Further evidence that the blood/brain barrier impedes paraquat entry into the brain

Abstract

<jats:p> The distribution of the non-selective herbicide paraquat was examined in the brain following subcutaneous admin istration of 20 mg kg <jats:sup>-1</jats:sup> paraquat ion containing [<jats:sup>14</jats:sup>C]paraquat to male adult rats in order to determine whether paraquat crosses the blood/brain barrier. Following administration, [<jats:sup>14</jats:sup>C]paraquat reached a maxi mal concentration in the brain (0.05% of administered dose) within the first hour and then rapidly disappeared from the brain. However, 24 h after administration of the herbicide, about 13% of the maximal recorded concentra tion of paraquat remained in the brain (1.6 nmol g<jats:sup>-1</jats:sup> wet weight) and could not be removed by intracardiac perfu sion. Using measurements of [<jats:sup>14</jats:sup>C]paraquat in dissected brain regions and using quantitative autoradiography we demonstrated an asymmetrical distribution in and around the brain at 30 min (maximal concentration) and 24 h after administration. Most of the paraquat was associated with five structures, two of which, the pineal gland and linings of the cerebral ventricles lie outside the blood/brain barrier whilst the remaining three brain areas, the anterior portion of the olfactory bulb, hypothalamus and area postrema do not have a blood/brain barrier. Overall, the distribution of [<jats:sup>14</jats:sup>C]paraquat in the brain 24 h after systemic administration was highly correlated to the blood volume. These data indicate that any remaining paraquat in the brain 24 h after systemic administration is associated with elements of the cerebro-circulatory sys tem, such as the endothelial cells that make up the capil lary network and that there is a limited entry of paraquat into brain regions without a blood/brain barrier. No [<jats:sup>14</jats:sup>C]paraquat was detected in regions where there has been demonstrated pathology in brains from humans with Parkinson's disease. Finally, we could find no evidence for paraquat-induced neuronal cell necrosis 24 or 48 h after systemic administration. Overall it may be concluded that systemically administered paraquat does not pose a direct major neurotoxicological risk in the majority of brain regions which have a functional blood/brain barrier since paraquat can be excluded from the brain by this barrier. </jats:p>

Paraquat and Parkinson's disease

“…Several studies now agree that PQ penetration into the brain is an age-dependent phenomenon. Higher PQ levels can be found in neonatal brains compared with brain regions of adult and elderly rats, 32 or in either very young (2 weeks old) or very old (12 and 24 months old) animals when compared with normal adult (3-month-old rats). 34,35 Thus, it is apparent that neonatal or very young animals are better able to sequester PQ.…”

“…After a single administration, most of the PQ that reaches the brain is apparently associated with structures outside the BBB (i.e., the pineal gland and the cerebral ventricles) or with three areas of the brain: the anterior portion of the olfactory bulb, the hypothalamus and the area postrema, which do not have a tight BBB. 32 Shimizu and colleagues 33 challenged these initial observations. Using a brain microdialysis technique in rats, they showed that PQ could be found in the dialysate after subcutaneous administration.…”

Parkinson's disease and pesticides: a toxicological perspective

“…Early studies suggested that the pharmacokinetic properties of paraquat made it an unlikely candidate due to its low partition coefficient, limited absorption and poor CNS penetration [27]. 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].…”

“…Some groups have reported no neurotoxic changes after paraquat exposure [28,32], whereas others have shown varying degrees of toxicity. For example, systemic paraquat exposure has been shown to cause a 20%-30% selective dopamine neuronal loss in the SNpc [33] and increased expression and aggregation of α-synuclein [33].…”

Homeostasis of glucose in the rainbow trout (Oncorhynchus mykiss Walbaum): the role of serotonin

“…The radioactive content was determined, 5min per sample, in a liquid scintillation counter (LS-6500, Beckman, USA), and the number of counts per minute detected in the plasma and in the brain tissue were expressed in nanomoles of 5-HT, based on the counts in the working solution of known concentration (N8). Times in the order of 10-15min are commonly used in studies of this type in mammals (Buschiazzo et al, 1970;Vitte et al, 1988;Naylor et al, 1995;Preston et al, 1995;Perasso et al, 2003) and fish . If a substance passes the BBB it will actually be detectable in the brain long before 15min.…”