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FDA-approved 5-HT_1F receptor agonist lasmiditan induces mitochondrial biogenesis and enhances locomotor and blood-spinal cord barrier recovery after spinal cord injury.

ABSTRACT: Vascular and mitochondrial dysfunction are well-established consequences of spinal cord injury (SCI). Evidence suggests mitigating these dysfunctions may be an effective approach in treating SCI. The goal of this study was to elucidate if mitochondrial biogenesis (MB) induction with a new, selective and FDA-approved 5-hydroxytryptamine receptor 1F (5-HT_1F) receptor agonist, lasmiditan, can stimulate locomotor recovery and restoration of the blood-spinal cord barrier (BSCB) after SCI. Female C57BL/6 J mice were subjected to moderate SCI using a force-controlled impactor-induced contusion model followed by daily administration of lasmiditan (0.1 mg/kg, i.p.) beginning 1 h after injury. In the naïve spinal cord, electron microscopy revealed increased mitochondrial density and mitochondrial area, as well as enhanced mitochondrial DNA content. FCCP-uncoupled oxygen consumption rate (OCR), a functional marker of MB, was also increased in the naïve spinal cord following lasmiditan treatment. We observed disrupted mitochondrial DNA content, PGC-1α levels and FCCP-OCR in the injury site 3d after SCI. Lasmiditan treatment attenuated, and in some cases restored these deficits. Lasmiditan treatment also resulted in increased locomotor capability as early as 7d post-SCI, with treated mice reaching a Basso-Mouse Scale score of 3.3 by 21d, while vehicle-treated mice exhibited a score of 2.0. Integrity of the BSCB was assessed using Evans Blue dye extravasation. While SCI increased dye extravasation at 3d and 7d, dye accumulation in the spinal cord of lasmiditan-treated mice was attenuated 7d post-SCI, suggesting accelerated BSCB recovery. Finally, lasmiditan treatment resulted in decreased lesion volume and spared myelinated tissue 7d post-SCI. Collectively, these data reveal that 5-HT_1F receptor agonist-induced MB using the FDA-approved drug lasmiditan may be an effective therapeutic strategy for the treatment of SCI.

SUBMITTER: Simmons EC

PROVIDER: S-EPMC9013231 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT1B/1D receptors. 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 5-HT1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT1B receptors, the activation of 5-HT1F receptors does not cause vasoconstriction.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 neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT1F receptors are also elements of descending pain modulation, presenting 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 mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.

Project description:BackgroundMigraine has a great impact on public health. Current acute therapies do not satisfy all migraineurs. The novel serotonin 5-HT1F receptor agonist appears more promising for aborting migraine attacks.ObjectiveTo evaluate the clinical efficacy and safety of lasmiditan in treating acute migraine attacks.MethodsThe literature search was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) which assessed the effect and safety of lasmiditan on migraine. The risk of bias was assessed using the Cochrane Collaboration's risk of bias tool. Results were extracted and pooled as risk ratios (RRs) with a fixed or random-effects model.ResultsBased on the four included RCTs, pooled estimates showed that lasmiditan with the 50 mg, 100 mg, and 200 mg doses was superior to placebo at 2 h after the first dose in terms of pain freedom, absence of migraine-associated symptoms, headache relief, no/mild disability, and global impression of change (very much/much better) (RRs ranged from 1.13 to 1.96), except for nausea-free and vomiting-free. Both lasmiditan 100 mg and 200 mg resulted in significantly fewer patients using rescue medication (100 mg: RR = 0.75, 95% CI (0.61, 0.92), P = 0.007; 200 mg: RR = 0.81, 95% CI (0.66, 0.99), P = 0.04) at 2-24 h postdose, compared with placebo. Safety data showed that the proportion of patients reporting at least one treatment-emergent adverse event (TEAE) and the incidence of most common TEAEs such as dizziness, paresthesia, fatigue, somnolence, and nausea was higher in the lasmiditan groups (50 mg, 100 mg, and 200 mg), compared with placebo. There was no significant difference between lasmiditan and placebo in terms of cardiovascular-related TEAEs (RR = 2.75, 95% CI (0.81, 9.37), P = 0.11). Compared with lasmiditan 100 mg, lasmiditan 200 mg was more effective in pain freedom at 2 h after the first dose (RR = 0.83, 95% CI (0.74, 0.94), P = 0.004) but associated with a higher risk of reporting at least one TEAE (RR = 0.88, 95% CI (0.81, 0.96), P = 0.006).ConclusionsLasmiditan with the 50 mg, 100 mg, and 200 mg doses are effective and safe in acute migraine treatment. Lasmiditan 200 mg is more effective than lasmiditan 100 mg in pain freedom, while lasmiditan 100 mg is better tolerated in the short-term follow-up. Further larger sample-size RCTs are required to verify the applicability and tolerability in the long term.

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FDA-approved 5-HT_1F receptor agonist lasmiditan induces mitochondrial biogenesis and enhances locomotor and blood-spinal cord barrier recovery after spinal cord injury.

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FDA-approved 5-HT1F receptor agonist lasmiditan induces mitochondrial biogenesis and enhances locomotor and blood-spinal cord barrier recovery after spinal cord injury.

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OmicsDI is part of the ELIXIR infrastructure

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FDA-approved 5-HT_1F receptor agonist lasmiditan induces mitochondrial biogenesis and enhances locomotor and blood-spinal cord barrier recovery after spinal cord injury.