title: Neuroprotective role of an N-acetyl serotonin derivative via activation of tropomyosin-related kinase receptor B after subarachnoid hemorrhage in a rat model.
abstract: N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC), an N-acetyl serotonin derivative, selectively activates tropomyosin-related kinase receptor B (TrkB). This study is to investigate a potential role of HIOC on ameliorating early brain injury after experimental subarachnoid hemorrhage (SAH). One hundred and fifty-six adult male Sprague-Dawley rats were used. SAH model was induced by endovascular perforation. TrkB small interfering RNA (siRNA) or scramble siRNA was injected intracerebroventricularly 24h before SAH. HIOC was administrated intracerebroventricularly 3h after SAH and compared with brain-derived neurotrophic factor (BDNF). SAH grade and neurologic scores were evaluated for the outcome study. For the mechanism study, the expression of TrkB, phosphorylated TrkB (p-TrkB), phosphorylated extracellular signal regulated kinase (p-ERK), B-cell lymphoma 2 (Bcl-2) and cleaved caspase 3 (CC3) was detected by Western blots, and neuronal injury was determined by double immunofluorescence staining of neuronal nuclei and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling. Knocking down of TrkB decreased the expression of Bcl-2 and aggravated neurologic deficits 24h after SAH. HIOC activated TrkB/ERK pathway, decreased neuronal cell death, and improved neurobehavioral outcome, and these effects were abolished by TrkB siRNA. HIOC was more potent than BDNF in reduction of apoptosis 24h post-SAH. Thus, we conclude that administration of HIOC activated TrkB/ERK signaling cascade and attenuated early brain injury after SAH. HIOC may be a promising agent for further treatment for SAH and other stroke events.
authors: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Departments of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA.
authors: Junjia
authors: J
authors: Tang
authors: Departments of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA.
authors: Qin
authors: Q
authors: Hu
authors: Departments of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA.
authors: Yujie
authors: Y
authors: Chen
authors: Departments of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA.
authors: Fei
authors: F
authors: Liu
authors: Departments of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA.
authors: Yun
authors: Y
authors: Zheng
authors: Departments of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA.
authors: Jiping
authors: J
authors: Tang
authors: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: zjm135@vip.sina.com.
authors: Jianmin
authors: J
authors: Zhang
authors: Departments of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA. Electronic address: johnzhang3910@yahoo.com.
authors: John H
authors: JH
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004195:Disease Models, Animal; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000819:agonists / Q000378:metabolism*; D012701:Serotonin / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D013345:Subarachnoid Hemorrhage / Q000378:metabolism* / Q000517:prevention & control*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D012701:Serotonin; D020813:Receptor, trkB
keywords: Apoptosis; Brain-derived neurotrophic factor; Early brain injury; N-acetyl serotonin derivative; Subarachnoid hemorrhage; Tropomyosin-related kinase receptor B