title: Repair of Neurological Function in Response to FK506 Through CaN/NFATc1 Pathway Following Traumatic Brain Injury in Rats.
abstract: Tacrolimus (FK506), an immunophilin ligand, has been widely shown to be neuroprotective in a posttraumatic period. The nuclear factor of activated T cells (NFATc1) pathway plays an important role in regenerating neurological function following traumatic brain injury (TBI), but the precise mechanism underlying FK506-induced repair of neurological functions remains unclear. In the present study, a total of 210 SD rats were enrolled and randomly divided into sham group, TBI group and FK506 group. The rats in the TBI and FK506 groups were inflicted with moderate TBI left lateral fluid percussion impact. A modified neurological severity score (mNSS) system was used to evaluate the severity of effects on nerve function. mNSS levels were significantly lower in the FK506 group than in the TBI group. The zaccumulation of cerebral water content was lower, cerebral Aquaporin 4 (AQP4) mRNA level was lower, the number of growth-associated protein-43 (GAP-43)-positive cells was higher, and the distribution of vesicles containing excitatory neurotransmitters was altered in the injured cortex in the FK506 group. Moreover, the cortical mRNA and serum protein expression levels of interleukin-2 (IL-2) and interferon-γ (IFN-γ) were decreased in FK506 group, especially at 6 h and at 1 day after TBI. At days 1-28 after TBI, the expression of cleaved-caspase 3, which indicates apoptosis, was lower in the FK506 group than in the TBI group. Mechanistically, FK506 significantly down-regulated the mRNA and protein levels of calcium-regulated phosphatase (calcineurin, CaN) and inhibited the activation of NFATc1. These results demonstrate that FK506 relieved inflammatory responses by regulating the NFATc1 signaling pathway and promoting the synaptic reconstruction of neurons and glial cells by regulating cell apoptosis, thereby facilitated improvements in neurological function.
authors.affiliation: Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin, 300060, China.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Eighth Department, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, 400042, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Liu
authors.affiliation: Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin, 300060, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Xu
authors.affiliation: Logistics University of PAP(People's Armed Police), Tianjin, 300162, China.
authors.forename: Xiaochang
authors.initials: X
authors.lastname: Wen
authors.affiliation: Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin, 300060, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin, 300060, China.
authors.forename: Weijia
authors.initials: W
authors.lastname: Fan
authors.affiliation: Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin, 300060, China.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Yao
authors.affiliation: Tianjin Key Laboratory of Cerebrovascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin, 300060, China. huanghuiling@126.com.
authors.forename: Huiling
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, 300060, China. lqg369@126.com.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Li
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D050778:NFATC Transcription Factors / Q000378:metabolism; D009424:Nervous System Physiological Phenomena / Q000187:drug effects*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D050778:NFATC Transcription Factors; D018696:Neuroprotective Agents; D007371:Interferon-gamma; D019703:Calcineurin; D016559:Tacrolimus
keywords: FK506; NFATc1 pathway; Neurological protection; Traumatic brain injury