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

Michel‐Flutot, Pauline; Efthimiadi, Laurie; Djerbal, Lynda; Deramaudt, Thérèse B.; Bonay, Marcel; Vinit, Stéphane

doi:10.3390/antiox11091665

Cited by 2 publications

(1 citation statement)

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“…Under oxidative stress, Nrf2 dissociates from Kelch-like ECH-associated protein 1 (Keap1) and translocates to the nucleus, where it binds to antioxidant response elements (AREs) and upregulates the expression of various antioxidant genes, notably HO-1 [52]. Additionally, Nrf2 inhibits the expression of pro-inflammatory cytokines, such as IL-1β and IL-6, by modulating the Atf3/IκBζ pathway [53][54][55][56]. Our study also found that the expressions of Nfe2l2, Hmox1, and Atf3 were elevated in the hippocampus of HI mice, suggesting that the mechanisms of anti-inflammatory and antioxidant are triggered during the early stages of HI.…”

Section: Discussionmentioning

confidence: 99%

Protecting effects of 4-octyl itaconate on neonatal hypoxic-ischemic encephalopathy via Nrf2 pathway in astrocytes

Yang,

Li,

Yang

et al. 2024

J Neuroinflammation

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Background Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most common neurological problems occurring in the perinatal period. However, there still is not a promising approach to reduce long-term neurodevelopmental outcomes of HIE. Recently, itaconate has been found to exhibit anti-oxidative and anti-inflammatory effects. However, the therapeutic efficacy of itaconate in HIE remains inconclusive. Therefore, this study attempts to explore the pathophysiological mechanisms of oxidative stress and inflammatory responses in HIE as well as the potential therapeutic role of a derivative of itaconate, 4-octyl itaconate (4OI). Methods We used 7-day-old mice to induce hypoxic-ischemic (HI) model by right common carotid artery ligation followed by 1 h of hypoxia. Behavioral experiments including the Y-maze and novel object recognition test were performed on HI mice at P60 to evaluate long-term neurodevelopmental outcomes. We employed an approach combining non-targeted metabolomics with transcriptomics to screen alterations in metabolic profiles and gene expression in the hippocampal tissue of the mice at 8 h after hypoxia. Immunofluorescence staining and RT-PCR were used to evaluate the pathological changes in brain tissue cells and the expression of mRNA and proteins. 4OI was intraperitoneally injected into HI model mice to assess its anti-inflammatory and antioxidant effects. BV2 and C8D1A cells were cultured in vitro to study the effect of 4OI on the expression and nuclear translocation of Nrf2. We also used Nrf2-siRNA to further validate 4OI-induced Nrf2 pathway in astrocytes. Results We found that in the acute phase of HI, there was an accumulation of pyruvate and lactate in the hippocampal tissue, accompanied by oxidative stress and pro-inflammatory, as well as increased expression of antioxidative stress and anti-inflammatory genes. Treatment of 4OI could inhibit activation and proliferation of microglial cells and astrocytes, reduce neuronal death and relieve cognitive dysfunction in HI mice. Furthermore, 4OI enhanced nuclear factor erythroid-2-related factor (Nfe2l2; Nrf2) expression and nuclear translocation in astrocytes, reduced pro-inflammatory cytokine production, and increased antioxidant enzyme expression. Conclusion Our study demonstrates that 4OI has a potential therapeutic effect on neuronal damage and cognitive deficits in HIE, potentially through the modulation of inflammation and oxidative stress pathways by Nrf2 in astrocytes.

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