Dexmedetomidine attenuates endoplasmic reticulum stress-induced apoptosis and improves neuronal function after traumatic brain injury in mice

Sun, Dongdong; Wang, Jianhao; Liu, Xilei; Fan, Yueshan; Yang, Ming; Zhang, Jianning

doi:10.1016/j.brainres.2020.146682

Cited by 31 publications

(15 citation statements)

References 33 publications

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“…Pretreatment with Dex increased cell viability and reduced the proportion of apoptosis cells in MPP + ‐induced SH‐SY5Y cells. The neuroprotective effects of Dex have also been observed in various ischemic and haemorrhagic brain injury models (Schoeler et al, 2012; Wang et al., 2018; Sun et al, 2020). The concentration of Dex used in our study was 10nM, and its neuroprotective effect was not dose dependent.…”

Section: Discussionmentioning

confidence: 95%

“…Dex is an adrenaline α2 agonist, which has sedative, anti‐anxiety and analgesic effects, and has no respiratory depression common to other sedatives (Mathews et al., 2017). Many evidences show that Dex plays a neuroprotective role in various ischemic and haemorrhagic brain injury models (Schoeler et al., 2012; Sun et al., 2020; Wang et al., 2018). Low‐dose Dex sedation and timed bright light exposure can effectively reduce postoperative delirium (Lu et al., 2019).…”

Section: Introductionmentioning

confidence: 99%

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Dexmedetomidine protects SH‐SY5Y cells against MPP⁺‐induced declining of mitochondrial membrane potential and cell cycle deficits

Chen

Song

Cheng

et al. 2021

Eur J of Neuroscience

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Dexmedetomidine (Dex), an adrenergic α2 receptor agonist, is commonly used in deep-brain stimulation surgery for Parkinson's disease (PD). However, there is evidence that the use of anaesthetics may accelerate the progression of neurodegenerative diseases. The effect of Dex on PD remains unclear. Here, we cultured the all-trans-retinoicacid (ATRA) differentiated SH-SY5Y cells in vitro and then treated with MPP + (1.5mM) with or without Dex (10nM) or Dex combined with Atipamezole (Ati,100nM, adrenergic α2 receptor inhibitor). The ratio of apoptotic cells, mitochondrial membrane potential (Δψm), reactive oxygen species (ROS), cell cycle and apoptotic markers (Cleaved caspase-3, 9) were analysed by flow cytometry and immunofluorescence. We found that the levels of apoptotic ratio and cleaved caspase-3, 9 increased, ROS accumulated, and mitochondrial membrane potential decreased after MPP+treatment, while these changes were partially reversed by Dex.Dex also prevented MPP + induced cell arrest by increasing G1 phase cells, decreasing S phase cells, and decreasing the expression of cyclinD1 and Cdk4. Moreover the effects of Dex were partially reversed by Ati. These findings reveal that Dex attenuated MPP + -induced apoptosis of SH-SY5Y cells by preventing the loss of Δψm, reducing ROS, and regulating the cell cycle. Our findings indicated that Dex is more likely to be a potential drug for the treatment of PD.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine protects SH‐SY5Y cells against MPP⁺‐induced declining of mitochondrial membrane potential and cell cycle deficits

Chen

Song

Cheng

et al. 2021

Eur J of Neuroscience

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“…In previous studies, DEX exhibited a protective role in the hearts of diabetic mice by interfering with ERS or autophagy, thereby suppressing IRI (6,23); however, the results were partially attributed to the diabetes context. Furthermore, researchers have focused on the study of cells other than cardiomyocytes, such as endothelial cells, under IRI or hypoxia/reoxygenation (H/R) conditions (24,25), and have examined several crucial ERS chaperones, proteins and apoptosis indicators that are produced by organs other than the heart under IRI or H/R conditions (6,(26)(27)(28)(29)(30). These studies have shown that DEX effectively regulates the function of non-cardiomyocytes and interferes with the ERS signaling pathway under these conditions.…”

Section: Dexmedetomidine At a Dose Of 1 µM Attenuates H9c2 Cardiomyocmentioning

confidence: 99%

Dexmedetomidine at a dose of 1 µM attenuates H9c2 cardiomyocyte injury under 3 h of hypoxia exposure and 3 h of reoxygenation through the inhibition of endoplasmic reticulum stress

et al. 2020

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Myocardial ischemia-reperfusion injury (MIRI) has been confirmed to induce endoplasmic reticulum stress (ERS) during downstream cascade reactions after the sufficient deterioration of cardiomyocyte function. However, clinically outcomes have been inconsistent with experimental findings because the mechanism has not been entirely elucidated. Dexmedetomidine (DEX), an α 2 adrenergic receptor agonist with anti-inflammatory and organ-protective activity, has been shown to attenuate IRI in the heart. The present study aimed to determine whether DEX is able to protect injured cardiomyocytes under in vitro hypoxia/reoxygenation (H/R) conditions and evaluate the conditions under which ERS is efficiently ameliorated. The cytotoxicity of DEX in H9c2 cells was evaluated 24 h after treatment with several different concentrations of DEX. The most appropriate H/R model parameters were determined by the assessment of cell viability and injury with Cell Counting Kit-8 and lactate dehydrogenase (LDH) release assays after incubation under hypoxic conditions for 3 h and reoxygenation conditions for 3, 6, 12 and 24 h. Additionally, the aforementioned methods were used to assess cardiomyocytes cultured with various concentrations of DEX under H/R conditions. Furthermore, the degree of apoptosis and the mRNA and protein expression levels of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and caspase-12 were evaluated in all groups. The addition of 1, 5 and 10 µM DEX to the cell culture significantly increased the proliferation of H9c2 cells by >80% under normal culture conditions. In the H/R model assessment, following 3 h of anoxia exposure, H9c2 cell viability decreased to 62.67% with 3 h of reoxygenation and to 36% with 6 h of reoxygenation compared with the control. The viability of H9c2 cells subjected to hypoxia for 3 h and reoxygenation for 3 h increased by 61.3% when pretreated with 1 µM DEX, and the LDH concentration in the supernatant was effectively decreased by 13.7%. H/R significantly increased the percentage of apoptotic cells, as detected by flow cytometry, and increased the expression levels of GRP78, CHOP and caspase-12, while treatment with either DEX or 4-phenylbutyric acid (4-PBA) significantly attenuated these effects. Additionally, despite the protective effect of DEX against H/R injury, 4-PBA attenuated the changes induced by DEX and H/R. In conclusion, treatment with 1 µM DEX alleviated cell injury, apoptosis and the increases in GRP78, CHOP and caspase-12 expression levels in H9c2 cells induced by 3 h of hypoxia and 3 h of reoxygenation.

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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 endoplasmic reticulum stress-induced apoptosis and improves neuronal function after traumatic brain injury in mice

Cited by 31 publications

References 33 publications

Dexmedetomidine protects SH‐SY5Y cells against MPP⁺‐induced declining of mitochondrial membrane potential and cell cycle deficits

Dexmedetomidine protects SH‐SY5Y cells against MPP⁺‐induced declining of mitochondrial membrane potential and cell cycle deficits

Dexmedetomidine at a dose of 1 µM attenuates H9c2 cardiomyocyte injury under 3 h of hypoxia exposure and 3 h of reoxygenation through the inhibition of endoplasmic reticulum stress

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

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Dexmedetomidine attenuates endoplasmic reticulum stress-induced apoptosis and improves neuronal function after traumatic brain injury in mice

Cited by 31 publications

References 33 publications

Dexmedetomidine protects SH‐SY5Y cells against MPP+‐induced declining of mitochondrial membrane potential and cell cycle deficits

Dexmedetomidine protects SH‐SY5Y cells against MPP+‐induced declining of mitochondrial membrane potential and cell cycle deficits

Dexmedetomidine at a dose of 1 µM attenuates H9c2 cardiomyocyte injury under 3 h of hypoxia exposure and 3 h of reoxygenation through the inhibition of endoplasmic reticulum stress

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

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Dexmedetomidine protects SH‐SY5Y cells against MPP⁺‐induced declining of mitochondrial membrane potential and cell cycle deficits

Dexmedetomidine protects SH‐SY5Y cells against MPP⁺‐induced declining of mitochondrial membrane potential and cell cycle deficits