A hallmark of the progressive cascade of damage referred to as secondary spinal cord injury (SCI) is vascular disruption resulting in decreased oxygen delivery and loss of mitochondria homeostasis. While therapeutics targeting restoration of single facets of mitochondrial function have proven largely ineffective clinically post-SCI, comprehensively addressing mitochondrial function via pharmacological stimulation of mitochondrial biogenesis (MB) is an underexplored strategy. This study examined the effects of formoterol, a mitochondrial biogenic Food and Drug Administration-approved selective and potent β2-adrenoreceptor (ADRB2) agonist, on recovery from SCI in mice. Female C57BL/6 mice underwent moderate SCI using a force-controlled impactor-induced contusion model, followed by daily formoterol intraperitoneal administration (0.1 mg/kg) beginning 1 h post-SCI. The SCI resulted in decreased mitochondrial protein expression, including PGC-1α, in the injury and peri-injury sites as early as 3 days post-injury. Formoterol treatment attenuated this decrease in PGC-1α, indicating enhanced MB, and restored downstream mitochondrial protein expression to that of controls by 15 days. Formoterol-treated mice also exhibited less histological damage than vehicle-treated mice 3 days after injury - namely, decreased lesion volume and increased white and gray matter sparing in regions rostral and caudal to the injury epicenter. Importantly, locomotor capability of formoterol-treated mice was greater than vehicle-treated mice by 7 days, reaching a Basso Mouse Scale score two points greater than that of vehicle-treated SCI mice by 15 days. Interestingly, similar locomotor restoration was observed when initiation of treatment was delayed until 8 h post-injury. These data provide evidence of ADRB2-mediated MB as a therapeutic approach for the management of SCI.
|Number of pages||11|
|Journal||Journal of Neurotrauma|
|State||Published - Mar 15 2019|
Bibliographical noteFunding Information:
This study was supported by the South Carolina Spinal Cord Injury Research Fund: SCIRF #2015 I-03 (R.G.S), the National Institutes of Health National Institute of General Medical Sciences: GM084147 (R.G.S), and the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs: BX: 000851 (R.G.S.).
© 2019, Mary Ann Liebert, Inc.
- mitochondrial biogenesis
- spinal cord injury
ASJC Scopus subject areas
- Clinical Neurology