Abstract Information


β2-adrenoreceptor-mediated mitochondrial biogenesis for the treatment of spinal cord injury

1Scholpa N, 2Narang A, 2Wang W, 2Corum D, 2Tomlinson S, 1Schnellmann R
1University of Arizona, Tucson, AZ, United states; 2Medical University of South Carolina, Charleston, SC, United states

Objective: A hallmark of the progressive cascade of damage referred to as secondary spinal cord injury (SCI) is vascular disruption leading to vasoconstriction and decreased oxygen delivery, directly reducing the ability of mitochondria to maintain homeostasis. This leads to loss of ATP-dependent cellular functions, calcium overload, excitotoxicity and oxidative stress, further exacerbating injury. While therapeutics targeting restoration of single facets of mitochondrial function have proven ineffective post-SCI, pharmacologically stimulating mitochondria biogenesis (MB) is an unexplored strategy.

Design/Methods: This study examined the effects of formoterol, an FDA-approved highly selective and potent β2-adrenoreceptor agonist, on spinal cord MB and functional recovery following SCI in mice. Female C57BL/6 mice were subjected to moderate SCI using a force-controlled pneumatic impactor-induced contusion model (80 Kdyn), and administered daily formoterol (0.1 mg/kg, i.p) beginning 1 h post-SCI. The Basso-Mouse Scale (BMS) was used to assess locomotor capability, where a BMS score of 0 indicates no movement of the hind limbs (observed 24 h following SCI) and a score of 9 indicates normal function (sham controls).

Results: Formoterol treatment induced MB in the injury and peri-injury sites post-SCI, as evidenced by increased mitochondrial DNA content and restoration of mitochondrial protein levels to that of sham controls. Drug-treated mice also exhibited less histological damage than vehicle-treated mice at 72 h post-SCI, namely decreased loss of white matter and structural preservation of the central canal and anterior median fissure. Importantly, following seven days of administration, the locomotor capability of formoterol-treated mice was greater than that of the vehicle-treated group (BMS = 1.2 v 0.5), and by fifteen days post-injury, formoterol-treated mice exhibited BMS scores twice that of vehicle-treated mice (BMS = 4 v 2). Finally, similar functional output was observed when initiation of treatment was delayed until 8 h post-injury.

Conclusion: Based on these data, we suggest β2-adrenoreceptor-mediated MB as a potential therapeutic avenue for the treatment of SCI.

Support: South Carolina Spinal Cord Injury Research Fund


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