Recent Advances in the Role of Nuclear Factor Erythroid-2-Related Factor 2 in Spinal Cord Injury: Regulatory Mechanisms and Therapeutic Options

Abstract

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a pleiotropic transcription factor, and it has been documented that it can induce defense mechanisms both oxidative stress and inflammatory injury. At present, more and more evidences show that the Nrf2 signaling pathway is a key pharmacological target for the treatment of spinal cord injury (SCI), and activating the Nrf2 signaling pathway can effectively treat the inflammatory injury and oxidative stress after SCI. This article firstly introduces the biological studies of the Nrf2 pathway. Meanwhile, it is more powerful to explain that activating the Nrf2 signaling pathway can effectively treat SCI by deeply exploring the relationship between Nrf2 and oxidative stress, inflammatory injury, and SCI. In addition, several potential drugs for the treatment of SCI by promoting Nrf2 activation and Nrf2-dependent gene expression are reviewed. And some other treatment strategies of SCI by modulating the Nrf2 pathway are also summarized. It will provide new ideas and directions for the treatment of SCI.

AMPK-Nrf2 Signaling Pathway in Phrenic Motoneurons following Cervical Spinal Cord Injury

“…This shows the pivotal role of AMPK following SCI and could explain its rebound in expression in phrenic motoneurons at 3 d P.I., considering no study explored AMPK function in phrenic motoneurons in this context. Concerning Nrf2, the cellular stress caused by glutamate excitotoxicity leads to anti-inflammatory and antioxidant responses, which requires Nrf2 signaling [ 31 ]. This could explain the rebound also observed for Nrf2 expression using immunolabeling at 1 d P.I., as well as the increased expression of Nrf2, HO-1, and NQO1 observed at 3 d P.I.…”

“…Considering that other neuronal and glial cells are in higher quantity than phrenic motoneurons, a difference in inflammatory kinetics would erase the increase in Nrf2 expression observed in phrenic motoneurons, specifically when using the immunoblotting method. Nrf2 appeared to be beneficial following injury [ 30 , 31 ]. In mice lacking Nrf2, SCI leads to more severe locomotor dysfunction and neural death compared to control animals [ 57 ], whereas activation of the Nrf2 pathway in rats leads to improved locomotor function and neuroprotective effects following SCI [ 31 , 37 , 58 ].…”

“…Nrf2 appeared to be beneficial following injury [ 30 , 31 ]. In mice lacking Nrf2, SCI leads to more severe locomotor dysfunction and neural death compared to control animals [ 57 ], whereas activation of the Nrf2 pathway in rats leads to improved locomotor function and neuroprotective effects following SCI [ 31 , 37 , 58 ]. Nrf2 is also expressed in glial cells, including astrocytes.…”

“…Nrf2 is a key regulator of the cellular anti-inflammatory and antioxidant responses [ 29 , 30 , 31 ]. Nrf2 is sequestered in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1) through the Neh2 domain and is degraded through ubiquitin-dependent proteasomal degradation under physiological conditions [ 32 , 33 ].…”

“…Nrf2 indeed has an important role in the reduction of TNF-α and MMP9 production following SCI [ 38 ], with these molecules being involved in spinal neuroinflammation [ 39 , 40 ]. Activation of Nrf2 has therefore been considered as a potential treatment following SCI, considering its anti-inflammatory and antioxidant effects [ 29 , 30 , 31 ]. The administration of Nrf2 activators has shown beneficial effects in this context, such as a reduction in inflammatory cytokine production, and an increase in Nrf2 expression and its related signaling pathway in neuronal and glial cells [ 29 ].…”