Abstract by Nana Isabella Svane

Triptans are potent 5-HT_1B/1D receptor agonists and are considered as the most effective treatment against acute migraine. While triptans were originally thought to exert their effects primarily via peripheral mechanisms, increasing evidence suggests they may also act centrally. However, their ability to penetrate the blood-brain barrier (BBB) remains uncertain. Given their hydrophilic nature, carrier-mediated transport may be involved. The aim of this thesis was to elucidate pathways for CNS uptake and clarify the role of the putative proton-coupled organic cation (H⁺/OC) antiporter through a combination of in vitro and in vivo studies. The research objectives included evaluating triptan transport across central and peripheral endothelial barriers, investigating the role of the H⁺/OC antiporter and P-glycoprotein (P-gp) in BBB transport of triptans, and exploring the molecular identity of the H⁺/OC antiporter.

Our findings demonstrated the highest extent of triptan transport into the peripheral trigeminal ganglion, whereas their central distribution was restricted by active efflux across the BBB. Despite this, triptans still reached unbound brain concentrations sufficient to activate central 5-HT_1B/1D receptors theoretically. Additionally, the potential role of the H⁺/OC antiporter in triptan transport across the BBB was explored. Most triptans inhibited H⁺/OC antiporter-mediated uptake of [³H]-pyrilamine in brain capillary endothelial cells, with eletriptan showing the highest inhibitory affinity and acting as an H⁺/OC antiporter substrate. In vivo studies confirmed active brain uptake of eletriptan in the absence of P-gp, while active efflux counteracted its uptake when P-gp was present. These findings suggest a dynamic interplay between active uptake and efflux mechanisms. Finally, the H⁺/OC antiporter appears to function through at least two distinct pathways: one dependent on the TM7SF3 and LHFPL6 proteins and another independent of these proteins, with the latter exhibiting greater transport capacity, although the full molecular characterization remains incomplete. Preliminary findings also indicate differential H⁺/OC antiporter capacities between the apical and basolateral membranes of intestinal epithelial cells.

In conclusion, triptan transport across the BBB is limited by predominant active efflux, although both active uptake and efflux mechanisms are involved. Despite restricted brain penetration, the findings support the possibility of central actions in antimigraine therapy with triptans. Future research is needed to determine whether central activity contributes to therapeutic effects and/or side-effects.