Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

DOI: https://doi.org/10.1186/s10194-020-01132-3

Abstract-Summary The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine.

The discovery that the serotonin 1F (5-HT1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine.

The potency of different serotonergic agonists towards 5-HT1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan.

Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites.

Lasmiditan activation of CNS-located 5-HT1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotrans- mitter glutamate, thus preventing and possibly reversing the development of central sensitization.

Activation of 5-HT1F receptors in the thalamus can block secondary central sen- sitization of this region, which is associated with progression of migraine and extra- cephalic cutaneous allodynia.

The 5-HT1F receptors are also elements of descending pain modulation, present-

ing another site where lasmiditan may alleviate migraine.

There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT1F receptors can promote mito- chondrial biogenesis.

While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT1F agonist activity that leads to inhibition of neuro- peptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.

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4 Treatment

Extended: The discovery that activation of 5-HT1F receptors could provide ben- efits without the cardiovascular risks associated with triptans was an important advancement in the research on therapeutics for the treatment of migraine. Lasmiditan is a highly selective, lipophilic, high-affinity 5-HT1F agonist. Lasmiditan activation of the 5-HT1F receptor does not mediate vasoconstriction,

thus eliminating a risk associated with triptans.

Background The activity of CGRP at CNS sites (e.g., amygdala, PAG, parabrachial nucleus, and NRM) can be either pronociceptive or antinociceptive, depending on the brain region involved, suggesting that the role of CNS CGRP in migraine may be com- plex [67–69].

Inhibition of glutamate release in the TNC via 5-HT receptor activation may not only attenuate early stages of migraine headache, but may reduce glutamate effects during the later stages where central sensitization and cutaneous allodynia are believed to occur [70–74].

Double-labeling studies performed in the vestibular nuclei of rats revealed that neurons positive for glutamate [75] or CGRP [76] also expressed label for the 5-HT1F receptor, providing additional evidence that activation of this receptor may inhibit the release of glutamate and CGRP in CNS sites.

Imaging studies have implicated several brain regions in migraine, including the

thalamus PAG, and the TNC [67, 77].

Lasmiditan Mechanism of Action These in vitro human isolated blood vessel and in vivo anesthetized canine results suggest that, unlike triptans, lasmiditan is not vasoconstrictive at active doses.

Lasmiditan may alleviate migraine at least in part by activation of 5-HT1F recep-

tors present on glutaminergic trigeminal nerve terminals in the TNC [78].

In another phase II RCT (NCT00883051), oral doses of 50, 100, 200, or 400 mg of lasmiditan likewise proved significantly superior to placebo in reducing migraine headache severity from moderate or severe at baseline to mild or no headache at 2 h [79].

The fact that lasmiditan has some central effects does not prove that its efficacy

against migraine is mediated in the CNS.

Treatment of human glomerular endothelial cells and mouse glomerular endo- thelial cells with 5-HT1F receptor agonists LY344864 or lasmiditan (0–500  nM) induced mitochondrial biogenesis as evidenced by maximal mitochondrial respira- tion, increased nuclear- and mitochondrial-encoded proteins, and increased mito- chondrial number [80].

Conclusion The discovery that activation of 5-HT1F receptors could provide benefits without the cardiovascular risks associated with triptans was an important advancement in the research on therapeutics for the treatment of migraine.

Evidence suggested lasmiditan PNS activation of the 5-HT1F receptor can inhibit the release of CGRP from trigeminal afferent nerves in the PNS [81], thus mimick- ing the behavior of triptans, CGRP antagonists, and CGRP antibodies.

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Lasmiditan appears to cross the BBB and may also act upon 5-HT1F receptors found in CNS sites where the receptor potentially can modulate central sensitization of the TNC and thalamus.

Lasmiditan activation of the 5-HT1F receptor does not mediate vasoconstriction,

thus eliminating a risk associated with triptans.

While the precise mechanism of action is unknown, preclinical in  vitro and in vivo animal data as well as ex vivo human evidence suggested that lasmiditan exerts its therapeutic effects through agonist action at PNS and CNS 5-HT1F receptors.

Acknowledgement A machine generated summary based on the work of Clemow, David B.; Johnson, Kirk W.; Hochstetler, Helen M.; Ossipov, Michael H.; Hake, Ann M.; Blumenfeld, Andrew M. 2020 in The Journal of Headache and Pain.

A global real-world assessment of the impact on health-related quality of life and work productivity of migraine in patients with insufficient versus good response to triptan medication