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

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.

Central nervous system stimulants promote nerve cell death under continuous hypoxia.

Intake of central nervous system (CNS) stimulants causes hypoxia and brain edema, which results in nerve cell death. However, no study has yet investigated the direct and continuous effects on nerve cells of CNS stimulants under hypoxia. Thus, based on autopsy cases, the effects of CNS stimulant drugs on the CNS were examined. The pathological changes in cultured nerve cells when various CNS stimulants were added under a hypoxic condition were also investigated. Five groups (Group A, stimulants; Group B, stimulants with psychiatric drugs; Group C, caffeine; Group D, psychiatric drugs; and Group E, no drugs) according to the detected drugs in autopsy cases were compared, and brain edema was evaluated using morphological findings. Furthermore, the number of dead cultured nerve cells was counted after the addition of drugs (4-aminopyridine (4-AP), caffeine, and ephedrine) under hypoxia (3% O2). Staining with anti-receptor-interacting protein 3 (RIP3) and other associated stains was also performed to investigate the neuronal changes in the brain. Group A showed significantly more brain edema than the other groups. In the culture experiments, the ratio of nerve cell death after the addition of 4-AP was the highest in the hypoxic condition. Groups with stimulants detected were stained more strongly by RIP3 immunostaining than by other staining. Addition of stimulants to cultured nerve cells in a persistent hypoxic condition led to severe cytotoxicity and nerve cell death. These findings suggest that necroptosis is involved in nerve cell death due to the addition of CNS stimulants in the hypoxic condition.