Rapid Brain Uptake of Manganese(II) Across the Blood‐Brain Barrier

Abstract

54Mn2+ uptake into brain and choroid plexus from the circulation was studied using the in situ rat brain perfusion technique. Initial uptake from blood was linear with time (30 s to 6 min) and extrapolated to zero with an average transfer coefficient of ∼6 × 10‐5 ml/s/g for brain and ∼7 × 10‐3 ml/s/g for choroid plexus. Influx from physiologic saline was three‐ to fourfold more rapid and exceeded that predicted for passive diffusion by more than one order of magnitude. The lower uptake rate from blood could be explained by plasma protein binding as the free fraction of 54Mn2+ in rat plasma was ≤30%. Purified albumin, transferrin, and α2‐macroglobulin were each found to bind 54Mn2+ significantly and to restrict brain 54Mn2+ influx. The results demonstrate that 54Mn2+ is readily taken up into the CNS, most likely as the free ion, and that transport is critically affected by plasma protein binding. The results support the hypothesis that Mn2+ transport across the blood‐brain barrier is facilitated by either an active or a passive mechanism.

Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: Implication for longitudinal studies

“…On the other hand, we cannot exclude the possibility that the increased accumulation of manganese in the functionally activated brain regions -at least to some extent -results from an accelerated direct transport of manganese from the blood stream across BBB of the cerebral capillaries via a non-specific metal transporters (Takeda, 2003). It has been shown that at high plasma concentrations transport across the choroid plexus is more prevalent, while at normal plasma concentrations the transport across cerebral capillaries dominates (Murphy et al, 1991;Rabin et al, 1993); the latter could be true in case of low doses of manganese. More experiments will be required to clarify the extent to which MEMRI is independent from neurovascular effects.…”

“…The ability of manganese to cross the BBB following systemic administration (Murphy et al, 1991;Rabin et al, 1993), enter excitable cells via voltage-gated Ca 2+ channels (Drapeau and Nachshen, 1984;Lin and Koretsky, 1997;Narita et al, 1990;Silva et al, 2004) and accumulate in the activated brain regions gives the unique opportunity to use MEMRI for the whole-brain functional mapping. Exposure to subtoxic levels of manganese extends the application of this method to behaving animals.…”

Manganese neurotoxicity: A focus on the neonate

“…It appears that facilitated diffusion (Rabin et al, 1993), active transport (Murphy et al, 1991;Aschner and Gannon, 1993;Rabin et al, 1993), DMT-1-mediated transport (Erikson et al, 2004a;Garrick et al, 2003), ZIP8-, store-operated calcium channels as well as transferrin (Tf)-dependent transport (Aschner and Gannon, 1993) mechanisms are all involved in shuttling Mn across the BBB. Although non-protein-bound Mn enters the brain more rapidly than Tfbound Mn (Murphy et al, 1991;Rabin et al, 1993), it is unclear as to which form represents the predominant mechanism of transport in situ.…”

Current status of functional MRI on small animals: application to physiology, pathophysiology, and cognition

“…When the plasma concentration of Mn 2þ increases, the influx of Mn 2þ into the ventricular CSF is 100 times faster than the influx into brain tissue protected by BBB. In other words, the blood-CSF barrier seems to be more permeable to Mn 2þ ions than the BBB, so that the uptake into the central nervous system via the choroid plexus becomes the predominant form (71,72). As the ependyma, the lining of the cerebral ventricles, regulates the transport of ions including Ca 2þ and Mn 2þ across the CSF-brain barrier into the interstitial fluid, brain regions adjacent to the ventricles may receive significant amounts of Mn 2þ not only from the cerebral capillaries but also via the ventricular CSF.…”

“…It may therefore be concluded that the predominant contribution to the axonal transport of Mn 2þ ions stems from the fast process. After transport along the microtubules to the synaptic cleft, the Mn 2þ is released at the synaptic cleft, where it can be taken up by the next neuron in the circuit (71,72,86,87). Quite interestingly, it has been shown that neurons that have been preloaded with Mn 2þ co-release the ion with glutamate upon stimulation, indicating the possibility that Mn 2þ is transported within synaptic vesicles (88).…”