Vekaria Hemendra J, Shelley Sarah J, Messmer Sarah J, Kunjadia Prashant D, McLouth Christopher J, Sullivan Patrick G, Fraser Justin F, Pennypacker Keith R, Pandya Chirayu D
Spinal Cord and Brain Injury Research Center (SCoBIRC), University of Kentucky, Lexington, KY 405036, USA.
Lexington Veterans Affairs Healthcare System, Lexington, KY 40502, USA.
Biomolecules. 2025 May 20;15(5):738. doi: 10.3390/biom15050738.
Oxidative stress due to increased reactive oxygen species (ROS) formation and/or inflammation is considered to play an important role in ischemic stroke injury. Leukemia inhibitory factor (LIF) has been shown to protect both oligodendrocytes and neurons from ischemia by upregulating endogenous anti-oxidants, though the effect of ischemia and the protective role of LIF treatment in mitochondrial function have not been studied. The goal of this study was to determine whether LIF protects ischemia-induced altered mitochondrial bioenergetics in reproductively senescent aged rats of both sexes (≥18 months old), approximately equivalent to the average age of human stroke patients. Animals were euthanized at 3 days after permanent middle cerebral artery occlusion (MCAO) surgery. We found that MCAO surgery significantly reduced mitochondrial oxidative phosphorylation in both the ipsilateral striatum and prefrontal cortex in male aged rats compared to their respective contralateral regions of the brain. MCAO injury showed mitochondrial bioenergetic dysfunction only in the striatum in female rats; however, the prefrontal cortex remained unaffected to the injury. LIF-treated rats significantly prevented mitochondrial dysfunction in the striatum in male rats compared to their vehicle-treated counterparts. Collectively, MCAO-induced mitochondrial dysfunction and LIF's potential as a therapeutic biomolecule exhibited sex- and tissue-specific effects, varying between the striatum and prefrontal cortex in male and female rats.
由于活性氧（ROS）生成增加和/或炎症导致的氧化应激被认为在缺血性脑卒中损伤中起重要作用。白血病抑制因子（LIF）已被证明可通过上调内源性抗氧化剂来保护少突胶质细胞和神经元免受缺血损伤，不过缺血的影响以及LIF治疗对线粒体功能的保护作用尚未得到研究。本研究的目的是确定LIF是否能保护两性生殖衰老的老年大鼠（≥18个月大），其年龄大致相当于人类中风患者的平均年龄，使其免受缺血诱导的线粒体生物能量学改变的影响。在永久性大脑中动脉闭塞（MCAO）手术后3天对动物实施安乐死。我们发现，与雄性老年大鼠大脑各自的对侧区域相比，MCAO手术显著降低了其同侧纹状体和前额叶皮质中的线粒体氧化磷酸化。MCAO损伤仅在雌性大鼠的纹状体中表现出线粒体生物能量功能障碍；然而，前额叶皮质未受该损伤影响。与接受载体治疗的雄性大鼠相比，接受LIF治疗的大鼠显著预防了纹状体中的线粒体功能障碍。总体而言，MCAO诱导的线粒体功能障碍以及LIF作为治疗性生物分子的潜力表现出性别和组织特异性效应，在雄性和雌性大鼠的纹状体和前额叶皮质之间存在差异。
