Characterizing fucoxanthin as a selective dopamine D₃/D₄ receptor agonist: Relevance to Parkinson's disease

Fucoxanthin and fucosterol are archetypal lipid components of edible brown algae that provide several health benefits. Lately, their protective role in Aβ_1-42-induced cognitive dysfunction in animal models has been reported (Alghazwi et al., 2019; Oh et al., 2018). However, their role in the aminergic system and as a prime treatment approach for multifactorial neurodegenerative diseases still requires exploration. The main aims of the present study are to characterize the role of fucoxanthin and fucosterol in the aminergic pathway via in vitro human monoamine oxidase (hMAO) inhibition and cell-based functional G-protein coupled receptor (GPCR) assays and to underline their possible mechanisms of action via in silico molecular docking studies. Fucoxanthin displayed weak inhibition with IC₅₀ values of 197.41 ± 2.20 and 211.12 ± 1.17 μM over two isoenzymes hMAO-A and hMAO-B, respectively. Fucosterol remained inactive up to 500 μM. In functional assay results, fucoxanthin showed a concentration-dependent agonist effect on dopamine D₃ and D₄ receptors. The half maximal effective concentration (EC₅₀) of fucoxanthin for dopamine D₃ and D₄ receptors was 16.87 ± 3.41 and 81.87 ± 6.11 μM, respectively. For dopamine as a reference agonist, the EC₅₀ values for these two receptors were 3.7 and 24 nM, respectively. Fucosterol showed no agonist activity on any of the tested receptors. Similarly, fucoxanthin showed a mild antagonist effect on dopamine D₁ and tachykinin (NK₁) receptor with inhibition of control agonist response by approximately 40% at 100 μM. Fucosterol displayed mild antagonist effects only on dopamine D₁ and D₄ receptors. In silico studies revealed potential mechanisms by which fucoxanthin binds to dopamine receptors to exert its agonist effects, including low binding energy and H-bond interactions with Ser196 and Thr115 at the D₃ receptor and with Ser196 and Asp115 at the D₄ receptor. Our results collectively suggest that fucoxanthin is a potential D₃/D₄ agonist for the management of neurodegenerative diseases, such as Parkinson's disease.