Molecular Insight into Receptor-mediated Therapeutic Potential of Lumirubin and 6-Formylindolo[3,2-b]carbazole in Phototherapy of Neonatal Hyperbilirubinemia

Author(s): Abdulla A-B Badawy* and Shazia Dawood

Objective: Neonatal hyperbilirubinemia (NNH) leading to kernicterus disturbs immune and neuronal functions through inflammation and excitotoxicity. Tryptophan metabolism along the kynurenine pathway may underpin both features. Because phototherapy of NNH converts only a small amount of bilirubin to oxidation products, the assumption is that the low levels of these oxidation products must exert highly protective effects despite the large bilirubin levels. We explored by molecular docking the likely interaction of the major photooxidation product lumirubin with enzymes and receptors involved in bilirubin toxicity. We also explored the interaction of the tryptophan photooxidation product 6-formylindolo[3,2-b] carbazole (FICZ), which may also be formed during NNH phototherapy.

Methods: We performed molecular docking of lumirubin and FICZ to the aryl hydrocarbon (AhR), N-methyl-D-aspartate (NMDA), kainate and γ-aminobutyric acid (GABA) receptors. Docking to the AhR was compared with that of bilirubin, biliverdin, indirubin and 2,3,7,8-tetrachlorodibenzop- dioxin. Docking of lumirubin and FICZ to the neuronal receptors was also compared with that of their endogenous modulators kynurenic (KA) and quinolinic (QA) acids.

Results: Lumirubin and FICZ docked very strongly to the AhR, whereas biliverdin and bilirubin did not. Both lumirubin and FICZ also docked strongly to the NMDA and GABA receptors, as did KA and QA.

Conclusions: AhR activation by lumirubin may underpin its immune protection. FICZ may afford a similar protection. Interaction of lumirubin and FICZ with glutamate and GABA receptors may underpin antagonism of the excitotoxicity of kernicterus. Development of lumirubin- and FICZbased pharmaceuticals may advance NNH therapy. Interaction of KA and QA with GABA receptors requires investigation at the pharmacological and behavioral levels.