Abstract
SummaryMoment‐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−1 day−1, 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).
Highlights
Normal functioning of the central nervous system (CNS) requires a continuous, tightly controlled supply of oxygen and nutrients as well as washout of harmful metabolites through uninterrupted cerebral blood flow (CBF)
On the basis of these findings, we proposed that novel therapeutic interventions should be developed to rescue functional hyperemia in elderly patients to prevent/delay cognitive impairment (Toth et al, 2014)
We found that a 14-day treatment with SS–31 significantly increased CBF responses induced by contralateral whisker stimulation in aged mice, restoring neurovascular coupling to levels observed in young mice (Figure 1)
Summary
Normal functioning of the central nervous system (CNS) requires a continuous, tightly controlled supply of oxygen and nutrients as well as washout of harmful metabolites through uninterrupted cerebral blood flow (CBF). Neurovascular coupling responses are impaired both in elderly patients (Fabiani et al, 2013; Stefanova et al, 2013; Topcuoglu, Aydin & Saka, 2009; Zaletel, Strucl, Pretnar-Oblak & Zvan, 2005) and aged laboratory animals (Park, Anrather, Girouard, Zhou & Iadecola, 2007; Toth et al, 2014), which likely contributes significantly to the progressive age-related decline in higher cortical function, including cognition (Sorond, Hurwitz, Salat, Greve & Fisher, 2013) and gait coordination (Sorond et al, 2011). This study was designed to test the hypothesis that pharmacological attenuation of mtROS can restore cerebromicrovascular endothelial function and improve neurovascular coupling in aged mice To achieve this goal, in aged mice mitochondrial oxidative stress was manipulated by treatment with the mitochondrial-targeted Szeto-Schiller (SS) peptide SS–31. To substantiate the in vivo findings, the effects of SS–31 on mitochondrial ROS production and mitochondrial respiration in cerebromicrovascular endothelial cells derived from aged animals were obtained in vitro
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
