Pharmacological Stimulation of Mitochondrial Biogenesis Using the Food and Drug Administration-Approved 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 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 b 2-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-1a, in the injury and peri-injury sites as early as 3 days post-injury. Formoterol treatment attenuated this decrease in PGC-1a, 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.

The acute effect of dopamine infusion on lipid and cytokine concentrations in persons with a cervical spinal cord injury—a pilot study

“…While not directly investigated in the present study, the increase in markers of lipid metabolism observed in CSCI suggests that peripheral dopaminergic and adrenergic signalling pathways remain intact following a spinal injury or undergo adjustments to compensate for the lack of intact sympathetic control. Studies investigating the vasculature and skeletal muscle tissue following SCI partially corroborate this suggestion, with a similar vasoconstrictive response to infusion of an αadrenergic agonist in people with SCI compared with AB persons [24] and a maintained responsiveness to β-adrenergic agonists as evidenced by skeletal muscle hypertrophy after formoterol treatment in mice with SCI [25]. Moreover, a larger increase in blood pressure following noradrenaline administration in persons with CSCI (when compared with able-bodied individuals) has been reported, potentially resulting from hypersensitivity of α-adrenergic receptors in the vasculature [10].…”

Ketogenesis controls mitochondrial gene expression and rescues mitochondrial bioenergetics after cervical spinal cord injury in rats

“…The implications of this compensation, and if this increase in mRNA is truly translated into protein stills to be determined. In regards to a proposed increase in mitochondrial biogenesis by KD, KD increases mitochondrial mass in other neurological disorders such as epilepsy 64 and ischemic stroke 65 ; and recent publications highlight how mitochondrial biogenesis could be a potential pharmaceutical target to treat SCI 66,67 . VDAC1 has also been linked to an increase in the transcription of multiple ETS complexes by interacting with TOM20, a component of the receptor complex responsible for the recognition and translocation of cytosolically synthesized mitochondrial pre-proteins or enzymes required to promote the activation of the transcriptional machinery of the mitochondria 68 .…”

The Integrated Transcriptome Bioinformatics Analysis Identifies Key Genes and Cellular Components for Spinal Cord Injury-Related Neuropathic Pain

“…Treatment with the ADRB2 agonist can enhance the recovery in rats post-SCI (Zeman et al, 1999;Zeman et al, 2006;Brown et al, 2014). Scholpa et al (2019) performed using an FDA-approved compound with the ability to be repurposed, reinforcing the potential clinical applicability of their findings and demonstrating the pharmacological activation of ADRB2 receptor for the treatment of SCI. However, it seemed no previous studies that reported the association between PECAM1/LRP1 and SCI.…”