Neuroprotective role of an N-acetyl serotonin derivative via activation of tropomyosin-related kinase receptor B after subarachnoid hemorrhage in a rat model

Junjia Tang, Qin Hu, Yujie Chen, Fei Liu, Yun Zheng, Jiping Tang, Jianmin Zhang, John H. Zhang

Research output: Contribution to journalArticlepeer-review

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 24. h before SAH. HIOC was administrated intracerebroventricularly 3. h 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 24. h 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 24. h 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.

Original languageEnglish
Pages (from-to)126-133
Number of pages8
JournalNeurobiology of Disease
Volume78
DOIs
StatePublished - Jun 1 2015

ASJC Scopus Subject Areas

  • Neurology

Keywords

  • Apoptosis
  • Brain-derived neurotrophic factor
  • Early brain injury
  • N-acetyl serotonin derivative
  • Subarachnoid hemorrhage
  • Tropomyosin-related kinase receptor B
  • Neuroprotective Agents/administration & dosage
  • Phosphorylation
  • Apoptosis/drug effects
  • Rats
  • Male
  • Rats, Sprague-Dawley
  • Subarachnoid Hemorrhage/metabolism
  • Serotonin/administration & dosage
  • Brain-Derived Neurotrophic Factor/metabolism
  • MAP Kinase Signaling System/drug effects
  • Animals
  • Neurons/metabolism
  • Proto-Oncogene Proteins c-bcl-2/metabolism
  • Receptor, trkB/agonists
  • Brain/metabolism
  • Disease Models, Animal

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