One of the greatest challenges facing clinical neuro-ophthalmology is the development of effective neuroprotective and restorative therapies for optic nerve disorders. Advancements in our understanding of disease pathogenesis combined with better diagnostic acumen and novel technologies have provided neuro-ophthalmologists with the opportunity to influence the clinical course of optic neuropathies and to design new approaches for restoring optic nerve function following injury. In optic neuritis, recent investigations have clarified the tempo and extent of retinal nerve fiber loss associated with clinical and subclinical damage (1-3). The data clearly indicate that despite clinical recovery, there is significant axonal injury following optic neuritis that may be preventable. In this issue of the Journal, there are 2 complementary articles that focus directly on this topic. In the State-of-the-Art Review, Moore and Goldberg (4) provide a comprehensive examination of the challenges confronting efforts to restore retinal ganglion cell function following injury, and in Basic Science in Neuro-Ophthalmology, Shindler et al (5) examine the ability of resveratrol to prevent retinal ganglion cell degeneration in an inflammatory model of optic neuritis.
Moore and Goldberg review the steps required to achieve optic nerve regeneration. This state-of-the-art discussion describes the complexity of reestablishing visual function following optic nerve injury and axonal loss. The authors outline 4 major hurdles: 1) retinal ganglion cell (RGC) survival, 2) breakthrough optic nerve inhibitory factors to regrow axons, 3) increase growth of RGC axons, and 4) rewiring to achieve visual restoration. The authors thoughtfully address each of these topics using specific questions and reviews of the supporting literature. For example, in the section titled, “Why is the response to trophic factors so limited?” Moore and Goldberg proceed to systematically discuss the downregulation of trophic factor receptors, the effectiveness of intracellular cyclic adenosine monophosphate on the surface recruitment of receptors such as trkB, and the likely need for a multifaceted approach to maintain responsiveness to survival signals.
One particular hurdle facing optic nerve restoration that may benefit from careful clinical investigations is the inhibitory microenvironment of the damaged optic nerve. It is clear that this field is awash with multiple theories of inhibition, including but not limited to the differences in the local cellular response to injury in the central and peripheral nervous systems. Progress in this area will be dependent on a more detailed understanding of the disease pathogenesis and the extent of neural and glial injury. Clarification of disease pathogenesis will assist in the identification of accessible final common pathway targets and help distinguish injurious from therapeutic responses. For instance, a variety of potential inhibitory molecules, such as Rho kinase, are activated or liberated by degenerating oligodendrocytes and proliferating astroglial scar and may represent potential therapeutic targets. And in inflammatory optic neuropathies, there is significant evidence that infiltrating immune cells may assist in overcoming the inhibitory environment. As therapeutic responses to immune modulation have sometimes led to unpredictable results, negative (eg, progressive multifocal leukoencephalopathy following natalizumab therapy) and positive (eg, therapeutic responses to B-cell depletion in presumed T-cell-mediated diseases) careful clinical investigations will be required to achieve a strategic breakthrough in this arena (6-8).
The third hurdle, encouraging axon regrowth by adult RGCs, is discussed in the context of the different capabilities of cells derived from embryonic versus adult tissues. The authors review their own exciting findings that indicate a critical role for Krüppel-like transcription factors in both developmental and regenerative axonal growth. Completion of the visual arc through restoration of brain connections remains at a nascent stage of inquiry; however, promising findings, such as changes in gene expression in the superior colliculus following optic nerve injury, support the feasibility of reestablishing important neural contacts.
A critical step prior to restoring optic nerve tissue is RGC neuroprotection. Neuroprotection in optic neuritis may be indirect or direct. Therapeutic agents may provide neuroprotection indirectly by ameliorating the inflammatory response and reducing secondary neuronal death and axonal injury. Alternatively, therapies may protect neurons by directly interfering with intrinsic pathways mediating neuronal cell death. In this issue of the Journal, Shindler et al report significantly lower axonal injury in optic nerves and spinal cords and increased RGC survival following resveratrol (SRT501) treatment in animals with experimental autoimmune encephalomyelitis (EAE), a model of acute neuroinflammation. Resveratrol activates SIRT1, a member of a conserved gene family of NAD+-dependent deacetylases (sirtuins), which are involved in multiple cellular pathways including cellular stress responses, apoptosis, and axonal degeneration (8). Interestingly, the neuroprotective effects observed with SRT501 treatment were found to be independent of any effects on disease initiation or the amount of inflammatory infiltrate in the optic nerves or spinal cords of treated animals. The results suggest that SRT501 may act as a direct neuroprotectant in the EAE model.
Despite their promising initial results, there are several key questions that need to be addressed prior to attributing a direct neuroprotective action to SRT501. While the extent of neuroinflammation in the relapsing EAE model appears unchanged following SRT501 administration, qualitative changes in the innate and adaptive immune responses require more intensive investigation. Given the pleiotropic effects of sirtuins, it is possible that alterations in the composition or activation of immune response are responsible for diminishing the level of neuronal injury. In their study, Shindler et al provide an initial assessment of the composition of the immune cells in the spinal cord of treated and untreated animals, but further analysis of regulatory T-cell populations, antigen presenting cells, and macrophage activation are critical. Indeed, recent reports (10-12) have shown that sirtuin function influences macrophage activation. Sirtuins may have additional effects in the EAE model that are specific to a targeted immune response against oligodendrocytes. Sirt2 is an abundant sirtuin transported into myelin channels by proteolipid protein that may affect myelin structure (13,14). Activation of Sirt2 in the proteolipid protein model of EAE may rescue myelin compaction and maintain trophic support for axons. Further investigations will be needed to establish whether sirtuin activation can provide a direct neuroprotection in other forms of optic nerve injury and whether there is a critical window for drug delivery.
The “holy grail” for clinicians who care for patients with optic neuropathies, whether traumatic, inflammatory, ischemic, or degenerative, is the ability to provide effective therapeutic approaches that preserve and restore function. The 2 articles published in this issue of the Journal discuss new experimental evidence for neuroprotection and the complexities facing therapies aimed at restoring visual function following optic nerve injuries. It is clear that significant progress is being made and that new challenges are being identified. The fields of neuroprotection and regenerative medicine are rapidly changing and will likely yield possible combinatorial therapy to help restore or preserve optic nerve tissue. These new therapeutic approaches will require thoughtful prospective clinical trials to test their safety and efficacy.
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