br Conclusions Triptans are HT B D F receptors agonists

Conclusions Triptans are 5-HT1B/1D/(1F) receptors agonists and are considered as the gold standard for acute migraine treatment that have been proven effective. Unfortunately, they are contraindicated in patients with cardiovascular diseases due to their vasoconstrictor (side) effects (MaassenVanDenBrink, Reekers, et al., 1998; MaassenVanDenBrink & Saxena, 2004). Furthermore, triptans are not effective in 25% of migraine patients (Diener & Limmroth, 2001); thus, it is important to develop new antimigraine drugs that are cardiovascularly completely safe and at least equally effective. The vasoconstrictor properties of triptans are thought to be mediated via activation of 5-HT1B receptors in blood vessels; this has led, in view of the contraindications in patients with cardiovascular pathologies, to the development of antimigraine drugs targeting the 5-HT1D and 5-HT1F receptors. While 5-HT1D cx 4945 activation was not effective in the acute treatment of migraine (Gómez-Mancilla et al., 2001), the 5­HT1F receptor agonists have shown to be effective (Farkkila et al., 2012; Ferrari et al., 2010). Furthermore, predictive preclinical models of migraine have shown that lasmiditan does not cause vasoconstriction and that its antimigraine effects are likely mediated via neural modulation (Labastida-Ramírez et al., 2017; Nelson et al., 2010; Rubio-Beltrán et al., 2016; Vila-Pueyo et al., 2016). Thus, 5-HT1F receptor agonists may provide migraine patients with another type of specific acutely acting antimigraine drug, with a cardiovascular safety advantage over the triptans, and with a mechanism of action that is likely to be, at least partly, different from that of the triptans. Based on the lack of vasoconstrictive properties and its presumably neuronal mode of action, 5-HT1F receptor agonists can be considered as an entity apart from that of the triptans in antimigraine therapy.
Conflict of interest statement
Acknowledgments Dr. Antoinette MaassenVanDenBrink was supported by the Netherlands Organization for Scientific Research (Vidi grant 917.113.349), whereas Prof. Carlos M. Villalón, Alejandro Labastida-Ramírez and Eloísa Rubio-Beltrán were supported by Consejo Nacional de Ciencia y Tecnología (CONACyT; Grant No. 219707 to CMV and fellowships 410778 to ALR and No. 409865 to ERB; Mexico City) Fig. 3 was modified from Servier Medical Art licensed under a Creative Common Attribution 3.0 Generic License, http://smart.servier.com.
Introduction Yokukansan is a traditional herbal medicine used in Japan. It has been reported to be clinically safe and to ameliorate the behavioral and psychological symptoms of dementia in patients with Alzheimer's disease, dementia with Lewy bodies, other forms of senile dementia, borderline personality disorder or schizophrenia (Iwasaki et al., 2005a, Iwasaki et al., 2005b, Miyaoka et al., 2008, Monji et al., 2009, Shinno et al., 2008, Shinno et al., 2007). Previously, we reported that geissoschizine methyl ether, an indole alkaloid in Uncaria hook (a constituent of yokukansan) shows affinity for several G protein-coupled serotonin (5-HT) and dopamine receptors (partial agonist for 5-HT1A and D1 receptors, and antagonist for 5-HT2A/2C and 5-HT7 receptors) (Ueda et al., 2011). These findings indicated that yokukansan administration could improve psychological symptoms (Ueda et al., 2011). Among monoamine receptors, the 5-HT3 receptor is the sole transmembrane ligand-gated ion channel responsible for rapid neurotransmission in central and peripheral nervous systems (Lester et al., 2004). The 5-HT3 receptor complex comprises five subunits that surround a cation-permeable (Na+, Ca2+, K+) channel pore (Davies et al., 1999, Green et al., 1995, Lummis et al., 2005). The human genome contains five genes encoding different 5-HT3 subunits (A–E) (Niesler et al., 2003). 5-HT3A and 5-HT3B subunits are primarily involved in the formation of functional receptors (Niesler et al., 2007). 5-HT3A subunits can form functional homomeric channels, whereas the 5-HT3B subunit alone cannot (Davies et al., 1999). Instead, the 5-HT3B subunit achieves functionality through formation of heteromeric complexes with 5-HT3A subunits in a proposed subunit stoichiometry of 2A:3B, with a receptor rosette arrangement of B-B-A-B-A (Barrera et al., 2005).