title: Melatonin attenuates neuronal apoptosis through up-regulation of K(+) -Cl(-) cotransporter KCC2 expression following traumatic brain injury in rats.
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(+) -Cl(-) cotransporter-2 (KCC2), the principal Cl(-) extruder in adult neurons, plays an important role in Cl(-) homeostasis and neuronal function. This present study was designed to investigate the expression pattern of KCC2 following TBI and to evaluate whether or not melatonin is able to prevent neuronal apoptosis by modulating KCC2 expression in a Sprague Dawley rat controlled cortical impact model of TBI. The time course study showed decreased mRNA and protein expression of KCC2 in the ipsilateral peri-core parietal cortex after TBI. Double immunofluorescence staining demonstrated that KCC2 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 KCC2 expression in both mRNA 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 KCC2 expression, inhibits neuronal apoptosis and attenuates secondary brain injury after TBI, partially through activation of BDNF/ERK pathway.
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.|Department of Neurosurgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Haijian
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Anwen
authors.initials: A
authors.lastname: Shao
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Mingfei
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liang
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Ligen
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Dixon
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Chenhan
authors.initials: C
authors.lastname: Ling
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.|Brain Research Institute, Zhejiang University, Hangzhou, Zhejiang, China.|Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000070642:Brain Injuries, Traumatic / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects*; D000096922:K Cl- Cotransporters
chemical_list: D008550:Melatonin; D027981:Symporters; D000096922:K Cl- Cotransporters
keywords: K+-Cl− cotransporter-2; melatonin; neuronal apoptosis; neuroprotection; traumatic brain injury