Dataset Information

Dexmedetomidine Protects Mouse Brain from Ischemia-Reperfusion Injury via Inhibiting Neuronal Autophagy through Up-Regulating HIF-1?.

ABSTRACT: Stroke is the leading cause of death in China and produces a heavy socio-economic burden in the past decades. Previous studies have shown that dexmedetomidine (DEX) is neuroprotective after cerebral ischemia. However, the role of autophagy during DEX-mediated neuroprotection after cerebral ischemia is still unknown. In this study, we found that post-conditioning with DEX and DEX+3-methyladenine (3-MA) (autophagy inhibitor) reduced brain infarct size and improved neurological deficits compared with DEX+RAPA (autophagy inducer) 24 h after transient middle cerebral artery artery occlusion (tMCAO) model in mice. DEX inhibited the neuronal autophagy in the peri-ischemic brain, and increased viability and decreased apoptosis of primary cultured neurons in oxygen-glucose deprivation (OGD) model. DEX induced expression of Bcl-1 and p62, while reduced the expression of microtubule-associated protein 1 light chain 3 (LC3) and Beclin 1 in primary cultured neurons through inhibition of apoptosis and autophagy. Meanwhile, DEX promoted the expression of hypoxia-inducible factor-1? (HIF-1?) both in vivo and in vitro, and 2-Methoxyestradiol (2ME2), an inhibitor of HIF-1?, could reverse DEX-induced autophagic inhibition. In conclusion, our study suggests that post-conditioning with DEX at the beginning of reperfusion protects mouse brain from ischemia-reperfusion injury via inhibition of neuronal autophagy by upregulation of HIF-1?, which provides a potential therapeutic treatment for acute ischemic injury.

SUBMITTER: Luo C

PROVIDER: S-EPMC5498477 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dexmedetomidine Protects Mouse Brain from Ischemia-Reperfusion Injury via Inhibiting Neuronal Autophagy through Up-Regulating HIF-1α.

Luo Cong C Ouyang Ming-Wen MW Fang Ying-Ying YY Li Shu-Ji SJ Zhou Quan Q Fan Jun J Qin Zai-Sheng ZS Tao Tao T

Frontiers in cellular neuroscience 20170706

Stroke is the leading cause of death in China and produces a heavy socio-economic burden in the past decades. Previous studies have shown that dexmedetomidine (DEX) is neuroprotective after cerebral ischemia. However, the role of autophagy during DEX-mediated neuroprotection after cerebral ischemia is still unknown. In this study, we found that post-conditioning with DEX and DEX+3-methyladenine (3-MA) (autophagy inhibitor) reduced brain infarct size and improved neurological deficits compared wi ...[more]

PMID: 28729825

Similar Datasets

Project description:The present study aimed to evaluate the role of autophagy in the protective effect of dexmedetomidine in lung injury caused by ischemia-reperfusion (IR) in rats. In total 48 adult male Sprague-Dawley rats were randomly divided into 6 groups (n=8) as follows: i) Sham group; ii) the IR group; iii) IR + 1 µg/kg dexmedetomidine preconditioning group (pre-LD); iv) IR + 10 µg/kg dexmedetomidine preconditioning group (pre-HD); v) IR + 1 µg/kg dexmedetomidine postconditioning group (post-LD); and vi) IR + 10 µg/kg dexmedetomidine postconditioning group (post-HD). After the rats were anesthetized, the hilum of the left lung was occluded with a non-invasive microvascular clip for 30 min to induce ischemia. The clip was then removed and the left lung was allowed to regain ventilation and blood for 2 h. The rats were then sacrificed, the left lung removed and the wet/dry (W/D) lung weight ratio was determined. Pathological changes to the lungs were evaluated by light and transmission electron microscopy. Furthermore, the rate of lung cell apoptosis was determined by the TUNEL assay. The expression of hypoxia-inducible factor 1α (HIF-1α), Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3), BNIP3 like (BNIP3 L) and microtubule-associated protein 1A/1B light chain 3B (LC3II) was determined by western blotting. Compared with the sham group, a significant increase in the W/D lung weight ratio, and malondialdehyde (MDA), BNIP3, BNIP3 L and LC3II levels were observed in the IR group, and HIF-1α levels and superoxide dismutase (SOD) activity were decreased. Furthermore, the W/D ratio was lower in the pre-LD and pre-HD groups than in the IR group. Additionally, SOD activity was significantly higher and MDA expression was significantly lower in the pre-LD and pre-HD groups compared with the IR group. BNIP3, BNIP3 L and LC3II protein levels were significantly lower in the pre-LD and pre-HD groups compared with the IR group, while HIF-1α was notably upregulated in the pre-LD and pre-HD groups compared with the IR group. In conclusion, the results of the present study indicate that dexmedetomidine preconditioning protects against lung injury induced by IR through inhibition of autophagy and apoptosis.

Project description:Background: Ischemia-reperfusion injury (I/R) strongly affects the prognosis of children with complicated congenital heart diseases (CHDs) who undergo long-term cardiac surgical processes. Recently, the α2-adrenergic receptor agonist Dexmedetomidine (Dex) has been reported to protect cardiomyocytes (CMs) from I/R in cellular models and adult rodent models. However, whether and how Dex may protect human CMs in young children remains largely unknown. Methods and Results: Human ventricular tissue from tetralogy of Fallot (TOF) patients and CMs derived from human-induced pluripotent stem cells (iPSC-CMs) were used to assess whether and how Dex protects human CMs from I/R. The results showed that when pretreated with Dex, the apoptosis marker-TUNEL and cleaved caspase 3 in the ventricular tissue were significantly reduced. In addition, the autophagy marker LC3II was significantly increased compared with that of the control group. When exposed to the hypoxia/reoxygenation process, iPSC-CMs pretreated with Dex also showed reduced TUNEL and cleaved caspase 3 and increased LC3II. When the autophagy inhibitor (3-methyladenine, 3-MA) was applied to the iPSC-CMs, the protective effect of Dex on the CMs was largely blocked. In addition, when the fusion of autophagosomes with lysosomes was blocked by Bafilomycin A1, the degradation of p62 induced by Dex during the autophagy process was suspended. Moreover, when pretreated with Dex, both the human ventricle and the iPSC-CMs expressed more AMP-activated protein kinase (AMPK) and phospho AMPK (pAMPK) during the I/R process. After AMPK knockout or the use of an α2-adrenergic receptor antagonist-yohimbine, the protection of Dex and its enhancement of autophagy were inhibited. Conclusion: Dex protects young human CMs from I/R injury, and α2-adrenergic receptor/AMPK-dependent autophagy plays an important role during this process. Dex may have a therapeutic effect for children with CHD who undergo long-term cardiac surgical processes.

Project description:BackgroundMyocardial ischemia-reperfusion injury (MIRI) is the most common cause of death worldwide. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the inflammatory response to MIRI. Dexmedetomidine (DEX), a specific agonist of α2-adrenergic receptor, is commonly used for sedation and analgesia in anesthesia and critically ill patients. Several studies have shown that dexmedetomidine has a strong anti-inflammatory effect in many diseases. Here, we investigated whether dexmedetomidine protects against MIRI by inhibiting the activation of the NLRP3 inflammasome in vitro.MethodsWe established an MIRI model in cardiomyocytes (CMs) alone and in coculture with cardiac fibroblasts (CFs) by hypoxia/reoxygenation (H/R) in vitro. The cells were treated with dexmedetomidine with or without MCC950 (a potent selective NLRP3 inhibitor). The beating rate and cell viability of cardiomyocytes, NLRP3 localization, the expression of inflammatory cytokines and NLRP3 inflammasome-related proteins, and the expression of apoptosis-related proteins, including Bcl2 and BAX, were determined.ResultsDexmedetomidine treatment increased the beating rates and viability of cardiomyocytes cocultured with cardiac fibroblasts. The expression of the NLRP3 protein was significantly upregulated in cardiac fibroblasts but not in cardiomyocytes after H/R and was significantly attenuated by dexmedetomidine treatment. Expression of the inflammatory cytokines IL-1β, IL-18 and TNF-α was significantly increased in cardiac fibroblasts after H/R and was attenuated by dexmedetomidine treatment. NLRP3 inflammasome activation induced the increased expression of cleaved caspase1, mature IL-1β and IL-18, while dexmedetomidine suppressed H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts. In addition, dexmedetomidine reduced the expression of Bcl2 and BAX in cocultured cardiomyocytes by suppressing H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts.ConclusionDexmedetomidine treatment can suppress H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts, thereby alleviating MIRI by inhibiting the inflammatory response.

Dataset Information

Dexmedetomidine Protects Mouse Brain from Ischemia-Reperfusion Injury via Inhibiting Neuronal Autophagy through Up-Regulating HIF-1?.

Publications

Dexmedetomidine Protects Mouse Brain from Ischemia-Reperfusion Injury via Inhibiting Neuronal Autophagy through Up-Regulating HIF-1α.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets