Ketone bodies promote stroke recovery via GAT-1-dependent cortical network remodeling
Yu-Hui Lin,
Di Yang,
Huan-Yu Ni,
Xiu-Mei Xu,
Feng Wu,
Long Lin,
Jie Chen,
Yan-Yu Sun,
Zhen-Quan Huang,
Shi-Yi Li,
Pei-Lin Jiang,
Hai-Yin Wu,
Lei Chang,
Bo Hu,
Chun-Xia Luo,
Jin Wu,
Dong-Ya Zhu
Affiliations
Yu-Hui Lin
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China; Corresponding author
Di Yang
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
Huan-Yu Ni
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
Xiu-Mei Xu
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
Feng Wu
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
Long Lin
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
Jie Chen
Department of Neurology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
Yan-Yu Sun
Department of Neurology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
Zhen-Quan Huang
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
Shi-Yi Li
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
Pei-Lin Jiang
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
Hai-Yin Wu
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
Lei Chang
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
Bo Hu
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Chun-Xia Luo
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
Jin Wu
Department of Neurology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China; Corresponding author
Dong-Ya Zhu
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China; Institution of Stem Cells and Neuroregeneration, Nanjing Medical University, Nanjing 211166, China; Corresponding author
Summary: Stroke is a leading cause of adult disability worldwide, and better drugs are needed to promote functional recovery after stroke. Growing evidence suggests the critical role of network excitability during the repair phase for stroke recovery. Here, we show that β-hydroxybutyrate (β-HB), an essential ketone body (KB) component, is positively correlated with improved outcomes in patients with stroke and promotes functional recovery in rodents with stroke during the repair phase. These beneficial effects of β-HB depend on HDAC2/HDAC3-GABA transporter 1 (GAT-1) signaling-mediated enhancement of excitability and phasic GABA inhibition in the peri-infarct cortex and structural and functional plasticity in the ipsilateral cortex, the contralateral cortex, and the corticospinal tract. Together with available clinical approaches to elevate KB levels, our results offer a clinically translatable means to promote stroke recovery. Furthermore, GAT-1 can serve as a pharmacological target for developing drugs to promote functional recovery after stroke.
