Dexmedetomidine attenuates neuronal injury after spinal cord ischaemia‐reperfusion injury by targeting the CNPY2‐endoplasmic reticulum stress signalling

Zhao, Lina; Zhai, Meili; Xu, Yang; Guo, Hongjie; Cao, Ying; Wang, Donghui; Li, Ping; Liu, Chong

doi:10.1111/jcmm.14688

Cited by 24 publications

(20 citation statements)

References 40 publications

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“…Autophagy is a ubiquitous and unique life phenomenon of eukaryotic cells. Mitophagy is a special type of autophagy, which can specifically engulf damaged mitochondria to maintain mitochondrial homeostasis [ 54 ]. Emerging evidence suggested a neuroprotective role of mitophagy in cerebral I/R [ 21 , 23 ], and enhancing mitophagy attenuated apoptosis after SCIRI [ 24 ].…”

Section: Resultsmentioning

confidence: 99%

Salidroside Ameliorates Mitochondria-Dependent Neuronal Apoptosis after Spinal Cord Ischemia-Reperfusion Injury Partially through Inhibiting Oxidative Stress and Promoting Mitophagy

Huang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Ischemia-reperfusion injury is the second most common injury of the spinal cord and has the risk of neurological dysfunction and paralysis, which can seriously affect patient quality of life. Salidroside (Sal) is an active ingredient extracted from Herba Cistanche with a variety of biological attributes such as antioxidant, antiapoptotic, and neuroprotective activities. Moreover, Sal has shown a protective effect in ischemia-reperfusion injury of the liver, heart, and brain, but its effect in ischemia-reperfusion injury of the spinal cord has not been elucidated. Here, we demonstrated for the first time that Sal pretreatment can significantly improve functional recovery in mice after spinal cord ischemia-reperfusion injury and significantly inhibit the apoptosis of neurons both in vivo and in vitro. Neurons have a high metabolic rate, and consequently, mitochondria, as the main energy-supplying suborganelles, become the main injury site of spinal cord ischemia-reperfusion injury. Mitochondrial pathway-dependent neuronal apoptosis is increasingly confirmed by researchers; therefore, Sal’s effect on mitochondria naturally attracted our attention. By means of a range of experiments both in vivo and in vitro, we found that Sal can reduce reactive oxygen species production through antioxidant stress to reduce mitochondrial permeability and mitochondrial damage, and it can also enhance the PINK1-Parkin signaling pathway and promote mitophagy to eliminate damaged mitochondria. In conclusion, our results show that Sal is beneficial to the protection of spinal cord neurons after ischemia-reperfusion injury, mainly by reducing apoptosis associated with the mitochondrial-dependent pathway, among which Sal’s antioxidant and autophagy-promoting properties play an important role.

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Section: Resultsmentioning

confidence: 99%

Salidroside Ameliorates Mitochondria-Dependent Neuronal Apoptosis after Spinal Cord Ischemia-Reperfusion Injury Partially through Inhibiting Oxidative Stress and Promoting Mitophagy

Huang

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…The overexpression of spinal cord pro‐apoptotic genes has been established in the early stage of the development of NPP, as evidenced by a marked increase in caspase‐9 expression in the dorsal horn spinal cord and TUNEL‐positive cells 3 days after CCI induction of sciatic nerve (Siniscalco et al., 2007). Similarly, Dex prevented pulmonary cell apoptosis in mice and spinal cord cells, as reflected by declines in the number of TUNEL‐positive cells and the protein expression of cleaved caspase‐9 (Kong et al., 2020; Zhao et al., 2019). NPP is initiated by nerve injury and characterized by elevated activity in the peripheral and central nervous system, in which various inflammatory cytokines and other biomolecules induce different pathways that participate in the development and/or maintenance of pain (Mai, Zhu, Huang, He, & Fan, 2020).…”

Section: Discussionmentioning

confidence: 97%

Analgesic effect of dexmedetomidine in rats after chronic constriction injury by mediating microRNA‐101 expression and the E2F2–TLR4–NF‐κB axis

Zhang

Cui

et al. 2020

Experimental Physiology

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New Findings What is the central question of this study?Dexmedetomidine has a capacity for sedation, anti‐anxiety and analgesia with minimal suppression of respiratory function; what is its role in neuropathic pain and what is the involvement of miRNAs? What is the main finding and its importance?Dexmedetomidine attenuates inflammation and apoptosis and the stimulation of TLR4–NF‐κB signalling in rat spinal cord via miR‐101 overexpression and E2F2 downregulation. Abstract The significant analgesic effect of dexmedetomidine (Dex) has been underscored in neuropathic pain (NPP), but the underlying mechanism remains unclear. This study explored the functional effect of Dex on microRNA (miR)‐101‐regulated E2 promoter binding factor 2 (E2F2) with the engagement of Toll‐like receptor 4 (TLR4)–nuclear factor‐κB (NF‐κB) signalling. Chronic constriction injury (CCI) was performed to generate an NPP rat model. The expression of miR‐101, E2F2 and TLR4–NF‐κB signalling‐relevant proteins was assessed by RT–quantitative PCR, immunoblotting and immunohistochemistry. Inflammatory factors were detected by enzyme‐linked immunosorbent assay. The results showed that Dex increased mechanical withdrawal threshold and thermal latency to withdraw. The expression of interleukin (IL)‐6, IL‐8 and tumour necrosis factor‐α was increased in CCI rats, but these trends were reversed by Dex. In addition, Dex repressed caspase‐9 expression and apoptotic cell numbers in spinal cord tissues in CCI rats. Moreover, the expression of E2F2 was significantly increased, while miR‐101 was diminished in CCI rats, which was reversed by Dex. Furthermore, miR‐101 inhibitor, E2F2 restoration or administration of a TLR4‐specific agonist weakened the effect of Dex. Together, these results suggest that Dex has the capacity to ameliorate NPP by regulating the miR‐101–E2F2–TLR4–NF‐κB axis in rats subjected to CCI.

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“…Judging from existing studies, DEX performs a protective role in inhibiting IRI in the heart of diabetic mice by interfering with ERS or autophagy; 6,15 however, these results were partly attributed to the diabetes context. Furthermore, researchers have focused on studying other non-cardiac cells, such as endothelial cells, under IRI or H/R conditions 16,17 and examining several crucial ERS chaperones, proteins and apoptosis indicators produced by organs other than the heart under IRI or H/R conditions, 6,[18][19][20][21][22] finding that DEX can effectively regulate the function of non-cardiac cells and interfere in the endoplasmic reticulum stress signalling pathway under certain circumstances. Few studies have explored the function of DEX in H9c2 cardiomyocytes under H/R conditions; 23,24 however, the exact regulatory effect of DEX on ERS remains unknown.…”

Section: Introductionmentioning

confidence: 99%

<p>Dexmedetomidine Attenuates Cellular Injury and Apoptosis in H9c2 Cardiomyocytes by Regulating p-38MAPK and Endoplasmic Reticulum Stress</p>

Zhu

Ling

Zhou

et al. 2020

DDDT

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Background: Myocardial ischaemia-reperfusion injury (IRI) has been confirmed to induce endoplasmic reticulum stress (ERS) when myocardial cell function continues to deteriorate to a certain degree. The clinical applications of effective tested strategies are sometimes inconsistent with the applications evaluated in experiments, although reasonable mechanisms and diverse signalling pathways have been broadly explored. Dexmedetomidine (DEX) has been shown to attenuate IRI of the heart in animal studies. This study aimed to determine whether DEX can protect injured cardiomyocytes under hypoxia/reoxygenation (H/R) at the cellular level and whether the mechanism is related to ERS and the p38 MAPK pathway. Methods: H9c2 cells were subjected to H/R or thapsigargin (TG) to build a model. DEX or 4-PBA was added to the medium either 1 h or 24 h before modelling, respectively. Model parameters were determined by assessing cell viability and injury, which were measured by assessing cell counting kit-8 (CCK8), lactate dehydrogenase (LDH) release and flow cytometry results, and the expression of GRP78, CHOP and caspase-12. In addition, the protein expression of p38MAPK and p-p38MAPK was examined, and SB202190, a negative regulator, was also preincubated in medium. Results: Compared to that of cells in the control group, the activity of cells in the H/R and TG groups was decreased dramatically, and the LDH concentration and proportion of apoptotic cells were increased. DEX could correspondingly reverse the changes induced by H/R or TG. Additionally, DEX effectively attenuated ERS defined as increased expression of GRP78, CHOP and caspase-12. Additionally, DEX could obviously depress the P38 MAPK phosphorylation and high p-p38 MAPK expression in the TG group, indicating DEX has a function similar to that of SB202190. Conclusion: H/R injury in H9c2 cells can lead to abnormal ERS and apoptosis, as well as activation of the p38MAPK signalling pathway. DEX can protect cardiomyocytes by intervening in ERS, regulating p38MAPK and the downstream apoptotic signalling pathway.

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Dexmedetomidine attenuates neuronal injury after spinal cord ischaemia‐reperfusion injury by targeting the CNPY2‐endoplasmic reticulum stress signalling

Cited by 24 publications

References 40 publications

Salidroside Ameliorates Mitochondria-Dependent Neuronal Apoptosis after Spinal Cord Ischemia-Reperfusion Injury Partially through Inhibiting Oxidative Stress and Promoting Mitophagy

Salidroside Ameliorates Mitochondria-Dependent Neuronal Apoptosis after Spinal Cord Ischemia-Reperfusion Injury Partially through Inhibiting Oxidative Stress and Promoting Mitophagy

Analgesic effect of dexmedetomidine in rats after chronic constriction injury by mediating microRNA‐101 expression and the E2F2–TLR4–NF‐κB axis

<p>Dexmedetomidine Attenuates Cellular Injury and Apoptosis in H9c2 Cardiomyocytes by Regulating p-38MAPK and Endoplasmic Reticulum Stress</p>

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