CCL5 via GPX1 activation protects hippocampal memory function after mild traumatic brain injury
Man-Hau Ho,
Chia-Hung Yen,
Tsung-Hsun Hsieh,
Tzu-Jen Kao,
Jing-Yuan Chiu,
Yung-Hsiao Chiang,
Barry J. Hoffer,
Wen-Chang Chang,
Szu-Yi Chou
Affiliations
Man-Hau Ho
Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research, Taiwan; Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Department of Biological Science and Technology, National Pingtung University of Science and Technology, Neipu, Pingtung, 91201, Taiwan
Chia-Hung Yen
Department of Biological Science and Technology, National Pingtung University of Science and Technology, Neipu, Pingtung, 91201, Taiwan
Tsung-Hsun Hsieh
School of Physical Therapy and Graduate Institute of Rehabilitation Science, Chang Gung University, Taoyuan, Taiwan; Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
Tzu-Jen Kao
Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research, Taiwan; Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
Jing-Yuan Chiu
Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
Yung-Hsiao Chiang
Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, 11031, Taiwan; Department of Neurosurgery, Taipei Medical University Hospital, Taipei, 11031, Taiwan; Neuroscience Research Center, Taipei Medical University, Taipei, 11031, Taiwan
Barry J. Hoffer
Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research, Taiwan; Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Neuroscience Research Center, Taipei Medical University, Taipei, 11031, Taiwan; Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Scientist Emeritus, National Institutes of Health, USA
Wen-Chang Chang
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan
Szu-Yi Chou
Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research, Taiwan; Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Corresponding author. Ph.D. Program for Neural Regenerative Medicine, Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Xing Street, Taipei City, 110, Taiwan.
Traumatic brain injury (TBI) is a prevalent head injury worldwide which increases the risk of neurodegenerative diseases. Increased reactive oxygen species (ROS) and inflammatory chemokines after TBI induces secondary effects which damage neurons. Targeting NADPH oxidase or increasing redox systems are ways to reduce ROS and damage. Earlier studies show that C–C motif chemokine ligand 5 (CCL5) has neurotrophic functions such as promoting neurite outgrowth as well as reducing apoptosis. Although CCL5 levels in blood are associated with severity in TBI patients, the function of CCL5 after brain injury is unclear. In the current study, we induced mild brain injury in C57BL/6 (wildtype, WT) mice and CCL5 knockout (CCL5-KO) mice using a weight-drop model. Cognitive and memory functions in mice were analyzed by Novel-object-recognition and Barnes Maze tests. The memory performance of both WT and KO mice were impaired after mild injury. Cognition and memory function in WT mice quickly recovered after 7 days but recovery took more than 14 days in CCL5-KO mice. FJC, NeuN and Hypoxyprobe staining revealed large numbers of neurons damaged by oxidative stress in CCL5-KO mice after mTBI. NADPH oxidase activity show increased ROS generation together with reduced glutathione peroxidase-1 (GPX1) and glutathione (GSH) activity in CCL5-KO mice; this was opposite to that seen in WT mice. CCL5 increased GPX1 expression and reduced intracellular ROS levels which subsequently increased cell survival both in primary neuron cultures and in an overexpression model using SHSY5Y cell. Memory impairment in CCL5-KO mice induced by TBI could be rescued by i.p. injection of the GSH precursor – N-acetylcysteine (NAC) or intranasal delivery of recombinant CCL5 into mice after injury. We conclude that CCL5 is an important molecule for GPX1 antioxidant activation during post-injury day 1–3, and protects hippocampal neurons from ROS as well as improves memory function after trauma.
