Influence of age on the passage of paraquat through the blood-brain barrier in rats: A distribution and pathological examination

Abstract

<jats:p> Experiments were performed to determine the extent of paraquat entry into the brain of neonatal and elderly rats, as compared with adult rats, which may be dependent on the efficacy of the blood-brain barrier. A single, median lethal dose (20 mg/kg s.c.) of paraquat containing [<jats:sup>14</jats:sup>C]paraquat was administered to neonatal (10 day old), adult (3 month old) and elderly (18 month old) rats. In contrast to the adult and elderly rats where paraquat levels fell over the 24 h post-dosing period to negligible levels, paraquat concentrations in neonatal brains did not decrease with time between 0.5 and 24 h following dosing. The distribution of [<jats:sup>14</jats:sup>C]paraquat was measured in selective brain regions using quantitative autoradiogra phy in all three age groups of rats, 30 min and 24 h following dosing. Autoradiography demonstrated that brain paraquat distributions were similar in the rat age groups. Most of the paraquat was confined to regions outside the blood-brain barrier and to brain regions that lack a complete blood-brain barrier e.g. dorsal hypotha lamus, area postrema and the anterior olfactory bulb. Between 0.5 h and 24 h following dosing, paraquat concentrations in deeper brain structures, some distance away from the sites of entry, began to slowly increase in all the rat age groups. By 24 h following dosing, a majority of brain regions examined using quantitative autoradiogra phy revealed significantly higher paraquat concentrations in neonatal brains as compared to brain regions of adult and elderly rats. Despite increased paraquat entry into neonatal brain, we could find no evidence for paraquat- induced neuronal cell damage following a detailed histopathological examination of perfused-fixed brains. In conclusion, impaired blood-brain barrier integrity in neonatal brain thus permitting more paraquat to enter than in adult brain, did not result in neuronal damage. </jats:p>

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

“…Interestingly, mice exposed to 0.36 mg/kg PQ at postnatal day 10 -11 show permanent hypoactivity and attenuated levels of striatal DA (Fredriksson et al, 1993). Uptake of PQ into brain is age dependent, with higher concentrations of PQ detected in very young (2-weeks-old) and old (24-months-old) animals (Corasaniti et al, 1991;Fredriksson et al, 1993;Widdowson et al, 1996a).…”

“…Occupational PQ exposures have been associated with parkinsonism (Hertzman et al, 1990;Liou et al, 1997). Although substantially impeded, PQ does cross the blood-brain barrier, with higher levels evident 24 hr as compared with 30 min after administration (Widdowson et al, 1996a).…”

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].…”

Paraquat: A Useful Tool for the in vivo Study of Mechanisms of Neuronal Cell Death

“…The finding that after systemic injection most of the [I4C]paraquat detected in the brain of rats is confined to areas lacking complete blood-brain barrier, such as the anterior portion of the olfactory bulb and the hypothalamus, led to the suggestion that the blood-brain barrier strongly limits the entry of paraquat into the brain (Naylor et al 1995;Widdowson et al 1996). However, it is also a fact that soon after systemic injection, detectable levels of the herbicide can be revealed also in deep brain areas (Corasaniti et al 1993) and they increase over time (Naylor et al 1995;Widdowson et al 1996), suggesting that paraquat does penetrate into the brain. On the other hand, it cannot be excluded that paraquat, when damaging the capillary wall (Hughes 1988), facilitates the penetration into the CNS.…”

“…The finding that the herbicide reaches higher concentrations in the brain of neonatal animals has been confirmed in a recent study in which it was also reported that, at variance with adult animals, paraquat levels in pup brain did not decrease with time between 30 min. and 24 hr after systemic administration (Widdowson et al 1996). …”