Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Translational Geroscience Laboratory, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Aging Cell. 2018 Apr;17(2). doi: 10.1111/acel.12731. Epub 2018 Feb 6.
Moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling has an essential role in maintenance of healthy cognitive function. In advanced age, increased oxidative stress and cerebromicrovascular endothelial dysfunction impair neurovascular coupling, likely contributing to age-related decline of higher cortical functions. There is increasing evidence showing that mitochondrial oxidative stress plays a critical role in a range of age-related cellular impairments, but its role in neurovascular uncoupling remains unexplored. This study was designed to test the hypothesis that attenuation of mitochondrial oxidative stress may exert beneficial effects on neurovascular coupling responses in aging. To test this hypothesis, 24-month-old C57BL/6 mice were treated with a cell-permeable, mitochondria-targeted antioxidant peptide (SS-31; 10 mg kg day , i.p.) or vehicle for 2 weeks. Neurovascular coupling was assessed by measuring CBF responses (laser speckle contrast imaging) evoked by contralateral whisker stimulation. We found that neurovascular coupling responses were significantly impaired in aged mice. Treatment with SS-31 significantly improved neurovascular coupling responses by increasing NO-mediated cerebromicrovascular dilation, which was associated with significantly improved spatial working memory, motor skill learning, and gait coordination. These findings are paralleled by the protective effects of SS-31 on mitochondrial production of reactive oxygen species and mitochondrial respiration in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, mitochondrial oxidative stress contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. We propose that mitochondria-targeted antioxidants may be considered for pharmacological microvascular protection for the prevention/treatment of age-related vascular cognitive impairment (VCI).
通过神经血管耦合实现的脑血流（CBF）的即时调整在维持健康的认知功能方面起着至关重要的作用。在老年时期，氧化应激增加和脑微血管内皮功能障碍会损害神经血管耦合，可能导致与年龄相关的高级皮质功能下降。越来越多的证据表明，线粒体氧化应激在一系列与年龄相关的细胞损伤中起着关键作用，但它在神经血管解偶联中的作用仍未得到探索。本研究旨在测试以下假设：减轻线粒体氧化应激可能对衰老过程中的神经血管耦合反应产生有益影响。为了验证这一假设，我们用一种细胞穿透性、靶向线粒体的抗氧化肽（SS-31；10mg/kg/day，腹腔注射）或载体处理 24 个月大的 C57BL/6 小鼠 2 周。通过测量对侧胡须刺激引起的 CBF 反应（激光散斑对比成像）来评估神经血管耦合。我们发现，神经血管耦合反应在老年小鼠中显著受损。用 SS-31 治疗可显著改善神经血管耦合反应，增加一氧化氮介导的脑微血管扩张，这与空间工作记忆、运动技能学习和步态协调能力的显著改善有关。SS-31 对培养的来自老年动物的脑微血管内皮细胞中线粒体产生的活性氧和线粒体呼吸的保护作用与这些发现相平行。因此，线粒体氧化应激导致与年龄相关的脑微血管功能障碍，加剧认知能力下降。我们提出，靶向线粒体的抗氧化剂可被考虑用于药理学微血管保护，以预防/治疗与年龄相关的血管性认知障碍（VCI）。
