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 language | English |
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Pages (from-to) | 126-133 |
Number of pages | 8 |
Journal | Neurobiology of Disease |
Volume | 78 |
DOIs | |
State | Published - 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