# 5-HT1F receptor mediated mitochondrial biogenesis for the treatment of spinal cord injury

> **NIH NIH F31** · UNIVERSITY OF ARIZONA · 2020 · $37,483

## Abstract

Project Summary/Abstract
The goal of this project is to study the 5-hydroxytryptamine 1F receptor in stimulating mitochondrial biogenesis
(MB) and recovery from spinal cord injury (SCI). SCI is a devastating disorder without meaningful treatment. SCI
is defined by direct trauma to the spinal cord, which disrupts the vasculature, leading to decreased oxygen
delivery within the injured area and reducing the ability of mitochondria to maintain cellular energetics. Studies
investigating mitochondria as a therapeutic target for SCI have only addressed individual aspects of
mitochondrial function. Therapeutics pursuing reestablishment of mitochondrial homeostasis through increased
mitochondrial biogenesis (MB) following SCI could alleviate multiple facets of injury progression.
Our MB drug discovery program identified the 5-HT1F receptor agonist LY344864 as a specific and potent inducer
of MB in mice. The 5-HT1F receptor is a lesser-studied 5-HT receptor found in the CNS and peripheral tissues.
Lasmiditan is a potent and specific 5-HT1F receptor agonist that is in phase III clinical trials for migraine
headaches. Our preliminary studies revealed that treatment with either LY344864 or lasmiditan improved
mitochondrial function, locomotion and blood spinal cord barrier (BSCB) integrity as early as 7 d post-SCI.
Locomotor capability further improved through 21 d. While similar efficacy of both agonists was observed when
administration was initiated 1 or 8 h after injury, lasmiditan was 20-fold more potent than LY344864 (0.1 vs 2
mg/kg). Exposure to either compound induced MB in primary cultures of mouse cerebral microvascular
endothelial cells, lasmiditan being 10 times more potent than LY344864 (3 vs 30 nM). Therefore, we hypothesize
that treatment with lasmiditan following SCI will increase MB, resulting in improved locomotor recovery,
decreased neuronal death and increased vascular repair post-SCI.
We will test this hypothesis in the following Specific Aims. Aim 1 will determine MB, locomotor capability and
lesion volume in response to lasmiditan treatment post-SCI in mice. Aim 2 will determine vascular recovery and
BSCB integrity in response to lasmiditan post-SCI in mice. Aim 3 will determine MB, regenerative capacity and
5-HT1F receptor signaling pathway in response to LY344864/lasmiditan under normal and injured conditions in
mouse cerebral endothelial cells (MCEC).

## Key facts

- **NIH application ID:** 10066434
- **Project number:** 1F31NS115413-01A1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Epiphani Simmons
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,483
- **Award type:** 1
- **Project period:** 2020-07-20 → 2021-07-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10066434

## Citation

> US National Institutes of Health, RePORTER application 10066434, 5-HT1F receptor mediated mitochondrial biogenesis for the treatment of spinal cord injury (1F31NS115413-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10066434. Licensed CC0.

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