The antioxidant effect of preischemic dexmedetomidine in a rat model: increased expression of Nrf2/HO-1 via the PKC pathway

Park, Yong‐Hee; Park, Hee Pyoung; Kim, Eugene; Lee, Hannah; Hwang, Jung‐Won; Jeon, Young-Tae; Lim, Young-Jin

doi:10.1016/j.bjane.2021.08.005

Cited by 5 publications

(5 citation statements)

References 31 publications

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“…In brain injury related to transient global cerebral ischemia in rats, study shows that preischemia dexmedetomidine administration has neuroprotective effect by enhancing NRF2/HO-1 expression and reducing caspase-3 activity [ 136 ]. In ischemia brain injury, BCP (β-Caryophyllene) has protective effects, whose mechanism is related to the activation of the NRF2/HO-1 pathway [ 137 ].…”

Section: Nrf2 In Ferroptosismentioning

confidence: 99%

NRF2, a Superstar of Ferroptosis

Yan,

Lin,

Jin

et al. 2023

Antioxidants

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Ferroptosis is an iron-dependent and lipid peroxidation-driven cell death cascade, occurring when there is an imbalance of redox homeostasis in the cell. Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) is key for cellular antioxidant responses, which promotes downstream genes transcription by binding to their antioxidant response elements (AREs). Numerous studies suggest that NRF2 assumes an extremely important role in the regulation of ferroptosis, for its various functions in iron, lipid, and amino acid metabolism, and so on. Many pathological states are relevant to ferroptosis. Abnormal suppression of ferroptosis is found in many cases of cancer, promoting their progression and metastasis. While during tissue damages, ferroptosis is recurrently promoted, resulting in a large number of cell deaths and even dysfunctions of the corresponding organs. Therefore, targeting NRF2-related signaling pathways, to induce or inhibit ferroptosis, has become a great potential therapy for combating cancers, as well as preventing neurodegenerative and ischemic diseases. In this review, a brief overview of the research process of ferroptosis over the past decade will be presented. In particular, the mechanisms of ferroptosis and a focus on the regulation of ferroptosis by NRF2 will be discussed. Finally, the review will briefly list some clinical applications of targeting the NRF2 signaling pathway in the treatment of diseases.

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Section: Nrf2 In Ferroptosismentioning

confidence: 99%

NRF2, a Superstar of Ferroptosis

Yan,

Lin,

Jin

et al. 2023

Antioxidants

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“…Previous studies have shown that DEX exhibited neuroprotection in various neuronal injury models, such as traumatic brain injury, I/R-induced brain injury, anesthetic-induced neuronal injury, and neurodegeneration ( 22 ). In recent years, both in vivo and in vitro studies have shown that DEX can exert neuroprotective effects against CIRI ( 23 - 25 ). Despite its neuroprotective effects being a hot topic, the specific molecular mechanism underlying these effects on CIRI has not been fully clarified.…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine pretreatment alleviates cerebral ischemia/reperfusion injury by inhibiting neuroinflammation through the JAK2/STAT3 pathway

Liu

Jiang

et al. 2022

Braz J Med Biol Res

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Dexmedetomidine (DEX) is known to provide neuroprotection against cerebral ischemia and reperfusion injury (CIRI), but the exact mechanisms remain unclear. This study was conducted to investigate whether DEX pretreatment conferred neuroprotection against CIRI by inhibiting neuroinflammation through the JAK2/STAT3 signaling pathway. Middle cerebral artery occlusion (MCAO) was performed to establish a cerebral ischemia/reperfusion (I/R) model. Specific-pathogen-free male Sprague-Dawley rats were randomly divided into Sham, I/R, DEX, DEX+IL-6, and AG490 (a selective inhibitor of JAK2) groups. The Longa score, TTC staining, and HE staining were used to evaluate brain damage. ELISA was used to exam levels of TNF-α. Western blotting was used to assess the levels of JAK2, phosphorylated-JAK2 (p-JAK2), STAT3, and phosphorylated-STAT3 (p-STAT3). Our results suggested that both pretreatment with DEX and AG490 decreased the Longa score and cerebral infarct areas following cerebral I/R. After treatment with IL-6, the effects of DEX on abrogating these pathological changes were reduced. HE staining revealed that I/R-induced neuronal pathological changes were attenuated by DEX application, consistent with the AG490 group. However, these effects of DEX were abolished by IL-6. Furthermore, TNF-α levels were significantly increased in the I/R group, accompanied by an increase in the levels of the p-JAK2 and p-STAT3. DEX and AG490 pretreatment down-regulated the expressions of TNF-α, p-JAK2, and p-STAT3. In contrast, the down-regulation of TNF-α, p-JAK2, and p-STAT3 induced by DEX was reversed by IL-6. Collectively, our results indicated that DEX pretreatment conferred neuroprotection against CIRI by inhibiting neuroinflammation via negatively regulating the JAK2/STAT3 signaling pathway.

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“…Nrf2 is a transcription factor that regulates the majority of antioxidant genes, including HO-1, GPx4 and NAD(P)H quinone dehydrogenase 1 ( 52 ). Under oxidative stress conditions, Nrf2 can be activated by phosphorylation ( 53 ) or Keap1 modification ( 54 ). Subsequently, it translocates to the nucleus by dissociating from Keap1 ( 55 ).…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, it translocates to the nucleus by dissociating from Keap1 ( 55 ). Park et al ( 53 ) reported the involvement of protein kinase C (PKC) in the antioxidant effect of DEX in a rat model of ischemia. PKC phosphorylated Nrf2 and activated its detachment from Keap1.…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine attenuates airway inflammation and oxidative stress in asthma via the Nrf2 signaling pathway

et al. 2022

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Allergic asthma is a chronic inflammatory disease in which oxidative stress serves a pivotal role. In clinical practice, dexmedetomidine (DEX), an α-2-adrenergic receptor agonist, is used as a sedative. DEX exhibits antioxidative and organ-protective properties. In a murine model of asthma, DEX has a therapeutic effect via the toll like receptor 4/NF-кB signaling pathway; however, whether DEX can exert an antioxidative effect on asthma has yet to be elucidated. In the present study, a T helper (Th)2-dominant murine asthma model was established. DEX treatment significantly reduced eosinophilic airway inflammation, mucus overproduction and airway hyperresponsiveness, as well as the concentrations of Th2 cytokines. The lung tissues of mice with asthma were characterized by redox imbalance (increased oxidative stress and impaired antioxidant capacity). DEX treatment alleviated this imbalance by decreasing the levels of malondialdehyde and reactive oxygen species, and increasing the levels of glutathione. Furthermore, the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway was inhibited in the lung tissues of asthmatic mice; these effects were noted in its downstream genes, heme oxygenase 1 and glutathione peroxidase 4. In mice with asthma, DEX treatment induced the expression of these antioxidant genes and the activation of Nrf2, whereas ML385 (an inhibitor of Nrf2) partially abrogated the antioxidative and therapeutic effects of DEX. To the best of our knowledge, the present study is the first to demonstrate the protective effect of DEX on Th2-dominant asthma through the activation of the Nrf2 signaling pathway. The results suggested that the antioxidative properties of DEX could be beneficial in clinical application of DEX for the relief of asthmatic symptoms.

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The antioxidant effect of preischemic dexmedetomidine in a rat model: increased expression of Nrf2/HO-1 via the PKC pathway

Cited by 5 publications

References 31 publications

NRF2, a Superstar of Ferroptosis

NRF2, a Superstar of Ferroptosis

Dexmedetomidine pretreatment alleviates cerebral ischemia/reperfusion injury by inhibiting neuroinflammation through the JAK2/STAT3 pathway

Dexmedetomidine attenuates airway inflammation and oxidative stress in asthma via the Nrf2 signaling pathway

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