Nerve growth factor role on retinal ganglion cell survival and axon regrowth: effects of ocular administration in experimental model of optic nerve injury

Retinal ganglion cell (RGC) degeneration occurs within 2 weeks following optic nerve crush (ONC) as a consequence of reduced retro-transport of growth factors including nerve growth factor (NGF). The hypothesis that intravitreal (ivt) and eye drop (ed) administration of recombinant human NGF (rhNGF) might counteract ONC in adult rats is explored in this study. We found that both ivt- and ed-rhNGF reduced RGC loss and stimulated axonal regrowth. Chiefly, survival and regenerative effects of rhNGF were associated with a reduction of cells co-expressing Nogo-A/p75NTR at crush site borders, which contribute to glia scar formation following nerve injury, and induce further degeneration. We also found that ocular application of rhNGF reduced p75NTR and proNGF and enhanced phosphorylation of TrkA and its intracellular signals at retina level. Nogo-R and Rock2 expression was also normalized by ed-rhNGF treatment in both ONC and contralateral retina. Our findings that ocular applied NGF reaches and exerts biological actions on posterior segment of the eye give a further insight into the neurotrophin diffusion/transport through eye structures and/or their trafficking in optic nerve. In addition, the use of a highly purified NGF form in injury condition in which proNGF/p75NTR binding is favored indicates that increased availability of mature NGF restores the balance between TrkA and p75NGF, thus resulting in RGC survival and axonal growth. In conclusion, ocular applied NGF is confirmed as a good experimental paradigm to study mechanisms of neurodegeneration and regeneration, disclose biomarkers, and time windows for efficacy treatment following cell or nerve injury

Cytokines and growth factors

Several cytokines have been used to treat autoimmune diseases, viral infections, and cancer and to regenerate the skin. In particular, interferons (INFs) have been used to treat cancer, hepatitis B and C, and multiple sclerosis, while interleukins (ILs) and tumor necrosis factors (TNFs) have been used in the management of different types of cancer. Concerning the hematopoietic growth factors (HGFs), epoetin has been used for anemia, whereas the colony-stimulating factors (CSFs) have been used for neutropenia. Other growth factors have been extensively explored, although most still need to demonstrate in vivo clinical relevance before reaching the market.This chapter provides an overview on the therapeutic applications of biological medicines containing recombinant cytokines and growth factors (HGFs and others). From this review, we concluded that the clinical relevance of recombinant cytokines has been increasing. Since the 1980s, the European Medicines Agency (EMA) and/or Food and Drug Administration (FDA) have approved 89 biological medicines containing recombinant cytokines. Among these, 18 were withdrawn, 24 are biosimilars, and 18 are orphans.So far, considerable progress has been made in discovering new cytokines, additional cytokine functions, and how they interfere with human diseases. Future prospects include the approval of more biological and biosimilar medicines for different therapeutic applications.info:eu-repo/semantics/publishedVersio