Enhancement of Autophagy by Histone Deacetylase Inhibitor Trichostatin A Ameliorates Neuronal Apoptosis After Subarachnoid Hemorrhage in Rats.
Trichostatin A (TSA), a pan-histone deacetylase inhibitor, exerts multiple neuroprotective properties. This study aims to examine whether TSA could enhance autophagy, thereby reduce neuronal apoptosis and ultimately attenuate early brain injury (EBI) following subarachnoid hemorrhage (SAH). SAH was performed through endovascular perforation method, and mortality, neurological score, and brain water content were evaluated at 24 h after surgery. Western blot were used for quantification of acetylated histone H3, LC3-II, LC3-I, Beclin-1, cytochrome c, Bax, and cleaved caspase-3 expression. Immunofluorescence was performed for colocalization of Beclin-1 and neuronal nuclei (NeuN). Apoptotic cell death of neurons was quantified with double staining of terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL) and NeuN. The autophagy inhibitor 3-methyladenine (3-MA) was used to manipulate the proposed pathway. Our results demonstrated that TSA reduced brain edema and alleviated neurological deficits at 24 h after SAH. TSA significantly increased acetylated histone H3, the LC3-II/LC3-I ratio, and Beclin-1 while decreased Bax and cleaved caspase-3 in the cortex. Beclin-1 and NeuN, TUNEL, and NeuN, respectively, were colocalized in cortical cells. Neuronal apoptosis in the ipsilateral basal cortex was significantly inhibited after TSA treatment. Conversely, 3-MA reversed the beneficial effects of TSA. These results proposed that TSA administration enhanced autophagy, which contributes to alleviation of neuronal apoptosis, improvement of neurological function, and attenuation of EBI following SAH.
Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
Anwen
A
Shao
Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
Zhen
Z
Wang
Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
Haijian
H
Wu
Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
Xiao
X
Dong
Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
Yong
Y
Li
Department of Thoracic Oncology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
Sheng
S
Tu
Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
Junjia
J
Tang
Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
Mingfei
M
Zhao
Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China. zjm153vip@sina.com.
Jianmin
J
Zhang
Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China. hy0904@live.cn.
Yuan
Y
Hong
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001930:Brain Injuries / Q000188:drug therapy; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A
Apoptosis; Autophagy; Histone deacetylase inhibition; Subarachnoid hemorrhage; Trichostatin A