Schematic diagram of the neural protective role of IMMH004 after TGCI/R Pharmacological Induction of Mitochondrial Biogenesis using the β2‐Adrenoreceptor Agonist Formoterol for the Treatment of Spinal Cord Injury

Abstract

A hallmark of the progressive cascade of damage referred to as secondary spinal cord injury (SCI) is vascular disruption resulting in ischemia and decreased oxygen delivery, which directly reduces the ability of mitochondria to maintain homeostasis. This leads to loss of ATP‐dependent cellular functions, Ca2+ overload, excitotoxicity and oxidative stress, further exacerbating injury. While therapeutics targeting restoration of single facets of mitochondrial function have proven largely ineffective post‐SCI, comprehensively addressing mitochondrial dysfunction via pharmacological stimulation of mitochondrial biogenesis (MB) is an underexplored strategy. The FDA‐approved, highly selective and potent β2‐adrenoreceptor (ADRB2) agonist formoterol is an effective inducer of MB in multiple organ systems in mice, including the spinal cord, as evidenced by increased mitochondrial DNA content and PGC‐1α expression. This study examined the effects of formoterol‐induced MB on recovery from SCI using a force‐controlled pneumatic impactor‐induced contusion model. Female C57bl/6 mice were subjected to moderate SCI (80 Kdyn) followed by daily formoterol administration (0.1 mg/kg, i.p) beginning 1 or 8 h post‐injury and continuing until euthanasia. SCI resulted in decreased mitochondrial protein expression, including PGC‐1α, in the injury and peri‐injury sites as early as 3 d after injury. Formoterol treatment attenuated this early decrease in PGC‐1α and restored downstream mitochondrial proteins to levels similar to that of sham controls by 15 d post‐SCI. Formoterol‐treated mice also exhibited less histological damage than vehicle‐treated mice 3 d after injury, namely reduced loss of white matter and structural preservation of the central canal and anterior median fissure. Importantly, as measured by the Basso‐Mouse Scale, the locomotor ability of formoterol‐treated injured mice reached twice that of vehicle‐treated SCI mice by 15 d (4.5 v 2), depicting nearly 50% recovery. Interestingly, a comparable degree of functional recovery was observed when formoterol treatment initiation was delayed until 8 h post‐SCI. These data provide evidence of ADRB2‐mediated MB as a therapeutic avenue for the treatment of SCI.Support or Funding InformationNational Institutes of Health National Institute of General Medical Sciences, Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs, South Carolina Spinal Cord Injury Research FundThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.