Strategies for Neuroprotection and Regeneration

The possibility of adapting neuroprotective strategies for glaucoma has received increasing attention. The identification of the agents that mediate secondary injury and a greater understanding of the pathways to apoptosis have raised the possibility of preventing the death of neurones that escape the primary insult. Some important biochemical events in apoptosis have been identified and it is hoped that cells rescued from apoptosis will continue to function. Toxic by-products of initial injury and secondary mediators of apoptosis might be neutralised or genes altered to inhibit apopotosis after glaucoma-related damage.

An ideal glaucoma drug would reduce IOP, increase ocular blood flow and prevent apoptosis and loss of RGCs. The therapeutic strategies for treating glaucomatous optic neuropathy have been summarised in table 3.

Overstimulation of the NMDA recep-tor allows excess calcium to enter the cell and produce a number of other effects that can trigger apoptosis. Unfortunately, drugs that cause prolonged or irrever-sible blockade of the NMDA receptors will also produce potentially serious side-effects. Neurotoxicity can follow NMDA receptor blockade, with cognitive dysfunction, psychosis or even death being possible outcomes.

NMDA receptor antagonists, such as amantadine, memantine and competitive NMDA antagonists such as selfotel might prove useful while glutamate release inhibitors (riluzole) and nitric oxide synthetase inhibitors all might slow progressive damage. Of these, the recently proposed agent, memantine, will soon be subject to clinical trial. Memantine can partially block the NMDA modulatory site and has been used safely for many years in Europe as a treat-ment for Parkinson's disease. It has few side-effects and may be protective to RGC neurones in experimental glaucoma cases.

Post-synaptic inhibition of excitatory amino acids has also been described for Parkinson's disease. L-deprenyl (selegiline) is a monoamine oxidase-B inhibitor and free radical scavenger that inhibits apoptosis by inducing new pro-tein synthesis.²⁸ It has also been used in experimental crush injury of the optic nerve and would appear to improve sur-vival of rat retinal ganglion cells in this situation.²⁹ Such anti-apoptotic actions might be useful for glaucoma treatment.

Betaxolol, a potent ß-1 selective adrenergic antagonist will also block kainate receptor-induced calcium influx into retinal neurones and be neuro-protective in sufficient doses. Retinas of rats treated with betaxolol 2.5 mg/kg seem to be protected from the effects of ischaemia and reperfusion after vascular occlusion (figure 3).³⁰ The preservation of the electroretinogram b wave after pretreatment with betaxolol would seem to emphasise the possible neuroprotec-tive role of this drug in ischaemic injury and glaucoma.

Figure 3. Betaxolol-induced neuroprotection after ischaemic injury30

The relatively new -agonist, bri-monidine, has also been shown to have neuroprotective actions, probably through a separate receptor mechanism that interferes with internal signaling stimu-lated by calcium influx. Brimonidine protects RGCs from secondary injury in both ischaemia-reperfusion conditions and following nerve crush injuries (figures 4 and 5).

Figure 4. Brimonidine protects the inner retina from retinal ischaemia.

Contro Ischaemic eye Brimonidine-treated ischaemic eye

Brimonidine has been shown to increase production of BDNF in rat retinas and may have a neuroprotective role in glaucoma treatment in addition to its influence on IOP.³¹ It might also be possible to replace deficient trophic factors or develop other agents that will stimulate their production to promote RGC survival. Neurotrophins injected into the vitreous can delay RGC loss after axotomy or crush injury, with BDNF being the most effective.

Figure 5. Brimonidine preserves nerve function following compressive injury31

Another possibility is to rescue damaged but functioning RGCs with so-called lazaroids. These 21-amino-steroids block lipid peroxidation and have been proposed in both CNS trauma and ischaemia. One of these compounds, trilazad mesylate, has been reported to produce a dose-dependent inhibition of RGC death.³²

During development, the gene bcl-2 prevents apoptosis but in glaucoma, the expression of p-53 is stimulated. This cycle is shown in figure 6. When
the balance is turned from bcl-2 in
favour of p-53, then this alters the equili-brium between the respective protein products of bcl-2 and bax. Bax homo-dimers are promoters of cell death.³³

Figure 6. Regulation of apoptosis in neuronal cells

Agents capable of upregulating protective genes, such as bcl-2, or down-regulating apoptotic genes such as p-53 could be employed as neuroprotective agents in glaucoma. If the expression of genes can be altered through defective viral vectors, perhaps to stimulate the expression of the protein product of bcl-2 in retinal ganglion cells then this might save surviving RGCs threatened by secondary injury and so preserve visual function.

In the course of evolution, the mam-malian CNS apparently lost the ability to regenerate and to recruit inflammatory cells, which are important for this pro-cess. It is well known that immature spinal cords can regenerate but how this process is controlled is the subject of much investigation.

Nine-day-old opossum spinal cords can regenerate after transection, how-ever, 12-day-old opossum spines do not recover. Promoter molecules decrease and inhibitors of regeneration increase in this time frame.^34,35 The identification of such factors in the spinal cord and then in the human retina might allow neurones that have lost their axon connections to regenerate. Such therapies directed to the retinal ganglion cell and its axon con-nections might preserve or enhance vision lost through glaucomatous optic neuropathy.

Conclusion

While the important risk factors and the pathophysiology of POAG are still being explored, it is clear that RGCs die by apoptosis. Those not damaged by the initial injury may be subjected to toxic products released from damaged

cells. The mediators of this secondary injury are common to many other neuro- degenerative disorders and may be blocked by a number of agents. In the future, it is likely that neuro-protective agents will be combined with ocular hypotensive treatments to treat pressure, blood flow and the secondary mediators of RGC death. Many important bio-chemical events in apoptosis have been identified, but the therapeutic utility of blocking cell death has yet to be demon-strated. Therefore, the important question is whether cells rescued from apoptosis can continue to function.

The manipulation of gene expression remains the most exciting prospect given our increased understanding of the human genome and our expanding ability to control nerve cell physiology. An understanding of the common neuro-degenerative processes might lead to improved outcomes and the effective management of many chronic CNS diseases. Unfortunately, many such diseases remain progressive and can create severe disability despite our best management and attentive care.

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