Orexin-A protects against oxygen-glucose deprivation/reoxygenation-induced cell damage by inhibiting endoplasmic reticulum stress-mediated apoptosis via the Gi and PI3K signaling pathways

Kong, Tingting; Qiu, Kaixin; Liu, Minghui; Cheng, Baohua; Pan, Yanyou; Yang, Chunqing; Chen, Jing; Wang, Chunmei

doi:10.1016/j.cellsig.2019.109348

Cited by 12 publications

(14 citation statements)

References 28 publications

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“…Our previous study initially confirmed that OXA can prevent CIRI in Sprague-Dawley (SD) rats subjected to middle cerebral artery occlusion (MCAO) model and reperfusion (17). In an oxygen/glucose deprivation and reoxygenation model in vitro, it was also revealed that OXA exerts its protective role by inhibiting ERS-mediated apoptosis (18). In the present study, an MCAO model was established to simulate CIRI and investigated whether OXA can exert neuroprotective effects by inhibiting ERS-mediated apoptosis in vivo.…”

Section: Orexin-a Alleviates Cerebral Ischemia-reperfusion Injury By mentioning

confidence: 85%

Orexin-A alleviates cerebral ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress-mediated apoptosis

Kong

Cheng

et al. 2021

Mol Med Rep

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Orexin-A (OXA) protects neurons against cerebral ischemia-reperfusion injury (CIRI). Endoplasmic reticulum stress (ERS) induces apoptosis after CIRI by activating caspase-12 and the CHOP pathway. The present study aimed to determine whether OXA mitigates CIRI by inhibiting ERS-induced neuronal apoptosis. A model of CIRI was established, in which rats were subjected to middle cerebral artery occlusion with ischemic intervention for 2 h, followed by reperfusion for 24 h. Neurological deficit examination and 2,3,5-triphenyltetrazolium chloride staining were performed to assess the level of CIRI and neuroprotection by OXA. Expression levels of ERS-related proteins and cleaved caspase-3 were measured via western blotting, while the rate of neuronal apoptosis in the cortex was determined using a TUNEL assay. OXA treatment decreased the infarct volume of rats after CIRI and attenuated neuron apoptosis. Furthermore, administration of OXA decreased the expression levels of GRP78, phosphorylated (p)-PERK, p-eukaryotic initiation factor-2α, p-inositol requiring enzyme 1α, p-JNK, cleaved caspase-12, CHOP and cleaved caspase-3, all of which were induced by CIRI. Collectively, these findings suggested that OXA attenuated CIRI by inhibiting ERS-mediated apoptosis, thus clarifying the mechanism underlying its neuroprotective effect and providing a novel therapeutic direction for the treatment of CIRI.

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Section: Orexin-a Alleviates Cerebral Ischemia-reperfusion Injury By mentioning

confidence: 85%

Orexin-A alleviates cerebral ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress-mediated apoptosis

Kong

Cheng

et al. 2021

Mol Med Rep

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“…To elucidate the additional mechanism of GTPs on antiapoptosis apart from antioxidation, we investigated the possibility of GTPs on the ER pathway concerning apoptosis in cerebral injury post-CA/PCR, since it is known that ER stress relates to pathophysiology of ischemia-reperfusion [29,30]. As the important site for protein folding and synthesis, ER is very sensitive to the homeostasis unbalance of the body [31].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, in in vivo experiment, the overexpressed GRP78 exerted cardioprotective effects and mitigates cell apoptosis by suppressing ROS after myocardial I/R injury [34]. Inhibition of caspase-12 pathway can reduce neuronal apoptosis in cerebral ischemia, and caspase-12-deficient rats can resist ER stress-induced apoptosis, while other death stimuli can still induce apoptosis [29,30,35]. So, our study suggests that the modulation of ER stress could be potential access for alleviating brain cell death after CA/PCR.…”

Section: Discussionmentioning

confidence: 99%

Green Tea Polyphenols Modulated Cerebral SOD Expression and Endoplasmic Reticulum Stress in Cardiac Arrest/Cardiopulmonary Resuscitation Rats

Qin

Chen

et al. 2020

BioMed Research International

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Background. Reducing cerebral ischemia-reperfusion injury is crucial for improving survival and neurologic outcomes after cardiac arrest/cardiopulmonary resuscitation (CA/CPR). The purpose of this study is to investigate the neuroprotective effects of green tea polyphenols (GTPs) concern with the modulation of endogenous antioxidation and endoplasmic reticulum stress. Methods. After subjecting to CA/CPR, rats were randomized into the saline group (NS, n = 40) and the GTPs group (GTPs, n = 40). Each group was blindly located into four subgroups according to four time points (12 h, 24 h, 48 h, and 72 h). Other rats without experiencing CA/CPR severed as the Sham group (Sham, n = 10). Brain tissue samples were harvested at relative time points. The expressions of superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), caspase-3, and C/EBP-homologous protein (CHOP) were detected by immunofluorescence, dead neurons were assayed by TUNEL staining, and the expressions of caspase-12 and glucose-regulated proteins 78 kDa (GRP78) were evaluated by western blotting, respectively. Results. Comparing with that in NS group, GTPs increased the expression of SOD1 and SOD2 at 12 h, 24 h, 48 h, 72 h, and the expression of GRP78 at 24 h and 48 h (p<0.05) butdecreased caspase-12, CHOP, caspase-3 level, and apoptotic number of neurons (p<0.05) after restoration of spontaneous circulation (ROSC). Conclusion. GTPs exert neuroprotective effects via mechanisms that may be related to the enhancement of endogenous antioxidant capacity and inhibition of endoplasmic reticulum stress in CA/CPR rat models.

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“…OX-A, a neuropeptide produced by the lateral hypothalamus, has a protective effect on cerebral ischemia-induced cell death [ 7 , 9 ]. Accordingly, in the present study we found that treatment with OX-A resulted in protection from ischemia/reperfusion injury in both the in vitro and in vivo models used.…”

Section: Discussionmentioning

confidence: 99%

“…The anatomical architecture of orexin neurons and the wide distribution of orexin receptors appear to be essential for the multiple functions of these neuropeptides. Orexins play an important role in many physiological aspects of mammalian life, including the control of food intake and sleep–wake behavior [ 5 , 6 ], as well as, among many others, the protection of neurons against oxidative stress and ischemic brain injury [ 7 , 8 , 9 ]. Brain ischemia is a neurological disorder that occurs when a part of the brain is deprived of oxygen and glucose, with subsequent neuronal cell death mainly due to oxygen and glucose deprivation (OGD)-mediated oxidative stress [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Role of 2-Arachidonoyl-Glycerol and CB1 Receptors in Orexin-A-Mediated Prevention of Oxygen–Glucose Deprivation-Induced Neuronal Injury

Palomba

Motta

Imperatore

et al. 2020

Cells

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Orexin-A (OX-A) protects the brain against oxidative stress-mediated ischemic injury. Since the endocannabinoid 2-arachidonoylglycerol (2-AG) and cannabinoid type-1 (CB1) receptors were previously shown to mediate some of the effects of OX-A exerted through the orexin-1 receptor (OX-1R), we investigated the involvement of 2-AG in OX-A-induced neuroprotection following oxygen and glucose deprivation (OGD) in mouse cortical neurons. OGD-induced reactive oxygen species (ROS) accumulation and neuronal death were prevented by both OX-A and arachidonyl-2′-chloroethylamide (ACEA), a synthetic CB1 receptor agonist, in a manner sensitive to OX-1R and CB1 receptor antagonists, SB334867 and AM251. OX-A stimulated 2-AG biosynthesis in cortical neurons. In neurons isolated from monoacylglycerol lipase (MAGL, a 2-AG hydrolyzing enzyme) null mice, 10-fold higher 2-AG concentrations were found and OGD failed to induce ROS production and cell death, whereas AM251 restored these noxious effects. OX-A-induced neuroprotection was mediated by the phosphoinositide-3-kinase/Akt (PI3K/Akt) survival pathway since both OX-A and ACEA induced phosphorylation of Akt and prevented OGD-induced cytochrome c release from the mitochondria, in a manner counteracted by SB334867 or AM251. Administration of OX-A reduced infarct volume and elevated brain 2-AG levels in a mouse model of transient ischemia. These results suggest that 2-AG and CB1 receptor mediate OX-A prevention of ischemia-induced neuronal apoptosis.

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Orexin-A protects against oxygen-glucose deprivation/reoxygenation-induced cell damage by inhibiting endoplasmic reticulum stress-mediated apoptosis via the Gi and PI3K signaling pathways

Abstract: Please refer to published version for the most recent bibliographic citation information. If a published version is known of, the repository item page linked to above, will contain details on accessing it.

Cited by 12 publications

References 28 publications

Orexin-A alleviates cerebral ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress-mediated apoptosis

Orexin-A alleviates cerebral ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress-mediated apoptosis

Green Tea Polyphenols Modulated Cerebral SOD Expression and Endoplasmic Reticulum Stress in Cardiac Arrest/Cardiopulmonary Resuscitation Rats

Role of 2-Arachidonoyl-Glycerol and CB1 Receptors in Orexin-A-Mediated Prevention of Oxygen–Glucose Deprivation-Induced Neuronal Injury

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