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Permeation of Dopamine Sulfate through the Blood-Brain Barrier.

Suominen T, Piepponen TP, Kostiainen R - PLoS ONE (2015)

Bottom Line: The results in the microdialysis samples demonstrated that brain concentrations of 13DA-S regioisomers clearly increased after the s.c. injections.The concentration of DA did not change, indicating the permeation of DA-S through an intact BBB.The results also showed that the concentrations of DA-3-S were around three times higher than the concentrations of DA-4-S in rat brain, as well as in the plasma samples after the s.c. injections, indicating that DA-3-S and DA-4-S permeate the BBB with similar efficiency.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.

ABSTRACT
Dopamine sulfate (DA-3- and DA-4-S) have been determined in the human brain, but it is unclear whether they are locally formed in the central nervous system (CNS), or transported into the CNS from peripheral sources. In the current study, permeation of the blood-brain barrier (BBB) by DA-S was studied by injecting 13C6-labelled regioisomers of DA-S (13DA-3-S and 13DA-4-S) and dopamine (DA) subcutaneously (s.c.) in anesthetized rats, then analyzing brain microdialysis and plasma samples by UPLC-MS/MS. The results in the microdialysis samples demonstrated that brain concentrations of 13DA-S regioisomers clearly increased after the s.c. injections. The concentration of DA did not change, indicating the permeation of DA-S through an intact BBB. The analysis of plasma samples, however, showed that DA-S only permeates the BBB to a small extent, as the concentrations in plasma were substantially higher than in the microdialysis samples. The results also showed that the concentrations of DA-3-S were around three times higher than the concentrations of DA-4-S in rat brain, as well as in the plasma samples after the s.c. injections, indicating that DA-3-S and DA-4-S permeate the BBB with similar efficiency. The fate of 13DA-S in brain was followed by monitoring 13C6-labelled DA-S hydrolysis products, i.e. 13DA and its common metabolites; however, no 13C6-labelled products were detected. This suggests that DA-S either permeates through the BBB back to the peripheral circulation or is dissociated or metabolized by unexpected mechanisms.

No MeSH data available.


Concentrations of the neurotransmitters (Left: dopamine metabolites, right: serotonin metabolites) during the test in rat brain microdialysates in one of the test animals (Rat 6).
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pone.0133904.g003: Concentrations of the neurotransmitters (Left: dopamine metabolites, right: serotonin metabolites) during the test in rat brain microdialysates in one of the test animals (Rat 6).

Mentions: The concentrations of the naturally occurring non-labelled metabolites of dopamine (DA-G, DOPAC, DOPAC-S, HVA and HVA-S) increased after the injections of 13C6-labelled DA-S. No clear trend in the levels of DA could be observed. Serotonin (5-HT) and its metabolites followed a similar trend: while the 5-HT levels decreased in all animals during the experiment, the concentrations of its metabolites (5-HT-G, 5-HIAA and 5-HIAA-S) increased during the experiment (Fig 3). The injected 13DA-S may affect the metabolism process of naturally occurring dopamine and/or other neurotransmitters, but anesthesia itself might also have an impact on the concentration changes. The influence of volatile anesthetics on neurotransmitter levels have been reported earlier: isoflurane has been shown to lower 5-HT levels in rats and mice compared to levels during wakefulness [39,40]. Isoflurane anesthesia has also been shown to increase DA levels at high doses (3% isoflurane), while the levels of DOPAC and HVA increased at all isoflurane concentrations studied [41,42]. Similar effects have been reported for halothane and sevoflurane [43,44]. Based on the literature it seems likely that the fluctuations in neurotransmitter levels are due to anesthesia. Moreover, the isoflurane concentrations had to be slightly adjusted during the experiments, which additionally might have influenced the neurotransmitter levels. However, this does not rule out that the injected DA-S might also have contributed to these level changes.


Permeation of Dopamine Sulfate through the Blood-Brain Barrier.

Suominen T, Piepponen TP, Kostiainen R - PLoS ONE (2015)

Concentrations of the neurotransmitters (Left: dopamine metabolites, right: serotonin metabolites) during the test in rat brain microdialysates in one of the test animals (Rat 6).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4514783&req=5

pone.0133904.g003: Concentrations of the neurotransmitters (Left: dopamine metabolites, right: serotonin metabolites) during the test in rat brain microdialysates in one of the test animals (Rat 6).
Mentions: The concentrations of the naturally occurring non-labelled metabolites of dopamine (DA-G, DOPAC, DOPAC-S, HVA and HVA-S) increased after the injections of 13C6-labelled DA-S. No clear trend in the levels of DA could be observed. Serotonin (5-HT) and its metabolites followed a similar trend: while the 5-HT levels decreased in all animals during the experiment, the concentrations of its metabolites (5-HT-G, 5-HIAA and 5-HIAA-S) increased during the experiment (Fig 3). The injected 13DA-S may affect the metabolism process of naturally occurring dopamine and/or other neurotransmitters, but anesthesia itself might also have an impact on the concentration changes. The influence of volatile anesthetics on neurotransmitter levels have been reported earlier: isoflurane has been shown to lower 5-HT levels in rats and mice compared to levels during wakefulness [39,40]. Isoflurane anesthesia has also been shown to increase DA levels at high doses (3% isoflurane), while the levels of DOPAC and HVA increased at all isoflurane concentrations studied [41,42]. Similar effects have been reported for halothane and sevoflurane [43,44]. Based on the literature it seems likely that the fluctuations in neurotransmitter levels are due to anesthesia. Moreover, the isoflurane concentrations had to be slightly adjusted during the experiments, which additionally might have influenced the neurotransmitter levels. However, this does not rule out that the injected DA-S might also have contributed to these level changes.

Bottom Line: The results in the microdialysis samples demonstrated that brain concentrations of 13DA-S regioisomers clearly increased after the s.c. injections.The concentration of DA did not change, indicating the permeation of DA-S through an intact BBB.The results also showed that the concentrations of DA-3-S were around three times higher than the concentrations of DA-4-S in rat brain, as well as in the plasma samples after the s.c. injections, indicating that DA-3-S and DA-4-S permeate the BBB with similar efficiency.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.

ABSTRACT
Dopamine sulfate (DA-3- and DA-4-S) have been determined in the human brain, but it is unclear whether they are locally formed in the central nervous system (CNS), or transported into the CNS from peripheral sources. In the current study, permeation of the blood-brain barrier (BBB) by DA-S was studied by injecting 13C6-labelled regioisomers of DA-S (13DA-3-S and 13DA-4-S) and dopamine (DA) subcutaneously (s.c.) in anesthetized rats, then analyzing brain microdialysis and plasma samples by UPLC-MS/MS. The results in the microdialysis samples demonstrated that brain concentrations of 13DA-S regioisomers clearly increased after the s.c. injections. The concentration of DA did not change, indicating the permeation of DA-S through an intact BBB. The analysis of plasma samples, however, showed that DA-S only permeates the BBB to a small extent, as the concentrations in plasma were substantially higher than in the microdialysis samples. The results also showed that the concentrations of DA-3-S were around three times higher than the concentrations of DA-4-S in rat brain, as well as in the plasma samples after the s.c. injections, indicating that DA-3-S and DA-4-S permeate the BBB with similar efficiency. The fate of 13DA-S in brain was followed by monitoring 13C6-labelled DA-S hydrolysis products, i.e. 13DA and its common metabolites; however, no 13C6-labelled products were detected. This suggests that DA-S either permeates through the BBB back to the peripheral circulation or is dissociated or metabolized by unexpected mechanisms.

No MeSH data available.