Spinal Peroxynitrite Contributes to Remifentanil-induced Postoperative Hyperalgesia via Enhancement of Divalent Metal Transporter 1 without Iron-responsive Element–mediated Iron Accumulation in Rats

2015 ◽  
Vol 122 (4) ◽  
pp. 908-920 ◽  
Author(s):  
Rui-Chen Shu ◽  
Lin-Lin Zhang ◽  
Chun-Yan Wang ◽  
Nan Li ◽  
Hai-Yun Wang ◽  
...  
Keyword(s):  
Manganese Superoxide Dismutase ◽  
Iron Concentration ◽  
Iron Chelator ◽  
Iron Accumulation ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Iron Responsive Element ◽  
Manganese Superoxide ◽  
Responsive Element

Abstract Background: Hyperalgesia is one of the negative consequences following intraoperative analgesia with remifentanil. Peroxynitrite is a critical determinant in nociceptive process. Peroxynitrite inactivates iron-sulfur cluster that results in mitochondrial dysfunction and the release of iron, leading to mitochondrial iron accumulation. Iron accumulation mediated by divalent metal transporter 1 (DMT1) plays a key role in N-methyl-d-aspartate neurotoxicity. This study aims to determine whether peroxynitrite contributes to remifentanil-induced postoperative hyperalgesia via DMT1-mediated iron accumulation. Methods: Behavior testing was performed in rat model at different time points. Three-nitrotyrosine, nitrated manganese superoxide dismutase, and DMT1 with/without iron-responsive element [DMT1(+)IRE and DMT1(-)IRE] in spinal cord were detected by Western blot and immunohistochemistry. Spinal iron concentration was measured using the Perl stain and atomic absorption spectrophotometer. Hydrogen-rich saline imparting selectivity for peroxynitrite decomposition and iron chelator was applied in mechanistic study on the roles of peroxynitrite and iron, as well as the prevention of hyperalgesia. Results: Remifentanil induced thermal and mechanical hyperalgesia at postoperative 48 h. Compared with control, there were higher levels of 3-nitrotyrosine (mean ± SD, hyperalgesia vs. control, 1.22 ± 0.18 vs. 0.25 ± 0.05, n = 4), nitrated manganese superoxide dismutase (1.01 ± 0.1 vs. 0.19 ± 0.03, n = 4), DMT1(-)IRE (1.42 ± 0.19 vs. 0.33 ± 0.06, n = 4), and iron concentration (12.87 ± 1.14 vs. 5.26 ± 0.61 μg/g, n = 6) in remifentanil-induced postoperative hyperalgesia, while DMT1(+)IRE was unaffected. Eliminating peroxynitrite with hydrogen-rich saline protected against hyperalgesia and attenuated DMT1(-)IRE overexpression and iron accumulation. Iron chelator prevented hyperalgesia in a dose-dependent manner. Conclusions: Our study identifies that spinal peroxynitrite activates DMT1(-)IRE, leading to abnormal iron accumulation in remifentanil-induced postoperative hyperalgesia, while providing the rationale for the development of molecular hydrogen and “iron-targeted” therapies.

scholarly journals Control of Systemic Iron Homeostasis by the 3’ Iron-Responsive Element of Divalent Metal Transporter 1 in Mice

HemaSphere ◽  
2020 ◽  
Vol 4 (5) ◽  
pp. e459
Author(s):  
Elisabeth Tybl ◽  
Hiromi Gunshin ◽  
Sanjay Gupta ◽  
Tomasa Barrientos ◽  
Michael Bonadonna ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Divalent Metal ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Iron Responsive Element ◽  
Responsive Element

scholarly journals Control of Systemic Iron Homeostasis by the 3’ Iron-Responsive Element of Divalent Metal Transporter 1 in Mice

2020 ◽  
Author(s):  
Elisabeth Tybl ◽  
Hiromi Gunshin ◽  
Sanjay Gupta ◽  
Tomasa Barrientos ◽  
Michael Bonadonna ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Mrna Translation ◽  
Divalent Metal ◽  
Targeted Mutagenesis ◽  
List Type ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Iron Responsive Element ◽  
Responsive Element

AbstractDivalent metal transporter 1 (DMT1) is essential for dietary iron assimilation and erythroid iron acquisition. The 3’ untranslated region of the murine DMT1 mRNA contains an iron responsive element (IRE) that is conserved in humans but whose functional role remains unclear. We generated and analyzed mice with targeted disruption of the DMT1 3’IRE. These animals display hypoferremia during the suckling period, associated with a reduction of DMT1 mRNA and protein in the intestine. In contrast, adult mice exhibit hyperferremia, accompanied by enlargement of hepatic and splenic iron stores. Intriguingly, disruption of the DMT1 3’IRE in adult animals augments intestinal DMT1 expression, in part due to increased mRNA translation. Hence, during postnatal growth, the DMT1 3’IRE promotes intestinal DMT1 expression and secures iron sufficiency; in adulthood, it suppresses DMT1 and prevents systemic iron loading. This work demonstrates that the 3’IRE of DMT1 plays a role in the control of DMT1 expression and systemic iron homeostasis, and reveals an age-dependent switch in its activity.Key pointsTargeted mutagenesis of the 3’IRE of DMT1 in mice reveals its importance for maintenance of systemic iron homeostasis.The 3’IRE stimulates intestinal DMT1 expression and prevents hypoferremia during early life, but exerts opposite effects in adulthood

Gene expression of divalent metal transporter 1 and transferrin receptor in duodenum of Belgrade rats

2000 ◽  
Vol 278 (6) ◽  
pp. G930-G936 ◽  
Author(s):  
Phillip S. Oates ◽  
Carla Thomas ◽  
Elizabeth Freitas ◽  
Matthew J. Callow ◽  
Evan H. Morgan
Keyword(s):  
Gene Expression ◽  
Transferrin Receptor ◽  
Wistar Rats ◽  
Iron Concentration ◽  
Divalent Metal ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Transferrin Cycle ◽  
Crypt Cells

Regulation of iron absorption is thought to be mediated by the amount of iron taken up by duodenal crypt cells via the transferrin receptor (TfR)-transferrin cycle and the activity of the divalent metal transporter (DMT1), although DMT1 cannot be detected morphologically in crypt cells. We investigated the uptake of transferrin-bound iron by duodenal enterocytes in Wistar rats fed different levels of iron and Belgrade (b/b) rats in which iron uptake by the transferrin cycle is defective because of a mutation in DMT1. We showed that DMT1 in our colony of b/b rats contains the G185R mutation, which in enterocytes results in reduced cellular iron content and increased DMT1 gene expression similar to levels in iron deficiency of normal rats. In all groups the uptake of transferrin-bound iron by crypt cells was directly proportional to plasma iron concentration, being highest in iron-loaded Wistar rats and b/b rats. We conclude that the uptake of transferrin-bound iron by developing enterocytes is largely independent of DMT1.

Spinal NR2B phosphorylation at Tyr1472 regulates IRE(−)DMT1-mediated iron accumulation and spine morphogenesis via kalirin-7 in tibial fracture-associated postoperative pain after orthopedic surgery in female mice

2020 ◽  
pp. rapm-2020-101883
Author(s):  
Linlin Zhang ◽  
Zhen Wang ◽  
Chengcheng Song ◽  
Haoyu Liu ◽  
Yize Li ◽  
...  
Keyword(s):  
Postoperative Pain ◽  
Iron Overload ◽  
Tibial Fracture ◽  
Iron Concentration ◽  
Iron Accumulation ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Female Mice ◽  
Spine Plasticity ◽  
Spine Morphogenesis

BackgroundProlonged postoperative pain is a major concern and occurs more frequently in women, but mechanisms remain elusive. NR2B-containging N-methyl-d-aspartate (NMDA) receptor is a key component of nociception transduction. Divalent metal transporter 1 (DMT1)-mediated iron overload involves NMDA-induced neurotoxicity in males. Kalirin-7 is vital in synaptic plasticity underlying pathological pain in males. Herein, the requirement for kalirin-7 in NR2B phosphorylation-dependent iron accumulation and spine plasticity in postoperative pain after tibial fracture in female mice has been examined.MethodsPain-related behavior, spinal NR2B phosphorylation at Tyr1472, kalirin-7 expression, DMT1 with/without iron-responsive element (IRE (+) DMT1 and IRE (−) DMT1) level, iron concentration and spine morphology were assessed in females. NR2B antagonist Ro25-6981, iron chelator deferoxamine and kalirin-7 knockdown by short hairpin RNA were employed to assess the potential cascade.ResultsTibial fracture initiates long-term allodynia lasting at least 21 days postoperatively, and upregulates spinal NR2B phosphorylation, kalirin-7 and IRE (−) DMT1 expression, iron overload and spine density. Ro25-6981 reduces postoperative mechanical and cold allodynia, spinal NR2B phosphorylation, kalirin-7 level and IRE (−) DMT1-mediated iron overload. Kalirin-7 knockdown impairs fracture-associated allodynia, IRE (−) DMT1-mediated iron overload and spine plasticity. Deferoxamine also attenuates behavioral allodynia and spine plasticity. Spinal NMDA application elicits NR2B-dependent mechanical allodynia and iron overload, which is reversed by kalirin-7 knockdown or coadministration of deferoxamine.ConclusionSpinal NR2B phosphorylation at Tyr1472 upregulates kalirin-7 expression to facilitate IRE (−) DMT1-mediated iron accumulation and spine morphogenesis in the development of fracture-associated postoperative pain in female mice.

Two routes of iron accumulation in astrocytes: ascorbate-dependent ferrous iron uptake via the divalent metal transporter (DMT1) plus an independent route for ferric iron

2010 ◽  
Vol 432 (1) ◽  
pp. 123-132 ◽  
Author(s):  
Darius J.R. Lane ◽  
Stephen R. Robinson ◽  
Hania Czerwinska ◽  
Glenda M. Bishop ◽  
Alfons Lawen
Keyword(s):  
Iron Uptake ◽  
Divalent Metal ◽  
Iron Accumulation ◽  
Mammalian Brain ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Uptake Pathway ◽  
Cultured Astrocytes

Astrocytes are central to iron and ascorbate homoeostasis within the brain. Although NTBI (non-transferrin-bound iron) may be a major form of iron imported by astrocytes in vivo, the mechanisms responsible remain unclear. The present study examines NTBI uptake by cultured astrocytes and the involvement of ascorbate and DMT1 (divalent metal transporter 1). We demonstrate that iron accumulation by ascorbate-deficient astrocytes is insensitive to both membrane-impermeant Fe(II) chelators and to the addition of the ferroxidase caeruloplasmin. However, when astrocytes are ascorbate-replete, as occurs in vivo, their rate of iron accumulation is doubled. The acquisition of this additional iron depends on effluxed ascorbate and can be blocked by the DMT1 inhibitor ferristatin/NSC306711. Furthermore, the calcein-accessible component of intracellular labile iron, which appears during iron uptake, appears to consist of only Fe(III) in ascorbate-deficient astrocytes, whereas that of ascorbate-replete astrocytes comprises both valencies. Our data suggest that an Fe(III)-uptake pathway predominates when astrocytes are ascorbate-deficient, but that in ascorbate-replete astrocytes, at least half of the accumulated iron is initially reduced by effluxed ascorbate and then imported by DMT1. These results suggest that ascorbate is intimately involved in iron accumulation by astrocytes, and is thus an important contributor to iron homoeostasis in the mammalian brain.

scholarly journals Transgenic Mice Overexpressing the Divalent Metal Transporter 1 Exhibit Iron Accumulation and Enhanced Parkin Expression in the Brain

2017 ◽  
Vol 19 (2-3) ◽  
pp. 375-386 ◽  
Author(s):  
Cheng-Wu Zhang ◽  
Yee Kit Tai ◽  
Bing-Han Chai ◽  
Katherine C. M. Chew ◽  
Eng-Tat Ang ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Divalent Metal ◽  
Iron Accumulation ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
The Brain
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