Abstract
Both in vivo and in vitro studies have shown the beneficial effects of the delta-opioid receptor (DOR) on neurodegeneration in hypoxia/ischemia. We previously reported that DOR stimulation with [(D-Ala2, D-Leu5) enkephalin] (DADLE), a potent DOR agonist, for both a short (minutes) and long (days) time has notable protective effects against sodium azide (NaN3)-induced cell injury in primary cultured rat cortical neurons. We further demonstrated that short-term DADLE stimulation increased neuronal survival through the PKC-mitochondrial ERK pathway. However, the mechanisms underlying long-term neuroprotection by DADLE remain unclear. Here, we showed that DOR stimulation with DADLE (0.1 μmol/L) for 2 d selectively activates the PI3K/Akt/NF-κB pathway in NaN3-treated neurons; this activation increased Bcl-2 expression, attenuated Cyto c release and promoted neuronal survival. Further investigation revealed that sustained DADLE stimulation increased Bcl-2 expression by enhancing NF-κB binding to the Bcl-2 promoter and upregulating the histone acetylation levels of the Bcl-2 promoter. Our results demonstrate that prolonged DADLE exposure epigenetically promotes Bcl-2 expression and elicits neuroprotective effects in the NaN3 model via the PI3K/Akt/NF-κB pathway.
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References
Zhang J, Haddad GG, Xia Y. delta-, but not mu- and kappa-, opioid receptor activation protects neocortical neurons from glutamate-induced excitotoxic injury. Brain Res 2000; 885: 143–53.
Law PY, Wong YH, Loh HH. Molecular mechanisms and regulation of opioid receptor signaling. Annu Rev Pharmacol Toxicol 2000; 40: 389–430.
Zhang J, Qian H, Zhao P, Hong SS, Xia Y. Rapid hypoxia preconditioning protects cortical neurons from glutamate toxicity through delta-opioid receptor. Stroke 2006; 37: 1094–9.
Ma MC, Qian H, Ghassemi F, Zhao P, Xia Y. Oxygen-sensitive {delta}-opioid receptor-regulated survival and death signals: novel insights into neuronal preconditioning and protection. J Biol Chem 2005; 280: 16208–18.
Zhang J, Gibney GT, Zhao P, Xia Y. Neuroprotective role of delta-opioid receptors in cortical neurons. Am J Physiol Cell Physiol 2002; 282: C1225–34.
Drolet G, Dumont EC, Gosselin I, Kinkead R, Laforest S, Trottier JF. Role of endogenous opioid system in the regulation of the stress response. Prog Neuropsychopharmacol Biol Psychiatry 2001; 25: 729–41.
Peng PH, Huang HS, Lee YJ, Chen YS, Ma MC. Novel role for the delta-opioid receptor in hypoxic preconditioning in rat retinas. J Neurochem 2009; 108: 741–54.
Zhu M, Li M, Yang F, Ou X, Ren Q, Gao H, et al. Mitochondrial ERK plays a key role in delta-opioid receptor neuroprotection against acute mitochondrial dysfunction. Neurochem Int 2011; 59: 739–48.
Narita M, Kuzumaki N, Miyatake M, Sato F, Wachi H, Seyama Y, et al. Role of delta-opioid receptor function in neurogenesis and neuroprotection. J Neurochem 2006; 97: 1494–505.
Chao D, Balboni G, Lazarus LH, Salvadori S, Xia Y. Na+ mechanism of delta-opioid receptor induced protection from anoxic K+ leakage in the cortex. Cell Mol Life Sci 2009; 66: 1105–15.
Chao D, Bazzy-Asaad A, Balboni G, Salvadori S, Xia Y. Activation of DOR attenuates anoxic K+ derangement via inhibition of Na+ entry in mouse cortex. Cereb Cortex 2008; 18: 2217–27.
Chao D, Donnelly DF, Feng Y, Bazzy-Asaad A, Xia Y. Cortical delta-opioid receptors potentiate K+ homeostasis during anoxia and oxygen-glucose deprivation. J Cereb Blood Flow Metab 2007; 27: 356–68.
Chao D, Bazzy-Asaad A, Balboni G, Xia Y. delta-, but not mu-, opioid receptor stabilizes K+ homeostasis by reducing Ca2+ influx in the cortex during acute hypoxia. J Cell Physiol 2007; 212: 60–7.
Ke S, Dian-san S, Xiang-rui W. Delta opioid agonist [D-Ala2, D-Leu5] enkephalin (DADLE) reduced oxygen-glucose deprivation caused neuronal injury through the MAPK pathway. Brain Res 2009; 1292: 100–6.
Heiss A, Ammer H, Eisinger DA. delta-Opioid receptor-stimulated Akt signaling in neuroblastoma x glioma (NG108-15) hybrid cells involves receptor tyrosine kinase-mediated PI3K activation. Exp Cell Res 2009; 315: 2115–25.
Lv MR, Li B, Wang MG, Meng FG, Yu JJ, Guo F, et al. Activation of the PI3K-Akt pathway promotes neuroprotection of the delta-opioid receptor agonist against cerebral ischemia-reperfusion injury in rat models. Biomed Pharmacother 2017; 93: 230–7.
Zhu M, Li MW, Tian XS, Ou XM, Zhu CQ, Guo JC. Neuroprotective role of delta-opioid receptors against mitochondrial respiratory chain injury. Brain Res 2009; 1252: 183–91.
Zhu L, Derijard B, Chakrabandhu K, Wang BS, Chen HZ, Hueber AO. Synergism of PI3K/Akt inhibition and Fas activation on colon cancer cell death. Cancer Lett 2014; 354: 355–64.
Safiulina D, Veksler V, Zharkovsky A, Kaasik A. Loss of mitochondrial membrane potential is associated with increase in mitochondrial volume: physiological role in neurones. J Cell Physiol 2006; 206: 347–53.
Marino S, Marani L, Nazzaro C, Beani L, Siniscalchi A. Mechanisms of sodium azide-induced changes in intracellular calcium concentration in rat primary cortical neurons. Neurotoxicology 2007; 28: 622–9.
Jiang X, Wang X. Cytochrome c-mediated apoptosis. Annu Rev Biochem 2004; 73: 87–106.
Barkett M, Gilmore TD. Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene 1999; 18: 6910–24.
Jeong S, Kim SJ, Jeong C, Lee S, Jeong H, Lee J, et al. Neuroprotective effects of remifentanil against transient focal cerebral ischemia in rats. J Neurosurg Anesthesiol 2012; 24: 51–7.
Tian J, Gu Y, Sun K, Wang B, Chen J, Wang X, et al. [D-Ala2, D-Leu5] encephalin (DADLE) reversibly inhibits cellular transcription in neurons without causing cell injury. Brain Res 2014; 1565: 1–7.
Wang Z, Tang B, Tang F, Li Y, Zhang G, Zhong L, et al. Protection of rat intestinal epithelial cells from ischemia/reperfusion injury by (D-Ala2, D-Leu5)-enkephalin through inhibition of the MKK7-JNK signaling pathway. Mol Med Rep 2015; 12: 4079–88.
Sen D, Huchital M, Chen YL. Crosstalk between delta opioid receptor and nerve growth factor signaling modulates neuroprotection and differentiation in rodent cell models. Int J Mol Sci 2013; 14: 21114–39.
Kesaraju S, Nayak G, Prentice HM, Milton SL. Upregulation of Hsp72 mediates anoxia/reoxygenation neuroprotection in the freshwater turtle via modulation of ROS. Brain Res 2014; 1582: 247–56.
Wang Q, Chao D, Chen T, Sandhu H, Xia Y. delta-Opioid receptors and inflammatory cytokines in hypoxia: differential regulation between glial and neuron-like cells. Transl Stroke Res 2014; 5: 476–83.
Bassik MC, Scorrano L, Oakes SA, Pozzan T, Korsmeyer SJ. Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis. EMBO J 2004; 23: 1207–16.
Ito T, Deng X, Carr B, May WS. Bcl-2 phosphorylation required for anti-apoptosis function. J Biol Chem 1997; 272: 11671–3.
Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 1994; 12: 141–79.
Li G, Kalabis J, Xu X, Meier F, Oka M, Bogenrieder T, et al. Reciprocal regulation of MelCAM and AKT in human melanoma. Oncogene 2003; 22: 6891–9.
Dhawan P, Singh AB, Ellis DL, Richmond A. Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-kappaB and tumor progression. Cancer Res 2002; 62: 7335–42.
Lanzillotta A, Sarnico I, Ingrassia R, Boroni F, Branca C, Benarese M, et al. The acetylation of RelA in Lys310 dictates the NF-kappaB-dependent response in post-ischemic injury. Cell Death Dis 2010; 1: e96.
Huang X, Qin J, Lu S. Kanglaite stimulates anticancer immune responses and inhibits HepG2 cell transplantation induced tumor growth. Mol Med Rep 2014; 10: 2153–9.
Shu G, Yang T, Wang C, Su H, Xiang M. Gastrodin stimulates anticancer immune response and represses transplanted H22 hepatic ascitic tumor cell growth: Involvement of NF-kappaB signaling activation in CD4+ T cells. Toxicol Appl Pharmacol 2013; 269: 270–9.
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This work was supported by the Science and Technology Commission Program of Shanghai (No 06DZ1734) and the National Natural Science Foundation of China (No 30873318).
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Zhu, M., Liu, M., Guo, Ql. et al. Prolonged DADLE exposure epigenetically promotes Bcl-2 expression and elicits neuroprotection in primary rat cortical neurons via the PI3K/Akt/NF-κB pathway. Acta Pharmacol Sin 39, 1582–1589 (2018). https://doi.org/10.1038/aps.2018.7
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DOI: https://doi.org/10.1038/aps.2018.7