N-octanoyl-Dopamine Is an Agonist at the Capsaicin Receptor TRPV1 and Mitigates Is Chemia-Induced Acute Kidney Injury in Rat

Abstract

Since stimulation of transient receptor potential channels of the vanilloid receptor subtype 1 (TRPV1) mitigates acute kidney injury (AKI) and endogenous N-acyl dopamine derivatives are able to activate TRPV1, we tested if synthetic N-octanoyl-dopamine (NOD) activates TRPV1 and if it improves AKI. These properties of NOD and its intrinsic anti-inflammatory character were compared with those of dopamine (DA). TRPV1 activation and anti-inflammatory properties of NOD and DA were tested using primary cell cultures in vitro. The influence of NOD and DA on AKI was tested in a prospective, randomized, controlled animal study with 42 inbred male Lewis rats (LEW, RT1), treated intravenously with equimolar concentrations of DA or NOD one hour before the onset of warm ischemia and immediately before clamp release. NOD, but not DA, activates TRPV1 channels in isolated dorsal root ganglion neurons (DRG) that innervate several tissues including kidney. In TNFα stimulated proximal tubular epithelial cells, inhibition of NFκB and subsequent inhibition of VCAM1 expression by NOD was significantly stronger than by DA. NOD improved renal function compared to DA and saline controls. Histology revealed protective effects of NOD on tubular epithelium at day 5 and a reduced number of monocytes in renal tissue of DA and NOD treated rats. Our data demonstrate that NOD but not DA activates TRPV1 and that NOD has superior anti-inflammatory properties in vitro. Although NOD mitigates deterioration in renal function after AKI, further studies are required to assess to what extend this is causally related to TRPV1 activation and/or desensitization.

N-Octanoyl dopamine transiently inhibits T cell proliferation via G1 cell-cycle arrest and inhibition of redox-dependent transcription factors

“…Endogenous NADD, e.g., N-arachidonoyl-, N-oleoyl-, N-palmitoyl-, and N-stearoyl dopamines are found predominantly in the brain with the highest levels in the striatum and low levels elsewhere [17]. In contrast to the endogenous NADD, NOD contains a short fatty acid but similar to endogenous NADD, activates TRPV1 [14]. This may.…”

“…Moreover, we have shown that conjugation of n-octanoic acid to the amine side chain of dopamine, which likely impairs adrenergic and dopaminergic receptor engagement, results in a far more protective compound [12]. NOD not only protects cells and tissues against prolonged hypothermic preservation, but it also strongly inhibits platelet function [13] and activation of NF-B in vitro and improves AKI in vivo [14]. In keeping with the notion that NF-B plays a pivotal role in cellular immunity, in the present study, we investigated further the potential benefit of NOD in transplantation medicine by assessing the influence of NOD on T cell activation in vitro.…”

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

“…These changes are likely present in ischemic tissue. The finding that NOD activates TRPV1 may explain its renoprotective properties in the setting of ischemia-induced AKI [50], yet the causality of this observation and its translation to clinical application warrants further supportive evidence.Immune modulation and inflammation…”

Dopamine and Lipophilic Derivates Protect Cardiomyocytes against Cold Preservation Injury

“…Hence, the efficacy of donor preconditioning could be further improved if a DA-like compound would be available, which at cytoprotective concentrations is devoid of dopaminergic and adrenergic action. Although NOD is not yet approved for clinical application, preclinical data on mitigation of ischemia-induced acute kidney injury in rats are promising and suggest superior protection than DA (Tsagogiorgas et al, 2012). Further biological evaluation of NOD, BBNB, and BBNO is ongoing and will clarify whether these compounds can also be considered for clinical testing.…”