Because quality of organ transplants is deteriorating as a consequence of hypothermic organ preservation and reperfusion injury, there is an unmet clinical demand for new compounds, which may have a potential use in transplantation medicine. In this thesis a new class of CO releasing molecules is described and, together with N-acyl dopamine derivatives (NADD), studied for their cytoprotective properties. We found that enzyme triggered CO-releasing molecules (ET-CORMs) are able to protect against cold inflicted injury and to inhibit TNF-a mediated VCAM induction. In addition, we have demonstrated that structural alterations of ET-CORMs significantly affect their biological activity. In the second part of this thesis we focused on N-octanoyl dopamine (NOD), a dopamine derivative that lack its hamodynamic properties and assessed its ability to interfere with different signaling pathways and the structural entities that are important for these interactions. We found that NOD transiently suppressed T cell proliferation and activation and showed a strong synergy with calcineurin inhibitors to inhibit T cell activation. Next, we found that NOD induces the unfolded protein response through oxidation of the catechol structure, and this not affect cell viability but it was rather associated with hypometabolism and thermotolerance. Finally, we could demonstrate that NOD activates TRPV1 and proposed a mechanistic model for this activation. In addition, we found that the anti-inflammatory effects of NADD dependent on the redox ability of these compounds. In conclusion, these studies suggest that both ET-CORMs as NADD could emerge as potential pharmaceutical candidates in the field of kidney transplantation.
|Qualification||Doctor of Philosophy|
|Place of Publication||[Groningen]|
|Publication status||Published - 2016|