Vitamin D Receptor Activation Influences NADPH Oxidase (NOX2) Activity and Protects against Neurological Deficits and Apoptosis in a Rat Model of Traumatic Brain Injury

Oxidative Medicine and Cellular Longevity, Dec 2017

Traumatic brain injury (TBI) is a worldwide phenomenon which results in significant neurological and cognitive deficits in humans. Vitamin D (VD) is implicated as a therapeutic strategy for various neurological diseases now. Recently, inhibition of the NADPH oxidase (NOX2) was reported to protect against oxidative stress (ROS) production. However, whether alterations in NOX2 expression and NOX activity are associated with calcitriol (active metabolite of VD) treatment following TBI remains unclear. In the present study, rats were randomly assigned to the sham, TBI, and calcitriol-treated groups. Calcitriol was administered intraperitoneally (2 μg/kg) at 30 min, 24 h, and 48 h after TBI insult. We observed that calcitriol treatment alleviated neurobehavioral deficits and brain edema following TBI. At the molecular levels, administration of calcitriol activated the expression of VDR and downregulated NOX2 as well as suppressed apoptosis cell rate in the hippocampus CA1 region of TBI rats. In conclusion, our findings indicate that the protective effects of calcitriol may be related to the modulation of NADPH oxidase and thereby ultimately inhibited the progression of apoptosis. Calcitriol may be promising as a protective intervention following TBI, and more study is warranted for its clinical testing in the future.

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Vitamin D Receptor Activation Influences NADPH Oxidase (NOX2) Activity and Protects against Neurological Deficits and Apoptosis in a Rat Model of Traumatic Brain Injury

Vitamin D Receptor Activation Influences NADPH Oxidase (NOX2) Activity and Protects against Neurological Deficits and Apoptosis in a Rat Model of Traumatic Brain Injury Changmeng Cui,1,2,3 Sixin Song,4 Jianzhong Cui,3 Yan Feng,5 Junling Gao,2 and Pei Jiang6 1Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, China 2School of Basic Medical Science, North China University of Science and Technology, Tangshan, Hebei 063000, China 3Department of Neurosurgery, Tangshan Gongren Hospital, Tangshan, Hebei 063000, China 4Department of Neurosurgery, Affiliated Hospital of Taishan Medical University, Taian, Shandong 271000, China 5Department of Neurosurgery, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China 6Institute of Clinical Pharmacy and Pharmacology, Jining First People’s Hospital, Jining Medical University, Jining, Shandong 272000, China Correspondence should be addressed to Junling Gao; moc.361@1002rdoaglj and Pei Jiang; moc.anis@usciepgnaij Received 5 April 2017; Revised 18 July 2017; Accepted 30 July 2017; Published 19 December 2017 Academic Editor: Arsenio Fernández-López Copyright © 2017 Changmeng Cui et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Traumatic brain injury (TBI) is a worldwide phenomenon which results in significant neurological and cognitive deficits in humans. Vitamin D (VD) is implicated as a therapeutic strategy for various neurological diseases now. Recently, inhibition of the NADPH oxidase (NOX2) was reported to protect against oxidative stress (ROS) production. However, whether alterations in NOX2 expression and NOX activity are associated with calcitriol (active metabolite of VD) treatment following TBI remains unclear. In the present study, rats were randomly assigned to the sham, TBI, and calcitriol-treated groups. Calcitriol was administered intraperitoneally (2 μg/kg) at 30 min, 24 h, and 48 h after TBI insult. We observed that calcitriol treatment alleviated neurobehavioral deficits and brain edema following TBI. At the molecular levels, administration of calcitriol activated the expression of VDR and downregulated NOX2 as well as suppressed apoptosis cell rate in the hippocampus CA1 region of TBI rats. In conclusion, our findings indicate that the protective effects of calcitriol may be related to the modulation of NADPH oxidase and thereby ultimately inhibited the progression of apoptosis. Calcitriol may be promising as a protective intervention following TBI, and more study is warranted for its clinical testing in the future. 1. Introduction Traumatic brain injury (TBI) is a worldwide phenomenon that affects all ages and socioeconomic classes and results in variation of immediate and delayed motor and cognitive deficiencies [1, 2]. As patients often present with a complexity of lesions of various severity and regional distributions, the pathogenesis of TBI is incompletely understood [3]. TBI is caused by both primary and secondary injury mechanisms. Primary damage is due to mechanical factors and occurs immediately at the moment of injury. It takes the form of intracranial hemorrhage, diffuse axonal injury (DAI), and surface contusions [4]. In comparison, the secondary injury is delayed and is produced via complicating processes that are initiated at the moment of impact but do not present clinically for a period of hours to days following trauma. It includes damage due to brain edema, ischemia, and alterations in neuronal function [4]. Until now, patients are still inadequately treated because of the lack of effective therapies on TBI [5]. As a result, to find new effective therapeutic drugs or to develop novel therapeutic strategies is an important issue. Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) is a multiunit enzyme composed of several subunits that include several isoforms of NOX1–5 [6]. NOX2, a catalytic subunit of NOX, is localized to the cerebral cortex and hippocampus CA1 region. Experimental evidence suggested that overactivated NOX2 significantly contributed to oxidative damage to neurons in ischemic and traumatic conditions [7, 8]. Recently, inhibition of the NADPH oxidase complex was reported to protect against oxidative stress (ROS) production, blood-brain barrier disruption, and neuronal death in vivo [9]. Our previous research also demonstrated that treatment with NADPH oxidase complex inhibitor attenuated the expression and activation of the NOX2 protein and reduced brain edema and spatial learning deficits in TBI rats [8]. Vitamin D (VD), which is most commonly associated with the regulation of calcium homeostasis, is implicated as a pleiotropic secosteroid affecting multiple aspects of human physiology now [10]. The biologically active metabolite of VD (calcitriol, (...truncated)


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Changmeng Cui, Sixin Song, Jianzhong Cui, Yan Feng, Junling Gao, Pei Jiang. Vitamin D Receptor Activation Influences NADPH Oxidase (NOX2) Activity and Protects against Neurological Deficits and Apoptosis in a Rat Model of Traumatic Brain Injury, Oxidative Medicine and Cellular Longevity, 2017, 2017, DOI: 10.1155/2017/9245702