Treatment with the Mitochondrial‐targeted Antioxidant Peptide SS‐31 Improves Cerebromicrovascular Function in Aged Mice

Abstract

Moment‐to‐moment adjustment of cerebral blood flow (CBF) via neurovascular coupling has a critical 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. The present study was designed to test the hypothesis that attenuation of mitochondrial oxidative stress may exert beneficial effects on neurovascular coupling 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, s.c.) or vehicle for 2 weeks. Neurovascular coupling was assessed by measuring CBF responses (laser Doppler flowmetry) and evoked field potentials in the somatosensory cortex evoked by contralateral electric whisker pad stimulation. We found that neurovascular coupling responses and ATP‐induced endothelium‐dependent CBF responses were significantly impaired in aged mice. Treatment with SS‐31 significantly improved neurovascular coupling responses, at least in part, by increasing NO‐mediated cerebromicrovascular dilation. These findings are paralleled by the protective effects of SS‐31 on mitochondrial production of reactive oxygen species in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, mitochondrial oxidative stress contributes to age‐related cerebromicovascular dysfunction. We propose that the antioxidant peptide SS‐31 should be considered for pharmacological microvascular protection for the prevention/treatments of age‐related diseases of the CNS.Support or Funding InformationThis work was supported by grants from the American Heart Association and the National Institute on Aging.