MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges

Abstract

Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous cellular signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Once activated through phosphorylation, these MAPKs in turn phosphorylate and activate transcription factors present either in the cytoplasm or in the nucleus, leading to the expression of target genes and, as a consequence, they elicit various biological responses. The aim of this work is to provide a comprehensive review focusing on the roles of MAPK signaling pathways in ocular pathophysiology and the potential to influence these for the treatment of eye diseases. We summarize the current knowledge of identified MAPK-targeting compounds in the context of ocular diseases such as macular degeneration, cataract, glaucoma and keratopathy, but also in rare ocular diseases where the cell differentiation, proliferation or migration are defective. Potential therapeutic interventions are also discussed. Additionally, we discuss challenges in overcoming the reported eye toxicity of some MAPK inhibitors.

Keywords: ERK; JNK; MAPK; eye toxicity; ocular diseases; p38; therapy.

Figure 1

Simplified schematic summary of the main MAPK signaling pathways.

Figure 2

Schematic overview of developmental events during mammalian eye development, and germ layer origin of structures in the eye. (A) The optic vesicle, derived from the neuroepithelium of ectodermal lineage, approaches the surface ectoderm where the lens placode (blue cells) forms at the area of proximity between the layers. (B) The optic vesicle forms the optic cup, by the concurrent invagination of both the lens placode, forming the lens pit, and the proximal layer of the optic vesicle to the surface ectoderm, forming the presumptive neural retina (red cells). (C) The lens pit closes up onto itself forming the lens vesicle, with the cells from the central part of the lens pit (blue cells) directed posteriorly, and the cells from the lens pit periphery (yellow cells) directed anteriorly. The optic cup continues to invaginate. (D) The invaginated (inner) layer of the optic cup differentiates into the neural retina (red cells), while the outer layer forms the retinal pigment epithelium, RPE (orange cells). Cells in the posterior surface of the lens vesicle elongate towards the opposite pole, forming the lens fibers and filling the central volume of the lens, while the cells on the anterior side form the lens anterior epithelium. The surface ectoderm closes after the lens vesicle detaches, and the now continuous surface ectoderm forms the cornea.

Figure 3

Graphical overview of eye structures and conditions for which MAPK interactions have been reported.