The Challenge of Dimethyl Fumarate Repurposing in Eye Pathologies

Abstract

Dimethyl fumarate (DMF) is a small molecule currently approved and used in the treatment of psoriasis and multiple sclerosis due to its immuno-modulatory, anti-inflammatory, and antioxidant properties. As an Nrf2 activator through Keap1 protein inhibition, DMF unveils a potential therapeutical use that is much broader than expected so far. In this comprehensive review we discuss the state-of-art and future perspectives regarding the potential repositioning of this molecule in the panorama of eye pathologies, including Age-related Macular Degeneration (AMD). The DMF’s mechanism of action, an extensive analysis of the in vitro and in vivo evidence of its beneficial effects, together with a search of the current clinical trials, are here reported. Altogether, this evidence gives an overview of the new potential applications of this molecule in the context of ophthalmological diseases characterized by inflammation and oxidative stress, with a special focus on AMD, for which our gene–disease (KEAP1-AMD) database search, followed by a protein–protein interaction analysis, further supports the rationale of DMF use. The necessity to find a topical route of DMF administration to the eye is also discussed. In conclusion, the challenge of DMF repurposing in eye pathologies is feasible and worth scientific attention and well-focused research efforts.

Novel potential pharmacological applications of dimethyl fumarate—an overview and update

“…Of interest, in vivo literature evidence of beneficial effects exerted by MMF, either orally or intraocularly administered, is consistent with the DMF-induced improvement of retinal health (for a comprehensive review, see Manai et al, 2022 ).…”

“…The potential repurposing of DMF in the context of chronic inflammatory diseases of the intestine, such as inflammatory bowel disorders and celiac disease, has been extensively discussed in a recent review reporting that DMF actually overturned from main suspect to potential ally against gut disorders ( Manai et al, 2022 ).…”

“…The use of DMF has a strong attractiveness also in the ophthalmological context, where it may be beneficial in more than one eye disease ( Manai et al, 2022 ). The rationale of positioning DMF in ocular pathologies indeed relies on evidence related to several diseases.…”

“…However, increasing evidence indicates that DMF effects are pleiotropic, and its clinical use may be broader than was conceived for decades. Accordingly, in recent years, several studies have underlined numerous promising alternatives for the repurposing of DMF, as its antioxidant, anti-inflammatory, neuroprotective properties constitute a convincing rationale for DMF use in different diseases (for comprehensive reviews on the specific topics, see, for example, Tastan et al, 2022 ; Manai et al, 2022 ; Morris et al, 2022 ; Sánchez-García et al, 2021 ; Kourakis et al, 2020 ; Al-Ani et al, 2020 ; Sachinvala et al, 2020 ; Scuderi et al, 2020 ; Saidu et al, 2019 ).…”

Ethosomal Gel for Topical Administration of Dimethyl Fumarate in the Treatment of HSV-1 Infections

“…Dimethyl fumarate (DMF) is a fumaric acid esters derivate that can be considered as a pleiotropic drug, possessing immuno-modulatory, anti-inflammatory, and antioxidant properties that make it efficacious in many conditions, including inflammatory, degenerative, neoplastic, and cardiovascular diseases [ 12 ]. Indeed, DMF is used in the systemic treatment of psoriasis with a safe profile for long-term therapy [ 13 , 14 ], it has been approved by the Food and Drug Administration in the USA to treat relapsing-remitting multiple sclerosis [ 15 ], has potential applications to limiting HIV disease progression [ 16 ], a strong potential in eye pathologies, suggesting its use in several ophthalmological context [ 17 , 18 ], while it is also able to improve wound healing under diabetic conditions [ 19 , 20 ].…”