Treatment with the mitochondrial‐targeted antioxidant peptide <scp>SS</scp>‐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 et al.

Aging Cell • 2018

View Abstract

Summary 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 C57 BL /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 ).

Treatment with the mitochondrial‐targeted antioxidant peptide <scp>SS</scp>‐31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice

Gait Coordination Test

Equipment8

Materials7

Software1

Protocol Steps

Animal treatment initiation

SS-31 or vehicle administration

Neurovascular coupling assessment via laser speckle contrast imaging

Open cranial window preparation

Laser Doppler flowmetry measurement

L-NAME administration and CBF measurement

Middle cerebral artery isolation and cannulation

Acetylcholine-induced vasodilation assessment

ATP-induced vasodilation assessment

Sodium nitroprusside-induced vasodilation assessment

Cerebromicrovascular endothelial cell isolation and culture

Mitochondrial ROS measurement via MitoSox fluorescence

SS-31 treatment of cultured CMVECs

Oxygen consumption rate measurement

Cerebral cortex tissue collection

qPCR analysis of gene expression

Behavioral testing battery

Gait coordination assessment

Statistical analysis