Luteolin Modulates the NF-E2-Related Factor 2/Glutamate-Cysteine Ligase Pathway in Rats with Spinal Cord Injury.
J Med Food. 2021 Mar ;24(3):218-225. PMID: 33739882
Spinal cord ischemia-reperfusion injury (SCII) easily causes unalterable neurological deficits. We previously demonstrated that the flavonoid luteolin (LU) has strong antioxidant, anti-inflammatory, and other neuroprotective efficacies against SCII. In our current study, we examined the contributions of the NF-E2-related factor 2 (Nrf2)/glutamate-cysteine ligase (GCL) pathway to LU-mediated neuroprotection in the transient abdominal aorta occlusion rat model of SCII. Rats were divided into four groups: Sham surgery, SCII alone, SCII plus LU pretreatment (SCII + LU), and SCII plus cotreatment with LU and the Nrf2 inhibitor ML385 (SCII + LU + ML385). The Basso-Beattie-Bresnahan (BBB) scale was used to assess neurological function, hematoxylin and eosin staining to evaluate pathological change to the spinal cord, and enzyme-linked immunosorbent assay to measure tissue markers of oxidative stress and inflammation induced by SCII. Mitochondrial injury and apoptosis were examined by flow cytometry and expression levels of Nrf2, GCL catalytic subunit (GCLc), and GCL modifier subunit (GCLm) by real-time quantitative polymerase chain reaction. LU pretreatment significantly enhanced recovery of motor function as evidenced by the BBB score and attenuated the pathological damage. Furthermore, LU effectively enhanced the antioxidative activity, alleviated mitochondrial swelling, decreased the expression levels of several proinflammatory cytokines after SCII, and significantly upregulated Nrf2, GCLc, and GCLm expression levels. Cotreatment with ML385 reversed all these protective effects of LU except the anti-inflammatory response. Collectively, these findings indicate that the neuroprotective efficacy of LU depends on suppression of oxidative stress and preservation of mitochondrial function through signaling pathways involving Nrf2 activation and downstream gene expression.