5-HT1F Receptor Agonism for the Treatment of Spinal Cord Injury

Abstract

Spinal cord injury (SCI) is characterized by vascular disruption leading to ischemia, decreased oxygen delivery and loss of mitochondrial homeostasis. The dysregulation observed with SCI leads to defective respiratory chain function and reduced ATP production, exacerbating neuronal death and loss of locomotor capability. A growing body of research supports pharmacological induction of mitochondrial biogenesis (MB) as an effective approach to treat SCI. MB is a multifaceted process involving the integration of highly regulated transcriptional events, lipid membrane and protein synthesis/assembly and replication of mitochondrial DNA (mtDNA). We previously identified 5-hydroxytryptamine receptor 1F (5-HT1F) agonism as a potent inducer of MB in multiple organ systems. The series of studies presented herein explores the therapeutic potential of 5-HT1F receptor agonism on MB induction and recovery following SCI using a moderate force-controlled impactor-induced contusion mouse model. Post-SCI, mitochondrial dysfunction presents in the spinal cord, as indicated by decreased mtDNA and mitochondrial protein expression. Daily treatment with LY344864 and lasmiditan, two highly specific 5-HT1F receptor agonists, beginning after injury, not only attenuates these decreases, indicating MB, but also accelerates recovery, as denoted by decreased lesion volume and enhanced locomotor function. 5-HT1F receptor agonism increased locomotor capability, with both LY344864- and lasmiditan-treated mice reaching a Basso-Mouse Scale (BMS) score of ~3.4 by 21d, while vehicle-treated mice exhibited a score of 1.9. Importantly, knockout of the 5-HT1F receptor blocked these effects. Remarkably, a similar degree of locomotor restoration was observed when treatment was initiated 1 or 8h after injury, emphasizing the potential clinical applicability of this therapeutic approach. Furthermore, lasmiditan is FDA-approved for the treatment of migraines and could be repurposed for the treatment of SCI. In addition, injured mice treated with 5-HT1F receptor agonists display decreased Evan’s Blue dye accumulation and increased protein expression of tight junctions in the spinal cord compared to vehicle-treated mice, suggesting enhanced restoration of vascular integrity. These findings led us to investigate if lasmiditan induces MB and function specifically in endothelial cells. In vitro studies determine lasmiditan induces MB and enhances early-phase angiogenic pathways via Akt-eNOS activation in primary cultures of mouse cerebral endothelial cells. These data provide evidence that induction of MB via 5-HT1F receptor agonism may be a promising strategy for the treatment of SCI and related CNS injuries characterized by mitochondrial and vascular dysfunction.