N-acyl dopamine derivates as lead compound for implementation in transplantation medicine

Wedel, Johannes; Pallavi, Prama; Stamellou, Eleni; Yard, Benito A.

doi:10.1016/j.trre.2014.12.004

Cited by 6 publications

(7 citation statements)

References 66 publications

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“…With the renewed interest in the role of DA in the functions of donor organs, the present study investigated the effects of high‐dose DA commonly used in brain‐death donors with hemodynamic instability on systemic and hepatic hemodynamics in a rodent brain‐death model, as well as its effect on hepatocytes at both the cellular and molecular levels. The results of the present study not only support the proposal that hemodynamic stabilization alone is insufficient in suppressing the inflammatory impact elicited by brain death on the organs to be transplanted, but also further demonstrate the proinflammatory effect of high‐dose DA on liver grafts contrary to the its anti‐inflammatory role previously reported …”

Section: Discussionsupporting

confidence: 89%

“…Clinically, low‐dose DA has been shown to improve transplantation outcome in renal and heart allograft recipients. Proposed mechanisms underlying the beneficial effects of DA include the activation of DA D3 receptor and other specific properties of DA derivatives . The results of other clinical studies, however, failed to support the findings …”

Section: Discussionmentioning

confidence: 91%

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Dopamine impairs functional integrity of rat hepatocytes through nuclear factor kappa B activity modulation: An in vivo, ex vivo, and in vitro study

et al. 2015

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Dopamine (DA) is commonly used to maintain the hemodynamic stability of brain-dead donors despite its controversial effects on organ functions. This study aimed at examining the hemodynamic effect of DA in a rat brain-dead model in vivo, alteration of hepatocyte integrity in liver grafts after ex vivo preservation, and changes in cultured clone-9 hepatocytes including cellular viability, cell cycle, apoptotic regulators, and lipopolysaccharide (LPS)-stimulated nuclear factor kappa B (NF-jB) signaling machinery. Although in vivo findings demonstrated enhanced portal venous blood flow and hepatic microcirculatory perfusion after DA infusion, no apparent advantage was noted in preserving hepatocyte integrity ex vivo. In vitro, prolonged exposure to high-dose DA reduced proliferation and induced G 1 growth arrest of clone-9 hepatocytes with concomitant decreases in B cell lymphoma 2 (BCL2)/B cell lymphoma 2-associated X protein (BAX) and heat shock protein 70/BAX protein ratios and intracellular NF-jB p65. Moreover, DA pretreatment suppressed LPS-elicited inhibitor of jBa phosphorylation and subsequent NF-jB nuclear translocation, suggesting that DA may down-regulate NF-jB signaling, thereby reducing expression of antiapoptotic regulators, such as BCL2. In conclusion, despite augmentation of hepatic perfusion, DA infusion failed to preserve hepatocyte integrity both in vivo and ex vivo. In vitro findings demonstrated that highdose DA may hamper the function of NF-jB signaling machinery and eventually undermine functional integrity of hepatocytes in liver grafts. Liver Transpl 21:1520-1532, 2015. V C 2015 AASLD.Received May 4, 2015; accepted September 11, 2015. Dopamine (DA) is a neurotransmitter structurally belonging to the catecholamine family (3,4-dihydroxyphenylethylamine) and well studied for its role in mental functioning including thinking and feeling. 1 DA is also one of the most popular medications being used in the intensive care unit for maintaining Additional supporting information may be found in the online version of this article.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 91%

Dopamine impairs functional integrity of rat hepatocytes through nuclear factor kappa B activity modulation: An in vivo, ex vivo, and in vitro study

et al. 2015

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“…NADA, an endocannabinoid which acts as an agonist of the CB 1 receptor and the transient receptor potential V1 (TRPV1), was found to be a potent inhibitor of PGE 2 synthesis in lipopolysaccharide (LPS) stimulated primary microglial cells, without modifying the expression or enzymatic activity of COX-2 and the production of prostaglandin D 2 . However, N -acyl dopamines derived from the polyunsaturated omega-3 fatty acids, such as DHDA and EPDA, have received limited attention so far. , …”

mentioning

confidence: 99%

N-Docosahexaenoyl Dopamine, an Endocannabinoid-like Conjugate of Dopamine and the n-3 Fatty Acid Docosahexaenoic Acid, Attenuates Lipopolysaccharide-Induced Activation of Microglia and Macrophages via COX-2

Wang¹,

Plastina

Vincken³

et al. 2016

ACS Chem. Neurosci.

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Several studies indicate that the n-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) contributes to an attenuated inflammatory status in the development of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. To explain these effects, different mechanisms are being proposed, including those involving endocannabinoids and related signaling molecules. Many of these compounds belong to the fatty acid amides, conjugates of fatty acids with biogenic amines. Conjugates of DHA with ethanolamine or serotonin have previously been shown to possess anti-inflammatory and potentially neuroprotective properties. Here, we synthesized another amine conjugate of DHA, N-docosahexaenoyl dopamine (DHDA), and tested its immune-modulatory properties in both RAW 264.7 macrophages and BV-2 microglial cells. N-Docosahexaenoyl dopamine significantly suppressed the production of nitric oxide (NO), the cytokine interleukin-6 (IL-6), and the chemokines macrophage-inflammatory protein-3α (CCL20) and monocyte chemoattractant protein-1 (MCP-1), whereas its parent compounds, dopamine and DHA, were ineffective. Further exploration of potential effects of DHDA on key inflammatory mediators revealed that cyclooxygenase-2 (COX-2) mRNA level and production of prostaglandin E (PGE) were concentration-dependently inhibited in macrophages. In activated BV-2 cells, PGE production was also reduced, without changes in COX-2 mRNA levels. In addition, DHDA did not affect NF-kB activity in a reporter cell line. Finally, the immune-modulatory activities of DHDA were compared with those of N-arachidonoyl dopamine (NADA) and similar potencies were found in both cell types. Taken together, our data suggest that DHDA, a potentially endogenous endocannabinoid, may be an additional member of the group of immune-modulating n-3 fatty acid-derived lipid mediators.

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“…We and others have previously reported that N-acyl dopamine derivatives (NADD) harbour biological properties that might be useful for preventing transplantation associated injury 29–31 . As such they limit cold inflicted 32 and ischemia reperfusion-injury 33 and modulate inflammation through inhibition of NFκB 21,34 .…”

Section: Discussionmentioning

confidence: 99%

N-Octanoyl-Dopamine inhibits cytokine production in activated T-cells and diminishes MHC-class-II expression as well as adhesion molecules in IFNγ-stimulated endothelial cells

Hofmann

Krapp

et al. 2019

Sci Rep

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IFNγ enhances allograft immunogenicity and facilitates T-cell mediated rejection. This may cause interstitial fibrosis and tubular atrophy (IFTA), contributing to chronic allograft loss. We assessed if inhibition of T-cell activation by N-octanoyl dopamine (NOD) impairs adherence of activated T-cells to endothelial cells and the ability of activated T-cells to produce IFNγ. We also assessed if NOD affects IFNγ mediated gene expression in endothelial cells. The presence of NOD during T-cell activation significantly blunted their adhesion to unstimulated and cytokine stimulated HUVEC. Supernatants of these T-cells displayed significantly lower concentrations of TNFα and IFNγ and were less capable to facilitate T-cell adhesion. In the presence of NOD VLA-4 (CD49d/CD29) and LFA-1 (CD11a/CD18) expression on T-cells was reduced. NOD treatment of IFNγ stimulated HUVEC reduced the expression of MHC class II transactivator (CIITA), of MHC class II and its associated invariant chain CD74. Since IFTA is associated with T-cell mediated rejection and IFNγ to a large extent regulates immunogenicity of allografts, our current data suggest a potential clinical use of NOD in the treatment of transplant recipients. Further in vivo studies are warranted to confirm these in vitro findings and to assess the benefit of NOD on IFTA in clinically relevant models.

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N-acyl dopamine derivates as lead compound for implementation in transplantation medicine

Cited by 6 publications

References 66 publications

Dopamine impairs functional integrity of rat hepatocytes through nuclear factor kappa B activity modulation: An in vivo, ex vivo, and in vitro study

Dopamine impairs functional integrity of rat hepatocytes through nuclear factor kappa B activity modulation: An in vivo, ex vivo, and in vitro study

N-Docosahexaenoyl Dopamine, an Endocannabinoid-like Conjugate of Dopamine and the n-3 Fatty Acid Docosahexaenoic Acid, Attenuates Lipopolysaccharide-Induced Activation of Microglia and Macrophages via COX-2

N-Octanoyl-Dopamine inhibits cytokine production in activated T-cells and diminishes MHC-class-II expression as well as adhesion molecules in IFNγ-stimulated endothelial cells

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