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Melatonin attenuates neuronal apoptosis through up‐regulation of K + – C l − cotransporter KCC 2 expression following traumatic brain injury in rats
Author(s) -
Wu Haijian,
Shao Anwen,
Zhao Mingfei,
Chen Sheng,
Yu Jun,
Zhou Jingyi,
Liang Feng,
Shi Ligen,
Dixon Brandon J.,
Wang Zhen,
Ling Chenhan,
Hong Yuan,
Zhang Jianmin
Publication year - 2016
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12344
Subject(s) - melatonin , traumatic brain injury , endocrinology , medicine , apoptosis , neurotrophic factors , biology , receptor , biochemistry , psychiatry
Abstract Traumatic brain injury ( TBI ) initiates a complex cascade of neurochemical and signaling changes that leads to neuronal apoptosis, which contributes to poor outcomes for patients with TBI . The neuron‐specific K + – C l − cotransporter‐2 ( KCC 2), the principal C l − extruder in adult neurons, plays an important role in C l − homeostasis and neuronal function. This present study was designed to investigate the expression pattern of KCC 2 following TBI and to evaluate whether or not melatonin is able to prevent neuronal apoptosis by modulating KCC 2 expression in a S prague D awley rat controlled cortical impact model of TBI . The time course study showed decreased m RNA and protein expression of KCC 2 in the ipsilateral peri‐core parietal cortex after TBI . Double immunofluorescence staining demonstrated that KCC 2 is located in the plasma membrane of neurons. In addition, melatonin (10 mg/kg) was injected intraperitoneally at 5 minutes and repeated at 1, 2, 3, and 4 hours after brain trauma, and brain samples were extracted 24 hours after TBI . Compared to the vehicle group, melatonin treatment altered the down‐regulation of KCC 2 expression in both m RNA and protein levels after TBI . Also, melatonin treatment increased the protein levels of brain‐derived neurotrophic factor ( BDNF ) and phosphorylated extracellular signal‐regulated kinase (p‐ ERK ). Simultaneously, melatonin administration ameliorated cortical neuronal apoptosis, reduced brain edema, and attenuated neurological deficits after TBI . In conclusion, our findings suggested that melatonin restores KCC 2 expression, inhibits neuronal apoptosis and attenuates secondary brain injury after TBI , partially through activation of BDNF / ERK pathway.