Neuroprotective Agents in Glaucoma Therapy: Recent Developments and Future Directions

Brian Chua; Ivan Goldberg

Disclosures

Expert Rev Ophthalmol. 2010;5(5):627-636. 

In This Article

Mechanisms of RGC Damage & Targets for Neuroprotective Agents

Glaucoma is a multifactorial disease with well-described risk factors such as IOP, age, race, family history and myopia.[15] The exact mechanism(s) of RGC damage in glaucoma is complex and unknown. In this report, we explore potential mechanisms for neuroprotection in terms of pathways initiated by mechanical or ischemic injury, or by the toxic substances liberated by the primary insult to affected cells leading to secondary degeneration and apoptotic death. Categories and examples are outlined in Table 1.

Neurotrophic Factors

A major destructive effect of increased or fluctuating IOP is deformation of the lamina cribrosa, mechanically compressing RGC axons. This reduces or blocks retrograde transport of essential neurotrophic factors such as brain-derived neurotrophic factor (BDNF), NGF, neurotrophin (NT)-3, NT-4 and NT-5, glial cell-derived neurotrophic factor, ciliary neurotrophic factor, and FGF-2, liberated by the superior colliculus and lateral geniculate body and transported to the RGC body by its axons.[16–18] A lack of appropriate target-derived trophic support causes cells to undergo apoptotic degeneration in a manner similar to neuronal death during embryonic development or following spinal cord injuries. Supplementation of these neurotrophic factors has been suggested to protect neurons from such degeneration.

Ischemia

Another major theory in the etiology of glaucoma is vascular insufficiency at the optic nerve head.[19,20] Arising from systemic hypotension, vasospasm or even mechanical compression of the microvasculature at the lamina cribrosa, low perfusion of the optic nerve head may cause RGC ischemia. This ischemic insult may reduce essential nutrients and substrates available for energy production in metabolically highly active neurons. Antivasospastic drugs such as calcium-channel blockers and some adrenergic antagonists have potential as neuroprotectants. Their proposed mechanisms of action are explored later in this article.

Mitochondrial Dysfunction

Increasingly, mitochondrial dysfunction is believed to contribute to the pathogenesis of neurodegenerative disorders, including glaucoma.[21] Mitochondria are the principal organelles for a cell's energy production via the electron transport chain. As ATP, this energy drives intracellular and intercellular signaling and is vital for cellular pump function, and thus cellular integrity. Mitochondrial dysfunction induces the intrinsic apoptotic pathway by upregulation of NF-κB and proapoptotic genes. As mitochondrial dysfunction may be triggered by aging, ischemia and/or oxidative stress, novel methods such as caloric restriction (to try to retard aging[22]), increasing optic head flow dynamics (with vasodilators) and decreasing oxidative stress (with antioxidants) may prove to be useful neuroprotective strategies.

Glutamate Excitotoxicity

Any hypoxic environment critically drops ATP production with failure of the vital sodium–potassium pump of both neurons and their supporting glia. Membranes depolarize with increased release and reduced clearance of glutamate by dying RGCs or by metabolically compromised glial cells. As an essential CNS neurotransmitter and the main excitatory retinal neurotransmitter, glutamate is tightly regulated in the presynaptic cells; excessive levels of glutamate are toxic not only to RGCs, but also to neighbouring healthy neurons. Excessive glutamate causes calcium influx through hyperactivation of the N-methyl-D-aspartate (NMDA) receptor in a process termed excitotoxicity.[23] NMDA receptor antagonists[24] and some calcium-channel blockers[25] may stabilize glutamate levels and prevent such cellular injury.

Oxidative Stress

Overstimulation of NMDA receptors also activates nitric oxide synthase (NOS), resulting in nitric oxide (NO) production. NO is a neuronal messenger critical for normal retinal neurotransmission and phototransduction. Unregulated, it has the potential to react with the superoxide anion to form peroxynitrite, a highly reactive oxidant species.[26] Oxidative stress is the leading cause of RGC loss, causing secondary degeneration to adjacent neurons either by direct neurotoxic insult through free-radical damage of cell membranes, enzymes, proteins and DNA; or indirectly through induction of glial dysfunction and activation of apoptotic pathways through its detrimental action on mitochondrial energy production.[27,28] A wide variety of free-radical scavengers and NOS inhibitors are being investigated as potential therapeutic agents.[29]

Protein Misfolding

Misfolded proteins such as amyloid β (Aβ) are a prominent feature of many neurodegenerative diseases, including Alzheimer's, Huntington's and Parkinson's, with an accumulation of abnormal protein plaques in the brain. As Aβ has been linked to glaucomatous RGC apoptosis in a dose- and time-dependent manner,[30] targeting different components of the Aβ formation and aggregation pathways (e.g., using Aβ antibodies) may effectively reduce glaucomatous RGC apoptosis.[31]

Heat-shock proteins (Hsps) are chaperone proteins that facilitate nascent and stress-induced protein folding and unfolding, and restoration of misfolded proteins. HspB1 (Hsp27) is strongly induced during the stress response and has been associated with increasing the survival of cells subjected to cytotoxic stimuli.[32] Antibodies against Hsp27 have been identified in patients with glaucoma.[33] It is unclear whether these autoantibodies exist as a result of RGC injury, or effect a mimicked T-cell-mediated response to RGC damage. Development of decoy antigens or vaccines may be a useful strategy for neuroprotection in glaucoma.

Glial Cell Modulation

Retinal ganglion cells are not the only cells damaged in glaucoma: Müller glial cells, amacrine and bipolar cells are also injured. In the nonmyelinated region of the optic nerve head, astrocytes are the major glial cells to provide support to neuronal axons, as well as interface between connective tissue and blood vessels. They help to maintain ion homeostasis and extracellular pH, as well as integrity of the perineural extracellular matrix. To try to maintain homeostasis, quiescent astrocytes are transformed into a reactive state by liberated cytokines such as TGF,[34] ciliary neurotrophic factor,[35] FGF[36] and PDGF.[37] Reactive astrocytes exhibit altered intercellular communication, migration, growth factor signaling, oxidative species buffering capacity and connective tissue properties at the optic nerve head.[38] Modulation of glial cell activity may therefore be useful as neuroprotective processes in the rescue of neurons following an injurious insult.[39,40]

Apoptotic Death Pathways

The final common pathway for any neuronal injury is necrosis or apoptosis, the latter playing a major role in RGC death in glaucoma. Apoptosis can be initiated by extrinsic or intrinsic pathways. Triggers for the extrinsic pathway include TNF-α, Fas ligand and TNF-related apoptosis-inducing ligand. The intrinsic pathway involves mitochondrial-mediated events. The exact processes of apoptosis and neuronal cell death are well described.[41]

Regardless of the initiating injury, there is activation of the caspase cascade,[42] increased expression of proapoptotic genes such as Bax/Bid[43] and downregulation of antiapoptotic genes such as Bcl-2/Bcl-xl,[44] leading to noninflammatory programmed cell death.[45] Taking a lead from viruses that use caspase inhibition to prevent apoptosis of infected cells, pharmacological interventions that block the caspase cascade may be neuroprotective.

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