Astrocytic Nrf2 expression protects spinal cord from oxidative stress following spinal cord injury in a male mouse model

Abstract

Background Spinal cord injury (SCI) induces a multitude of deleterious processes, including neuroinflammation and oxidative stress (OS) which contributed to neuronal damage and demyelination. Recent studies have suggested that increased formation of reactive oxygen species (ROS) and the consequent OS are critical events associated with SCI. However, there is still little information regarding the impact of these events on SCI. Astrocytes are key regulators of oxidative homeostasis in the CNS and astrocytic antioxidant responses promote the clearance of oxidants produced by neurons. Therefore, dysregulation of astrocyte physiology might largely contribute to oxidative damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) is the main transcriptional regulator of cellular anti-oxidative stress responses. Methods In the current study, we hypothesized that astrocytic activation of Nrf2 protects the spinal cord post injury via suppression of neuroinflammation. Thus, using mice line with a GFAP-specific kelch-like ECH-associated protein 1 (Keap1)-deletion, we induced a hyperactivation of Nrf2 in astrocytes and further its effects on SCI outcomes. SCI-induction was performed in mice using the Infinite Horizon Spinal Cord Impactor with a force of 60 kdyn. To assess the quantitative pattern of Nrf2/ARE-activation, we included transgenic ARE-Luc mice. Data were analyzed with GraphPad Prism 8 (GraphPad Software Inc., San Diego, CA, USA). Brown–Forsythe test was performed to test for equal variances and normal distribution was tested with Shapiro–Wilk. Results In ARE-Luc mice, a significant induction of luciferase-activity was observed as early as 1 day post-injury, indicating a functional role of Nrf2-activity at the epicenter of SCI. Furthermore, SCI induced loss of neurons and oligodendrocytes, demyelination and inflammation in wild type mice. The loss of myelin and oligodendrocytes was clearly reduced in Keap1 KO mice. In addition, Keap-1 KO mice showed a significantly better locomotor function and lower neuroinflammation responses compared to wild type mice. Conclusions In summary, our in vivo bioluminescence data showed Nrf2-ARE activation during primary phase of SCI. Furthermore, we found that cell specific hyperactivation of Nrf2 was sufficient to protect the spinal cord against injury which indicate a promising therapeutic approach for SCI-treatment.

Recent Advances in Cell and Functional Biomaterial Treatment for Spinal Cord Injury

“…Recently, it has been found that Nrf2 is a major transcriptional regulator of cellular antioxidant stress response in astrocytes; its regulation of antioxidant system plays a key role in the early stage after spinal cord injury. Increased Nrf2 activity in astrocytes can improve the inflammatory response after spinal cord injury and promote the recovery of motor function [ 38 ].…”

Specific Blood RNA Profiles in Individuals with Acute Spinal Cord Injury as Compared with Trauma Controls

“…The results of GO biological processes and KEGG pathways of hub genes were in line with many previous studies. Inflammation, oxidative stress, IL-17 signaling pathway, and so on were regarded as indispensable parts of specific mechanisms in SCI [43][44][45]. There are 93 molecules involved in IL-17 family signaling events in the IL-17 signaling pathway resource [46].…”

Wnt5a/Ror2 promotes Nrf2‐mediated tissue protective function of astrocytes after brain injury

“…It has been reported that activation of Nrf2 in astrocytes can protect themselves and neighboring cells, including neurons, from oxidative damage in the injured or diseased brains and spinal cords, thereby improving their pathological conditions (Draheim et al, 2016; Sigfridsson et al, 2018; Vargas et al, 2008; Zhao et al, 2022). In the injured brains, hemin, released from hemoglobin during hemorrhage at these injury sites, is thought to elicit iron‐mediated cellular damage, leading to the dysfunction of BBB (Imai et al, 2019).…”