Neuroprotective effects of mild hypothermia against traumatic brain injury by the involvement of the Nrf2/ARE pathway

Abstract

Background Traumatic brain injury (TBI) is the leading cause of death and disability worldwide. Mild hypothermia (32–35°C) has been found to show neuroprotective effects against TBI. However, the specific mechanism is still elusive. In the current study, we explored the relationship between oxidative damage after TBI and treatment with mild hypothermia as well as the underlying molecular mechanisms. Methods We used the closed cortex injury model to perform the brain injury and a temperature monitoring and control system to regulate the body temperature of mice after injury. Adult male C57BL/6 mice were adopted in this study and divided into four experimental groups. Tissue samples were harvested 24 h after injury. Results First, our results showed that treatment with mild hypothermia significantly improved neurobehavioral dysfunction and alleviated brain edema after TBI. Moreover, treatment with mild hypothermia enhanced the activity of the antioxidant enzymes superoxide dismutase and glutathione peroxidase and reduced the accumulation of lipid peroxidation malondialdehyde. Importantly, the expression and activation of the nuclear factor erythroid 2‐related factor 2‐antioxidant response element (Nrf2‐ARE) pathway were upregulated by mild hypothermia after TBI. Finally, treatment with hypothermia significantly decreased the cell apoptosis induced by TBI. Conclusion Our results showed that the protective effects of mild hypothermia after TBI may be achieved by the upregulation of the Nrf2‐ARE pathway and revealed Nrf2 as a potentially important target to improve the prognosis of TBI.

Multi-Mechanistic Approaches to the Treatment of Traumatic Brain Injury: A Review

“…Additionally, applying a combination of pharmacologic and non-pharmacologic interventions is a possible means to address the pathophysiology of TBI and TBI-associated secondary damage, as non-pharmacologic interventions can target similar mechanisms of secondary injury through different targets in a multimodal approach to TBI treatment. For example, a hypothetical combination of mild therapeutic hypothermia and a free radical scavenger would target oxidative stress through decreasing ROS/RNS and upregulating anti-oxidative enzymes, potentially impacting oxidative stress at the hyperacute and early acute time periods [ 61 , 147 ]. While non-pharmacologic interventions are an appealing avenue for treatment of TBI, the mechanisms that underlie these interventions are not always well characterized.…”

Non-pharmacological interventions for traumatic brain injury

“…30,32,34 Similarly, hypothermia, HBO, and DC reduce edema and ICP. 27,32,38,95 Other molecular mechanisms targeted by non-pharmacological interventions in TBI include ferroptosis (in IF), autophagy via mTOR (in IF and CR), and metabolism via SIRT1 (in IF, CR, and KD). 60,61,63,64 Stem cells transplanted at the site of injury secrete factors such as neurotrophic factors, cytokines, and chemokines and regulate the function of surrounding cells.…”

Multi-mechanistic Approaches to the Treatment of Traumatic Brain Injury: A Review

“…Additionally, applying a combination of pharmacologic and non-pharmacologic interventions is a possible means to address the pathophysiology of TBI and TBIassociated secondary damage, as non-pharmacologic interventions can target similar mechanisms of secondary injury through different targets in a multimodal approach to TBI treatment. For example, a hypothetical combination of mild therapeutic hypothermia and a free radical scavenger would target oxidative stress through decreasing ROS/RNS and upregulating anti-oxidative enzymes, potentially impacting oxidative stress at the hyperacute and early acute time periods [14,114]. While non-pharmacologic interventions are an appealing avenue for treatment of TBI, the mechanisms that underlie these interventions are not always well characterized.…”