Abstract
Abstract
Background
The present study aimed to further explore the potential interaction between oxidative stress and autophagy in the progression of traumatic brain injury (TBI) and therapeutic mechanism of calcitriol, the active form of vitamin D (VitD).
Methods
Neuroprotective effects of calcitriol were examined following TBI. We further evaluated the impacts of TBI and calcitriol treatment on autophagic process and nuclear factor E2-related factor 2 (Nrf2) signaling.
Results
We found that treatment of calcitriol markedly ameliorated the neurological deficits and histopathological changes following TBI. The brain damage impaired autophagic flux and impeded Nrf2 signaling, the major regulator in antioxidant response, consequently leading to uncontrolled and excessive oxidative stress. Meanwhile, calcitriol promoted autophagic process and activated Nrf2 signaling as evidenced by the reduced Keap1 expression and enhanced Nrf2 translocation, thereby mitigating TBI-induced oxidative damage. In support, we further found that chloroquine (CQ) treatment abrogated calcitriol-induced autophagy and compromised Nrf2 activation with increased Keap1 accumulation and reduced expression of Nrf2-targeted genes. Additionally, both CQ treatment and Nrf2 genetic knockout abolished the protective effects of calcitriol against both TBI-induced neurological deficits and neuronal apoptosis.
Conclusions
Therefore, our work demonstrated a neuroprotective role of calcitriol in TBI by triggering Nrf2 activation, which might be mediated by autophagy.
Funder
national natural science foundation of china
natural science foundation of shandong province
taishan scholar project of shandong province
jining key research and development program
lin he’s academician workstation of new medicine and clinical translation of jining medical university
shandong medical and health science and technology development program project
Publisher
Springer Science and Business Media LLC
Subject
Genetics(clinical),Genetics,Molecular Biology,Molecular Medicine
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