ROCK inhibition as a novel potential strategy for axonal regeneration in optic neuropathies.

Abstract

Optic neuropathies or optic nerve diseases are a frequent cause of permanent vision loss that can occur after inflammation, ischemia, infection, tumors, trauma and/or an elevated pressure inside the eye (also called intraocular pressure or IOP). Glaucoma or glaucomatous optic neuropathy is the most commonly acquired optic neuropathy and the second leading cause of blindness worldwide. This neurodegenerative disorder is characterized by a slow and progressive loss of retinal ganglion cells (RGCs) and their axons, and is often associated with an elevated IOP. Current glaucoma treatments therefore focus on reducing the raised IOP. Unfortunately, not all patients benefit from an IOP-lowering therapy, also because the pathophysiology of this multifactorial disease is not merely associated with an altered eye pressure. The exact mechanisms underlying apoptotic RGC death, which is a common feature of all types of glaucoma, remains complex and largely unsolved. Therefore, new therapeutic strategies should focus on preventing or retarding RGC death, but also on sufficient and lengthy repair/regrowth of damaged RGC axons in the optic nerve and on proper axonal guidance, all in order to preserve or improve structural and functional connectivity and ultimately restore vision. Unfortunately, the damaged or diseased mammalian central nervous system (CNS) is characterized by poor axonal regeneration, which is generally believed to depend on a combination of factors, in particular the presence of reactive astrocytes, oligodendrocytes, and their associated inhibitory molecules, and the insufficient intrinsic growth capacity of mature CNS neurons. Yet, also the loss of neurotrophic support, apoptotic cell death and poor debris clearance contribute to this regenerative failure. To date, no clinical therapy is available to cure the damaged CNS, although there has been considerable progress in understanding the underlying mechanisms of regenerative failure and in providing possible ways to achieve long-distance regeneration. In order to develop novel potential regenerative strategies and treatments, the optic nerve crush (ONC) paradigm has been a frequently used in vivo rodent model over the past decades. Indeed, research using this model resulted in novel insights into the destructive cellular and molecular pathways underlying axonal degeneration and RGC death, and importantly contributed to the discovery of potential axon growth and guidance-stimulating molecules and treatments (Van de Velde et al., 2015). Within our research group, ONC injury in mice has been frequently used as an experimental model to mimic glaucoma pathology, in order to identify novel neuroprotective/regenerative molecules, such as Rho kinase inhibitors. Within this perspective, we aim to highlight the current status of research on Rho-associated coiled-coil protein kinase (ROCK) in the promotion of neurite outgrowth and axonal regeneration in experimental optic neuropathy models.