous silver triflate to the corresponding quaternary

Acknowledgment

Support by a National Cancer Institute training grant (CA09206 to RMB) is gratefully acknowledged.

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