Abstract
The nuclear erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway plays an essential role in the cellular antioxidant and anti-inflammatory responses. Spinal cord injury (SCI) results in a massive release of inflammatory factors and free radicals, which seriously compromise nerve recovery and axon regeneration. In this study, we examined the efficacy of probucol on anti-inflammatory responses and functional recovery after SCI by activating the Nrf2/ARE signaling pathway. We also investigated the mechanism by which inflammation is inhibited in this process. We found that treatment of injured rats with probucol significantly increased levels of Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 (NQO1), while levels of inflammatory cytokines, interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were decreased. This was associated with a reduction in neural cell apoptosis and promotion of nerve function recovery. These results demonstrate that the neuroprotective effects of probucol after SCI are mediated by activation of the Nrf2/ARE signaling pathway. These findings indicate that the anti-inflammatory effects of probucol represent a viable treatment for improving functional recovery following SCI.
Highlights
Spinal cord injury (SCI) involves two pathophysiological stages consisting of the primary and secondary injuries
The secondary injury is the cause of a series of detrimental effects, including mitochondrial dysfunction, inflammation and oxidative stress, which contribute to neuronal apoptosis and inhibit nerve recovery and axon regeneration [1, 2]
To elucidate the mechanism underlying the therapeutic effects of probucol after SCI, we investigated the involvement of the Akt/nuclear erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway
Summary
Spinal cord injury (SCI) involves two pathophysiological stages consisting of the primary and secondary injuries. The secondary injury is the cause of a series of detrimental effects, including mitochondrial dysfunction, inflammation and oxidative stress, which contribute to neuronal apoptosis and inhibit nerve recovery and axon regeneration [1, 2]. The inflammatory response is a crucial intracellular catabolic process in the secondary injury [3,4,5]. Astrocytes produce a variety of chemokines and cytokines, which participate in immune and inflammatory responses, which lead either directly or indirectly, to neuronal death [8]. Reduction in the early inflammatory response after SCI has a neuroprotective effect and promotes functional recovery. Effective prevention of secondary damage by reduction of inflammatory cytokine production and neuronal apoptosis to promote functional recovery after SCI is a key therapeutic approach for improved prognosis
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