Delta opioid receptor agonist BW373U86 attenuates post-resuscitation brain injury in a rat model of asphyxial cardiac arrest

Yang, Lu; Zhao, Xiaoyong; Sun, Meiyan; Sun, Xude; Yao, Linong; Yu, De‐Quan; Ding, Qian; Gao, Changjun; Chai, Weidong

doi:10.1016/j.resuscitation.2013.10.022

Cited by 11 publications

(9 citation statements)

References 32 publications

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“…We detected both MOR and DOR proteins in microglia derived from the hypothalamus using both immunocytochemistry and flow cytometry methods. The difference between our and Mika et al [33] findings might be related to differential characteristics of microglia in various parts of the brain [34]. …”

Section: Discussioncontrasting

confidence: 98%

Mu-opioid receptor and delta-opioid receptor differentially regulate microglial inflammatory response to control proopiomelanocortin neuronal apoptosis in the hypothalamus: effects of neonatal alcohol

Shrivastava

Cabrera

Chastain

et al. 2017

J Neuroinflammation

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BackgroundOpioid receptors are known to control neurotransmission of various peptidergic neurons, but their potential role in regulation of microglia and neuronal cell communications is unknown. We investigated the role of mu-opioid receptors (MOR) and delta-opioid receptors (DOR) on microglia in the regulation of apoptosis in proopiomelanocortin (POMC) neurons induced by neonatal ethanol in the hypothalamus.MethodsNeonatal rat pups were fed a milk formula containing ethanol or control diets between postnatal days 2–6. Some of the alcohol-fed rats additionally received pretreatment of a microglia activation blocker minocycline. Two hours after the last feeding, some of the pups were sacrificed and processed for histochemical detection of microglial cell functions or confocal microscopy for detection of cellular physical interaction or used for gene and protein expression analysis. The rest of the pups were dissected for microglia separation by differential gradient centrifugation and characterization by measuring production of various activation markers and cytokines. In addition, primary cultures of microglial cells were prepared using hypothalamic tissues of neonatal rats and used for determination of cytokine production/secretion and apoptotic activity of neurons.ResultsIn the hypothalamus, neonatal alcohol feeding elevated cytokine receptor levels, increased the number of microglial cells with amoeboid-type circularity, enhanced POMC and microglial cell physical interaction, and decreased POMC cell numbers. Minocycline reversed these cellular effects of alcohol. Alcohol feeding also increased levels of microglia MOR protein and pro-inflammatory signaling molecules in the hypothalamus, and MOR receptor antagonist naltrexone prevented these effects of alcohol. In primary cultures of hypothalamic microglia, both MOR agonist [D-Ala 2, N-MePhe 4, Gly-ol]-enkephalin (DAMGO) and ethanol increased microglial cellular levels and secretion of pro-inflammatory cell signaling proteins. However, a DOR agonist [D-Pen2,5]enkephalin (DPDPE) increased microglial secretion of anti-inflammatory cytokines and suppressed ethanol’s ability to increase microglial production of inflammatory signaling proteins and secretion of pro-inflammatory cytokines. In addition, MOR-activated inflammation promoted while DOR-suppressed inflammation inhibited the apoptotic effect of ethanol on POMC neurons.ConclusionsThese results suggest that ethanol’s neurotoxic action on POMC neurons results from MOR-activated neuroinflammatory signaling. Additionally, these results identify a protective effect of a DOR agonist against the pro-inflammatory and neurotoxic action of ethanol.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0844-3) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 98%

Mu-opioid receptor and delta-opioid receptor differentially regulate microglial inflammatory response to control proopiomelanocortin neuronal apoptosis in the hypothalamus: effects of neonatal alcohol

Shrivastava

Cabrera

Chastain

et al. 2017

J Neuroinflammation

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“…An intriguing possibility is that arrest in the context of antecedent use of opioids or benzodiazepines may actually protect the brain from anoxic injury, either by decreasing the cerebral metabolic oxygen demand or through direct neuroprotective mechanisms. Animal models of cardiac arrest or anoxic brain injury have supported the concept of neuroprotection by benzodiazepines [ 22 ] and opioid agonists [ 23 , 24 ]. In humans, observational data have associated opioid use immediately before or during CPR with improved survival from in-hospital cardiac arrest [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…Traditional concern has been for elevation in intracranial pressure, however use of the NMDA antagonist ketamine has been associated with similar ICP effects as opioids when used for sedation in patients with intracranial pathology [ 22 ]. Finally, opioid agonists, while contributing to sedation and potentially diminished cerebral oxygen demand, may also contribute to cerebral cellular preservation via δ-opioid receptor associated reduction in the kinases ERK1 and ERK2 and TNF-α inflammatory mediator activity and production [ 23 ]. Opioid agonist effects at receptors other than the well-studied μ-receptor may have neuroprotective applications as further evidence is elucidated.…”

Section: Discussionmentioning

confidence: 99%

Recreational drug overdose-related cardiac arrests: Break on through to the other side

et al. 2015

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Introduction The annual rate of recreational overdose (OD)-related death is increasing exponentially, making unintentional overdose the leading cause of injury-related death in America. Unfortunately, little attention in the resuscitation community has focused on the post-arrest care of this rapidly growing population. Methods We included patients presenting between January 2009 and February 2014 after out-of-hospital cardiac arrest (OHCA) and abstracted baseline clinical characteristics and neurological outcomes. We considered an arrest to be an OD OHCA if toxicology screens were positive and not explained by therapeutic medication administration or home medications; or if there was a history strongly suggestive of OD. We compared the baseline clinical characteristics and outcomes between the OD and non-OD cohorts. Results In total, 591 OHCA patients were admitted, of which 85 (14%) arrests were OD-related. OD OHCA patients were significantly younger, had fewer medical comorbdities, were more likely to present with non-shockable rhythms and had worse baseline neurological function. However, overall survival, neurological outcomes and length of stay did not vary between groups. OD OHCA patients who survived to discharge had a significantly higher rate of favorable discharge dispositions (83% of OD OHCA survivors discharged to home or acute rehabilitation vs 62% of non-OD OHCA (P=0.03)). Conclusion Patients who have suffered an OD OHCA make up a significant proportion of the overall OHCA population. Despite poor baseline prognostic factors, survival after OD OHCA was no worse than after non-OD OHCA, and among survivors a majority had a good neurological outcome.

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“…Even after return of spontaneous circulation, reperfusion injury, cerebral edema and inflammation could exist for long time and lead to massive apoptosis of neuronal cells 17, 23 . It is well known that neuronal cell apoptosis is one of the main pathological change induced by CA post-ROSC, which is also the main form of brain cell death.…”

Section: Discussionmentioning

confidence: 99%

Hypertonic saline infusion suppresses apoptosis of hippocampal cells in a rat model of cardiopulmonary resuscitation

Zhou

Liu

Huang

et al. 2017

Sci Rep

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Hypertonic saline (HS) attenuates cerebral edema, improves microcirculation perfusion and alleviates inflammation. However, whether the beneficial effect of HS on neurological function after cardiopulmonary resuscitation (CPR) in rat model of asphyxial cardiac arrest (CA) is mediated via attenuating apoptosis of neurons is not known. We studied the neuroprotective effect of HS in rats after CA and CPR, and explored the likely underlying mechanisms. Animals were randomly assigned to 4 equal groups (n = 15 each) according to the different infusions administered during resuscitation: control (C), normal saline (NS), hypertonic saline (HS), and hydroxyethyl starch (HES) groups. NDS at 12, 24, 48 and 72 h post-ROSC in the HS group were significantly higher than those in the NS and HES groups. Western blot analysis demonstrated a significant increase in Bcl-2 expression in HS, as compared to that in the NS and HES groups. However, Bax and Caspase-3 expressions in HS were significantly lower than that in the NS and HES groups. The apoptosis rate in HS was significantly lower than that in the NS and HES groups, suggesting HS treatment during resuscitation could effectively suppress neuronal cell apoptosis in hippocampal CA1 post-ROSC and improve neuronal function.

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Delta opioid receptor agonist BW373U86 attenuates post-resuscitation brain injury in a rat model of asphyxial cardiac arrest

Cited by 11 publications

References 32 publications

Mu-opioid receptor and delta-opioid receptor differentially regulate microglial inflammatory response to control proopiomelanocortin neuronal apoptosis in the hypothalamus: effects of neonatal alcohol

Mu-opioid receptor and delta-opioid receptor differentially regulate microglial inflammatory response to control proopiomelanocortin neuronal apoptosis in the hypothalamus: effects of neonatal alcohol

Recreational drug overdose-related cardiac arrests: Break on through to the other side

Hypertonic saline infusion suppresses apoptosis of hippocampal cells in a rat model of cardiopulmonary resuscitation

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