Formoterol, a β2-adrenoreceptor agonist, induces mitochondrial biogenesis and promotes cognitive recovery after traumatic brain injury

Neurobiology of Disease

Malinda L. Spry¹  W. Brad Hubbard¹  Jennifer L. Gooch²  Rick G. Schnellmann³  Sydney J. Prince⁴  Natalie E. Scholpa⁵  Patrick G. Sullivan⁵  Hemendra J. Vekaria⁵ 

[1] Department of Neuroscience, University of Kentucky College of Medicine, Lexington, KY, USA;Lexington VA Health Care System, Lexington, KY, USA;SAVAHCS, Tucson, AZ, USA;Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA;Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky College of Medicine, Lexington, KY, USA;

关键词: Mitochondrial bioenergetics;    PGC1-α;    Novel object recognition;    Controlled cortical impact;    Calcium buffering;   

DOI  :  

来源: DOAJ

【 摘 要 】

Traumatic brain injury (TBI) leads to acute necrosis at the site of injury followed by a sequence of secondary events lasting from hours to weeks and often years. Targeting mitochondrial impairment following TBI has shown improvements in brain mitochondrial bioenergetics and neuronal function. Recently formoterol, a highly selective β2-adrenoreceptor agonist, was found to induce mitochondrial biogenesis (MB) via Gβγ-Akt-eNOS-sGC pathway. Activation of MB is a novel approach that has been shown to restore mitochondrial function in several disease and injury models. We hypothesized that activation of MB as a target of formoterol after TBI would mitigate mitochondrial dysfunction, enhance neuronal function and improve behavioral outcomes. TBI-injured C57BL/6 male mice were injected (i.p.) with vehicle (normal saline) or formoterol (0.3 mg/kg) at 15 min, 8 h, 16 h, 24 h and then daily after controlled cortical impact (CCI) until euthanasia. After CCI, mitochondrial copy number and bioenergetic function were decreased in the ipsilateral cortex of the CCI-vehicle group. Compared to CCI-vehicle, cortical and hippocampal mitochondrial respiration rates as well as cortical mitochondrial DNA copy number were increased in the CCI-formoterol group. Mitochondrial Ca2+ buffering capacity in the hippocampus was higher in the CCI-formoterol group compared to CCI-vehicle group. Both assessments of cognitive performance, novel object recognition (NOR) and Morris water maze (MWM), decreased following CCI and were restored in the CCI-formoterol group. Although no changes were seen in the amount of cortical tissue spared between CCI-formoterol and CCI-vehicle groups, elevated levels of hippocampal neurons and improved white matter sparing in the corpus callosum were observed in CCI-formoterol group. Collectively, these results indicate that formoterol-mediated MB activation may be a potential therapeutic target to restore mitochondrial bioenergetics and promote functional recovery after TBI.

【 授权许可】

Unknown