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. 2022 Feb 7;23(3):1862.
doi: 10.3390/ijms23031862.

Central Nervous System Stimulants Limit Caffeine Transport at the Blood-Cerebrospinal Fluid Barrier

Kei Ikeda-Murakami  1 , Naoto Tani  1   2 , Tomoya Ikeda  1   2 , Yayoi Aoki  1 , Takaki Ishikawa  1   2
Affiliations

Central Nervous System Stimulants Limit Caffeine Transport at the Blood-Cerebrospinal Fluid Barrier

Kei Ikeda-Murakami et al. Int J Mol Sci. .

Abstract

Caffeine, a common ingredient in energy drinks, crosses the blood-brain barrier easily, but the kinetics of caffeine across the blood-cerebrospinal fluid barrier (BCSFB) has not been investigated. Therefore, 127 autopsy cases (Group A, 30 patients, stimulant-detected group; and Group B, 97 patients, no stimulant detected group) were examined. In addition, a BCSFB model was constructed using human vascular endothelial cells and human choroid plexus epithelial cells separated by a filter, and the kinetics of caffeine in the BCSFB and the effects of 4-aminopyridine (4-AP), a neuroexcitatory agent, were studied. Caffeine concentrations in right heart blood (Rs) and cerebrospinal fluid (CSF) were compared in the autopsy cases: caffeine concentrations were higher in Rs than CSF in Group A compared to Group B. In the BCSFB model, caffeine and 4-AP were added to the upper layer, and the concentration in the lower layer of choroid plexus epithelial cells was measured. The CSF caffeine concentration was suppressed, depending on the 4-AP concentration. Histomorphological examination suggested that choroid plexus epithelial cells were involved in inhibiting the efflux of caffeine to the CSF. Thus, the simultaneous presence of stimulants and caffeine inhibits caffeine transfer across the BCSFB.

Keywords: BCSFB model; GC/MS; blood–cerebrospinal fluid barrier (BCSFB); caffeine; choroid plexus; stimulants; vacuolation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The correlation between the concentration of caffeine in Rs and that in CSF in Groups A (red) and B (blue). There is a correlation between the caffeine concentrations in Rs and in CSF in both groups (Group A: r = 0.795, p < 0.0001; Group B: r = 0.903, p < 0.0001). The concentration of caffeine is higher in Rs than in CSF in Group A.
Figure 2
Figure 2
The correlation between the concentration of caffeine in Rs and that in CSF in Groups I (red), II (blue), III (green), and IV (orange). There is a correlation between the concentration of caffeine in Rs and in CSF in all groups (Group I: r = 0.651, p < 0.01; Group II: r = 0.928, p < 0.0001; Group III: r = 0.917, p < 0.0001; Group IV: r = 0.884, p < 0.0001). The concentration of caffeine is higher in Rs than in CSF in Groups I and II.
Figure 3
Figure 3
Concentration of caffeine after the addition of 4-AP by the time after administration of each concentration of 4-AP in the BCSFB model.
Figure 4
Figure 4
The histopathological findings of choroid plexus epithelial cells in autopsy cases in each group (H&E staining 400×). Cytoplasmic vacuolations are seen. In particular, more than 10% of choroid plexus epithelial cells have cytoplasmic vacuolations in Groups I (27.5%) and II (13.6%), with 9.2% in Group III and 2.1% in Group IV.
Figure 5
Figure 5
Morphological findings of choroid plexus epithelial cells using TEM. In Groups A and B, cytoplasmic vacuoles of the same size as the nuclei are observed; it seems that something has pooled in the cytoplasmic vacuole.
Figure 6
Figure 6
Concentrations of caffeine in vascular endothelial cells and in choroid plexus epithelial cells. Under all conditions, the concentration of caffeine is higher in choroid plexus epithelial cells than in vascular endothelial cells. In particular, a significant difference in caffeine concentration is observed 6 h after 1000 ng/mL 4-AP was added.
Figure 7
Figure 7
A rough drawing of the BCSFB model.
Figure 8
Figure 8
Caffeine and 4-AP administered in the BCSFB model. Caffeine concentration in CSF side was measured using GC/MS at 1, 3 and 6 h, respectively.
Figure 9
Figure 9
The drug-containing method for measurement under all conditions after the administration of drugs in the BCSFB model. The concentrations of caffeine in vascular and choroid plexus epithelial cells were measured using GC/MS at 1 and 6 h, respectively.
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