5-hydroxytryptamine 1F receptor agonist induces mitochondrial biogenesis and promotes recovery from spinal cord injury

Epiphani C. Simmons, Natalie E. Scholpa, Kristan H. Cleveland, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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 3 days post-SCI. LY344864 treatment beginning 1 h 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 with vehicle-treated mice 7 days after injury, suggesting restoration of vascular integrity. LY344864 also increased locomotor capability, with treated mice reaching a Basso-Mouse Scale score of 3.4 by 21 days, whereas 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 8 h after injury. Furthermore, cross-sectional analysis of the spinal cord 21 days 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.

Original languageEnglish (US)
Pages (from-to)216-223
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume372
Issue number2
DOIs
StatePublished - Feb 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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