**4. Phytonutrients as a therapeutic perspective in the treatment of Zika-virus-induced ocular inflammation**

It is well known that retinal degeneration can be induced by several factors, including genetic mutations, oxidative stress, and inflammation. Several treatments employing natural molecules, with antioxidant and/or anti-inflammatory actions, have shown efficacy in slowing the progression of retinal degeneration (e.g., AMD) [46].

## **Figure 8.**

*Mechanism of action of resveratrol in the treatment of Zika virus retinal infection. Zika virus takes advantage of host mitochondrial enzymes for viral replication; resveratrol is able to inhibit these enzymes (GMPR2 and DHODH), effectively blocking virus replication.*

Moreover, recent studies have demonstrated the antioxidant activity of Saffron, Naringenin, and Quercetin, the last are two polyphenols with known antioxidant and anti-inflammatory activities, in slowing the progression of retinal degeneration in several animal models [47, 48].

There is also a study that illustrates the efficacy of Hesperidin in protecting a retinal pigmented epithelium cell line (ARPE-19) from H2O2-induced damage, by inhibiting both apoptosis and ROS hyperproduction. Showing, once again, the efficacy of a polyphenol in the treatment of a retinal degeneration, such as AMD [49].

Regarding the Zika virus specifically, although the clinical manifestations at the ocular level are known, to date there is still a lack of research on the stages of the virus and consequently on potential treatments with natural molecules.

There is only one study on the efficacy of resveratrol treatment in the Zika-virusinfected ARPE-19 cell line with a focus on mitochondrial morphology.

Russo et al first showed how Zika virus infection altered the balance of mitochondrial dynamics toward the fission process in RPE cell and how these organelles lose their typical tubular shape during infection. Through a docking analysis, they study how resveratrol treatment restores the typical mitochondrial shape by acting as an inhibitor on enzymes critical for viral RNA replication (e.g., GMPR2 and DHODH). Indeed, viruses use host-specific factors to complete their multiplication cycles, and inhibition of mitochondrial enzymes involved in nucleoside biosynthesis has been shown to be an effective antiviral strategy. In conclusion, they demonstrated the efficacy of resveratrol as an antiviral agent in the treatment of Zika-virus-induced eye diseases [50]. A schematic representation of the mechanism of action of resveratrol, proposed by the authors [50], is shown in **Figure 8**.
