Formoterol, a β2-adrenoreceptor agonist, induces mitochondrial biogenesis and promotes cognitive recovery after traumatic brain injury
Formoterol, a β2-adrenoreceptor agonist, induces mitochondrial biogenesis and promotes cognitive recovery after traumatic brain injury
复制标题
DOI：
10.1016/j.nbd.2020.104866
复制
发表时间：
2020-07-01
影响因子：
6.1
通讯作者：
Sullivan, Patrick G.
中科院分区：
文献类型：
--
作者：
Vekaria, Hemendra J.;Hubbard, W. Brad;Sullivan, Patrick G.
创伤性脑损伤 (TBI) 会导致受伤部位急性坏死，随后发生一系列持续数小时至数周甚至数年的继发事件。针对 TBI 后的线粒体损伤已显示出脑线粒体生物能学和神经元功能的改善。最近发现福莫特罗是一种高选择性 β(2)-肾上腺素受体激动剂，可通过 G beta gamma-Akt-eNOS-sGC 途径诱导线粒体生物合成 (MB)。 MB 的激活是一种新方法，已被证明可以在多种疾病和损伤模型中恢复线粒体功能。我们假设 TBI 后激活 MB 作为福莫特罗的靶点可以减轻线粒体功能障碍，增强神经元功能并改善行为结果。 TBI 损伤的 C57BL/6 雄性小鼠在 15 分钟、8 小时、16 小时、24 小时时（腹腔注射）媒介物（生理盐水）或福莫特罗（0.3 mg/kg），然后在控制皮质冲击（CCI）后每天注射，直至安乐死。 CCI 后，CCI 载体组同侧皮层的线粒体拷贝数和生物能功能下降。与 CCI 载体相比，CCI 福莫特罗组的皮质和海马线粒体呼吸速率以及皮质线粒体 DNA 拷贝数均增加。与 CCI 载体组相比，CCI 福莫特罗组海马线粒体 Ca2+ 缓冲能力更高。 CCI 后认知表现、新物体识别 (NOR) 和莫里斯水迷宫 (MWM) 的两项评估均有所下降，而 CCI-福莫特罗组则恢复。尽管CCI-福莫特罗组和CCI-载体组之间保留的皮质组织数量没有变化，但在CCI-福莫特罗组中观察到海马神经元水平升高和胼胝体白质保留改善。总的来说，这些结果表明福莫特罗介导的 MB 激活可能是恢复线粒体生物能并促进 TBI 后功能恢复的潜在治疗靶点。
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 beta(2)-adrenoreceptor agonist, was found to induce mitochondrial biogenesis (MB) via G beta gamma-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.