%0 Journal Article %A Epiphani C Simmons %A Natalie E Scholpa %A Kristan H Cleveland %A Rick G Schnellmann %T 5-HT1F Receptor Agonist Induces Mitochondrial Biogenesis and Promotes Recovery from Spinal Cord Injury %D 2019 %R 10.1124/jpet.119.262410 %J Journal of Pharmacology and Experimental Therapeutics %P jpet.119.262410 %X Spinal cord injury (SCI) is characterized by vascular disruption leading to ischemia, decreased oxygen delivery and loss of mitochondrial homeostasis. This mitochondrial dysfunction results in loss of cellular functions, calcium overload and oxidative stress. Pharmacological induction of mitochondrial biogenesis (MB) may be an effective approach to treat SCI. LY344864, a 5-hydroxytryptamine 1F (5-HT1F) receptor agonist, is a potent inducer of MB in multiple organ systems. To assess the efficacy of LY344864-induced MB on recovery post-SCI, female mice were subjected to moderate force-controlled impactor-induced contusion SCI followed by daily LY344864 administration for 21 days. Decreased mitochondrial DNA and protein content was present in the injury site 3d post-SCI. LY344864 treatment beginning 1hr after injury attenuated these decreases, indicating MB. Additionally, injured mice treated with LY344864 displayed decreased Evan's Blue dye accumulation in the spinal cord compared to vehicle-treated mice 7d after injury, suggesting restoration of vascular integrity. LY344864 also increased locomotor capability, with 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 LY344864-induced recovery. Remarkably, a similar degree of locomotor restoration was observed when treatment initiation was delayed until 8hr after injury. Furthermore, cross-sectional analysis of the spinal cord 21d after injury revealed decreased lesion volume with delayed LY344864 treatment initiation, emphasizing the potential clinical applicability of this therapeutic approach. These data provide evidence that induction of MB via 5-HT1F receptor agonism may be a promising strategy for the treatment of SCI.SIGNIFICANCE STATEMENT Treatment with LY344864 induces mitochondrial biogenesis in both the naive and injured mouse spinal cord. In addition, treatment with LY344864 beginning after impactor-induced contusion SCI improves mitochondrial homeostasis, BSCB integrity and locomotor function within 7 days. Importantly, similar locomotor results are observed whether treatment is initiated at 1 hour after injury or 8 hours after injury. These data indicate the potential for pharmacological induction of mitochondrial biogenesis through a 5-HT1F agonist as a novel therapeutic approach for SCI. %U https://jpet.aspetjournals.org/content/jpet/early/2019/11/27/jpet.119.262410.full.pdf