Molecular Neurobiology

, Volume 56, Issue 7, pp 5229–5240 | Cite as

δ-Opioid Receptor-Nrf-2-Mediated Inhibition of Inflammatory Cytokines in Neonatal Hypoxic-Ischemic Encephalopathy

  • Jie Qiu
  • Dongman Chao
  • Shiying Sheng
  • Dhiaedin Khiati
  • Xiaoyu Zhou
  • Ying XiaEmail author


Neonatal hypoxic-ischemic encephalopathy (HIE) causes serious neurological disability; there are, however, currently few promising therapies for it. We have recently shown that δ-opioid receptor (DOR) is neuroprotective by downregulating TNF-α. Since hypoxia-ischemia (HI) triggers a robust inflammatory response, which exacerbates HI brain damage, we investigated, in this study, whether DOR activation could regulate inflammatory cytokine expression, thereby playing a protective effect on the neonatal brain under HI. Twenty-five neonatal rats were randomly divided into five groups: (1) control (control); (2) HI; (3) HI with saline (HI + NS); (4) DOR activation with UFP-512 (a potent and specific DOR agonist) under HI conditions (HI + U); and (5) DOR inhibition using NT treatment under HI conditions (HI + NT). The rats were sacrificed by decapitation at 24 h after HI, and their brains were rapidly removed for measurements. The protein expression of TNF-α, IL-6, ICAM-1, IL-10, IL-18, NQO-1, Nrf-2, and HO-1 was measured using Western blot. In the hemispheres exposed to HI, DOR activation significantly decreased the expressions of TNF-α, IL-6, and ICAM-1 in the cortex, while it significantly increased IL-10 and had no effect on IL-18 in the same region. In contrast, DOR had no appreciable effect on inflammatory cytokine expression in non-cortical tissues including hippocampal, subcortical, and cerebellar tissues. Moreover, HI stress triggered an upregulation of Nrf-2 nuclear protein as well as some of its downstream anti-inflammatory genes such as HO-1 and NQO-1 in the cortex, while DOR activation further augmented such a protective reaction against HI injury. DOR plays an important role in protecting against HI by regulating the expression of inflammatory and anti-inflammatory cytokines in the cortex, which is likely mediated by the Nrf-2/HO-1/NQO-1 signaling.


Hypoxic-ischemic encephalopathy δ-Opioid receptor Inflammatory cytokines Nrf-2 



This project was partially supported by the U.S. National Institutes of Health (NIH R01-004422), the National Natural Science Foundation of China (81671500, 81873361), and the Science and Technology Commission of Shanghai Municipality (18401970100).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


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Authors and Affiliations

  1. 1.Department of Newborn InfantsChildren’s Hospital of Nanjing Medical UniversityNanjingChina
  2. 2.Department of NeurosurgeryThe University of Texas McGovern Medical SchoolHoustonUSA
  3. 3.Department of NeurologyThe Third Affiliated Hospital of Soochow UniversityChangzhouChina
  4. 4.Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint FunctionFudan UniversityShanghaiChina
  5. 5.Department of Aeronautics and AstronauticsFudan UniversityShanghaiChina

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