Drug Design, Development and Therapy (Mar 2021)
Edaravone Alleviated Propofol-Induced Neurotoxicity in Developing Hippocampus by mBDNF/TrkB/PI3K Pathway
Abstract
Yangliang Yang, Jing Yi, Mengzhi Pan, Baoji Hu, Hongwei Duan Department of Anesthesiology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of ChinaCorrespondence: Hongwei DuanDepartment of Anesthesiology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, No. 2800 Gongwei Road, Shanghai, 201399, People’s Republic of ChinaEmail [email protected]: To investigate the neuroprotective effect of edaravone on excessive-dose propofol-induced neurotoxicity in the hippocampus of newborn rats and HT22 cells.Methods: Cell proliferation was investigated by assessing ki67 expression in the neural stem of the hippocampus of newborn rats and by cell counting kit-8 (CCK8) assay in HT22 cells. Cell apoptosis was assessed in vivo by caspase 3 detection in Western blots and measurement of apoptosis in neurons and glial cells by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Apoptosis was analyzed by flow cytometry in HT22 cells. The Morris water maze was used to evaluate the long-term learning and memory ability of rats. Inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). The expression of mBDNF/TrkB/PI3K pathway-related proteins was detected by Western blot and quantitative reverse transcription-polymerase chain reaction (q-RT PCR).Results: In neonatal rat hippocampus and HT22 cells, edaravone increased cell proliferation and decreased cell apoptosis after excessive propofol-induced neurotoxicity. In addition, the levels of proinflammatory factors interleukin (IL)-6 and tumor necrosis factor (TNF)-α were reduced by edaravone pretreatment. The use of the tropomyosin receptor kinase B (TrkB) antagonist ANA-12 and TrkB agonist 7,8DHF with propofol groups showed that edaravone mitigated excessive propofol-induced neurotoxicity through the mature brain-derived neurotrophic factor (mBDNF)/TrkB/phosphoinositide 3-kinase (PI3K) pathway. However, the current dose of propofol did not significantly affect long-term learning and memory in rats.Conclusion: Edaravone pretreatment ameliorated propofol-induced proliferation inhibition, neuroapoptosis, and neural inflammation by activating the mBDNF/TrkB/PI3K pathway.Keywords: edaravone, propofol, hippocampus, the brain-derived neurotrophic factor, BDNF, the tyrosine kinase receptor B, TrkB, 7,8-dihydroxyflavone, 7,8-DHF, ANA-12
