Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice

Stefano Tarantini, Noa M. Valcarcel-Ares, Andriy Yabluchanskiy, Gabor A. Fulop, Peter Hertelendy, Tripti Gautam, E. Farkas, Aleksandra Perz, Peter S. Rabinovitch, William E. Sonntag, Anna Csiszar, Zoltan Ungvari

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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−1day−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).

Original languageEnglish
Article numbere12731
JournalAging Cell
Volume17
Issue number2
DOIs
Publication statusPublished - Apr 1 2018

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Cognition
Antioxidants
Cerebrovascular Circulation
Oxidative Stress
Mitochondria
Social Adjustment
Vibrissae
Motor Skills
Gait
Inbred C57BL Mouse
Short-Term Memory
Blood Vessels
arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide
Neurovascular Coupling
Dilatation
Reactive Oxygen Species
Respiration
Lasers
Endothelial Cells
Maintenance

Keywords

  • aging
  • cerebral circulation
  • endothelial dysfunction
  • oxidative stress
  • vascular cognitive impairment

ASJC Scopus subject areas

  • Ageing
  • Cell Biology

Cite this

Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice. / Tarantini, Stefano; Valcarcel-Ares, Noa M.; Yabluchanskiy, Andriy; Fulop, Gabor A.; Hertelendy, Peter; Gautam, Tripti; Farkas, E.; Perz, Aleksandra; Rabinovitch, Peter S.; Sonntag, William E.; Csiszar, Anna; Ungvari, Zoltan.

In: Aging Cell, Vol. 17, No. 2, e12731, 01.04.2018.

Research output: Contribution to journalArticle

Tarantini, S, Valcarcel-Ares, NM, Yabluchanskiy, A, Fulop, GA, Hertelendy, P, Gautam, T, Farkas, E, Perz, A, Rabinovitch, PS, Sonntag, WE, Csiszar, A & Ungvari, Z 2018, 'Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice', Aging Cell, vol. 17, no. 2, e12731. https://doi.org/10.1111/acel.12731
Tarantini, Stefano ; Valcarcel-Ares, Noa M. ; Yabluchanskiy, Andriy ; Fulop, Gabor A. ; Hertelendy, Peter ; Gautam, Tripti ; Farkas, E. ; Perz, Aleksandra ; Rabinovitch, Peter S. ; Sonntag, William E. ; Csiszar, Anna ; Ungvari, Zoltan. / Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice. In: Aging Cell. 2018 ; Vol. 17, No. 2.
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