Calcitriol confers neuroprotective effects in traumatic brain injury by activating Nrf2 signaling through an autophagy-mediated mechanism

Changmeng Cui,Lingsheng Kong,Changshui Wang,Pei Jiang,Wenxiu Han,Feng Jin,Mengqi Yang

doi:10.1186/s10020-021-00377-1

Abstract

BackgroundThe 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).MethodsNeuroprotective 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.ResultsWe 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.ConclusionsTherefore, our work demonstrated a neuroprotective role of calcitriol in TBI by triggering Nrf2 activation, which might be mediated by autophagy.

Highlights

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)
It has been demonstrated that p62 directly interacts with Kelch-like ECH-associated protein 1 (Keap1), thereby dissociating it from nuclear factor E2-related factor 2 (Nrf2) and directing it toward autophagic degradation (Deng et al 2020; Dodson et al 2015)
The effects of calcitriol on TBI‐induced neurological deficits The neurological severity scores were assessed at 1–14 days after TBI (Additional file 4)

Summary

Introduction

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). Autophagy is a major proteolytic system that senses intracellular stressful conditions and rapidly mounts a molecular response to deal with the damage through sequestration and degradation of dysfunctional organelles and compromised proteins (Zhang et al 2019a). P62 activates nuclear factor E2-related factor 2 (Nrf2) signaling, a well-characterized cellular defense mechanism against oxidative stress, by interacting with Kelch-like ECH-associated protein 1 (Keap1) (Saito et al 2020). It has been demonstrated that p62 directly interacts with Keap, thereby dissociating it from Nrf and directing it toward autophagic degradation (Deng et al 2020; Dodson et al 2015)

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Results

Discussion

Conclusion