Inhibiting Histone Deacetylase 2 (HDAC2) Promotes Functional Recovery From Stroke

Autor: Yu-Hui Lin, Hai-Yin Wu, Yu Zhang, Hong-Jin Yuan, Chun-Xia Luo, Hai-Ying Liang, Ying Tang, Qi-Gang Zhou, Dong-Ya Zhu, Jian Dong, Meng-Cheng Yao, Huan-Yu Ni, Lei Chang
Rok vydání: 2017
Předmět:
0301 basic medicine
Male
Time Factors
functional recovery
medicine.medical_treatment
Pharmacology
Hydroxamic Acids
Epigenesis
Genetic
0302 clinical medicine
Conditional gene knockout
Mechanisms
Stroke
Original Research
Mice
Knockout
Neurons
Vorinostat
Neuronal Plasticity
Histone deacetylase 2
Histone deacetylase inhibitor
Brain
Cardiology and Cardiovascular Medicine
Stroke recovery
medicine.drug
medicine.medical_specialty
medicine.drug_class
histone deacetylase 2
Motor Activity
03 medical and health sciences
Physical medicine and rehabilitation
Neuroplasticity
medicine
Animals
cardiovascular diseases
histone deacetylase inhibitor
Ischemic Stroke
epigenetics
business.industry
Recovery of Function
medicine.disease
HDAC1
Histone Deacetylase Inhibitors
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Trichostatin A
Animal Models of Human Disease
business
030217 neurology & neurosurgery
Basic Science Research
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
Popis: Background Stroke is a leading cause of long‐term disability worldwide. However, current therapies that promote functional recovery from stroke are limited to physical rehabilitation. No pharmacological therapy is available. Thus, understanding the role of histone deacetylase 2 (HDAC2) in the pathophysiological process of stroke‐induced functional loss may provide a novel strategy for stroke recovery. Methods and Results Focal stroke was induced by photothrombosis. LV‐HDAC2‐shRNA‐GFP, LV‐GFP, Ad‐HDAC2‐Flag, or Ad‐inactive‐HDAC2‐Flag was microinjected into the peri‐infarct area immediately after stroke. HDAC inhibitors were microinjected into the peri‐infarct area 4 to 10 days after stroke. Grid‐walking task and cylinder task were conducted to assess motor function. Golgi‐Cox staining, chromatin immunoprecipitation, and electrophysiology were used to reveal the mechanisms underlying stroke recovery. Knockdown or knockout of HDAC2 promoted stroke recovery, whereas overexpression of HDAC2 worsened stroke‐induced functional impairment. More importantly, trichostatin A, a pan‐HDAC inhibitor, promoted functional recovery from stroke in WT mice when used in the delayed phase, but it was ineffective in Hdac2 conditional knockout ( Hdac2 CKO) mice. Treatment with suberoylanilide hydroxamic acid, a selective HDAC1 and HDAC2 inhibitor, in the delayed phase of stroke produced sustained functional recovery in mice via epigenetically enhancing neuroplasticity of surviving neurons in the peri‐infarct zone. Conclusions Our novel findings provide evidence that HDAC2 is a crucial target for functional recovery from stroke. As there are clinically available HDAC inhibitors, our findings could be directly translated into clinical research of stroke.
Databáze: OpenAIRE
Externí odkaz: