title: Glucose-Dependent Insulinotropic Polypeptide Ameliorates Mild Traumatic Brain Injury-Induced Cognitive and Sensorimotor Deficits and Neuroinflammation in Rats.
abstract: Mild traumatic brain injury (mTBI) is a major public health issue, representing 75-90% of all cases of TBI. In clinical settings, mTBI, which is defined as a Glascow Coma Scale (GCS) score of 13-15, can lead to various physical, cognitive, emotional, and psychological-related symptoms. To date, there are no pharmaceutical-based therapies to manage the development of the pathological deficits associated with mTBI. In this study, the neurotrophic and neuroprotective properties of glucose-dependent insulinotropic polypeptide (GIP), an incretin similar to glucagon-like peptide-1 (GLP-1), was investigated after its steady-state subcutaneous administration, focusing on behavior after mTBI in an in vivo animal model. The mTBI rat model was generated by a mild controlled cortical impact (mCCI) and used to evaluate the therapeutic potential of GIP. We used the Morris water maze and novel object recognition tests, which are tasks for spatial and recognition memory, respectively, to identify the putative therapeutic effects of GIP on cognitive function. Further, beam walking and the adhesive removal tests were used to evaluate locomotor activity and somatosensory functions in rats with and without GIP administration after mCCI lesion. Lastly, we used immunohistochemical (IHC) staining and Western blot analyses to evaluate the inflammatory markers, glial fibrillary acidic protein (GFAP), amyloid-β precursor protein (APP), and bone marrow tyrosine kinase gene in chromosome X (BMX) in animals with mTBI. GIP was well tolerated and ameliorated mTBI-induced memory impairments, poor balance, and sensorimotor deficits after initiation in the post-injury period. In addition, GIP mitigated mTBI-induced neuroinflammatory changes on GFAP, APP, and BMX protein levels. These findings suggest GIP has significant benefits in managing mTBI-related symptoms and represents a novel strategy for mTBI treatment.
authors.affiliation: 1 PhD Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes , Taipei, Taiwan .
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Yu
authors.affiliation: 1 PhD Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes , Taipei, Taiwan .|2 Center for Neurotrauma and Neuroregeneration, Taipei Medical University , Taipei, Taiwan .|3 Department of Physical Therapy and Graduate Institute of Rehabilitation Science, College of Medicine, Chang Gung University , Taoyuan, Taiwan .
authors.forename: Tsung-Hsun
authors.initials: TH
authors.lastname: Hsieh
authors.affiliation: 1 PhD Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes , Taipei, Taiwan .|2 Center for Neurotrauma and Neuroregeneration, Taipei Medical University , Taipei, Taiwan .
authors.forename: Kai-Yun
authors.initials: KY
authors.lastname: Chen
authors.affiliation: 4 Department of Surgery, College of Medicine, Taipei Medical University , Taipei, Taiwan .
authors.forename: John Chung-Che
authors.initials: JC
authors.lastname: Wu
authors.affiliation: 1 PhD Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes , Taipei, Taiwan .|5 Department of Neurosurgery, Case Western Reserve University , School of Medicine, Cleveland, Ohio.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Hoffer
authors.affiliation: 6 Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health , Baltimore, Maryland.
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.affiliation: 6 Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health , Baltimore, Maryland.
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Li
authors.affiliation: 2 Center for Neurotrauma and Neuroregeneration, Taipei Medical University , Taipei, Taiwan .|4 Department of Surgery, College of Medicine, Taipei Medical University , Taipei, Taiwan .
authors.forename: Jing-Huei
authors.initials: JH
authors.lastname: Lai
authors.affiliation: 4 Department of Surgery, College of Medicine, Taipei Medical University , Taipei, Taiwan .
authors.forename: Cheng-Fu
authors.initials: CF
authors.lastname: Chang
authors.affiliation: 4 Department of Surgery, College of Medicine, Taipei Medical University , Taipei, Taiwan .
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Lin
authors.affiliation: 7 Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan .|8 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University , Taipei, Taiwan .
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Chen
authors.affiliation: 7 Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan .|9 Research Center for Biomedical Devices and Prototyping Production, Taipei Medical University , Taipei, Taiwan .|11 School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan .
authors.forename: Liang-Yo
authors.initials: LY
authors.lastname: Yang
authors.affiliation: 1 PhD Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes , Taipei, Taiwan .|2 Center for Neurotrauma and Neuroregeneration, Taipei Medical University , Taipei, Taiwan .|4 Department of Surgery, College of Medicine, Taipei Medical University , Taipei, Taiwan .|10 Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan .
authors.forename: Yung-Hsiao
authors.initials: YH
authors.lastname: Chiang
mesh_terms: D000818:Animals; D001924:Brain Concussion / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D005749:Gastric Inhibitory Polypeptide / Q000008:administration & dosage*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007279:Injections, Subcutaneous; D008297:Male; D011597:Psychomotor Performance / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018836:Inflammation Mediators; D005749:Gastric Inhibitory Polypeptide
keywords: BMX; GFAP; amyloid-β precursor protein; cognitive dysfunction; controlled cortical impact; glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; mild traumatic brain injury; neuroinflammation