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History of neuroprotection and rationale as a therapy for glaucoma
Leonard A Levin1, Patti Peeples
1University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, Madison, WI 53792-4673, USA. lalevin@facstaff.wisc.edu
Abstract:
Neuroprotection is any therapy that prevents, retards, or reverses apoptosis-associated neuronal cell death resulting from primary neuronal lesions. Although more than 500 products have been investigated for neuroprotective effects, there has been a low rate of success in human trials. Reasons include failure of the animal model to simulate human disease, human disease variability, brain size and development differences, variations in the ratio of axonal to neuronal damage, and lack of efficacy of the compound under study. Other reasons include narrow drug therapeutic index, drug molecular size, the small treatment window after cellular injury, multiple comorbidities of test subjects causing recruitment and statistical challenges, and insufficiently valid and reliable end points. Glaucoma is a neurodegenerative disease for which the neuropathic pathology has been studied since 1972. There have been recent significant advances in understanding the mechanisms for death of retinal neurons, and numerous agents are under development. Memantine, currently approved for Alzheimer's disease and in phase 3 trials for glaucoma progression, is one of the most studied neuroprotectants in glaucoma. Therapies that prevent death of the retinal ganglion cell (neuroprotection), its axon (axoprotection), or both, theoretically should be useful in treating glaucoma.
Insights
Neuroprotection therapies aim to prevent neuronal cell death, but human trials show low success rates due to various factors. Memantine is a promising neuroprotectant for glaucoma, targeting retinal ganglion cell death.
Area of Science:
- Neuroscience
- Ophthalmology
- Pharmacology
Background:
- Neuroprotection seeks to prevent or reverse neuronal cell death, crucial for neurodegenerative diseases.
- Despite extensive research, neuroprotective therapies have faced significant challenges in human clinical trials.
- Glaucoma, a neurodegenerative disease, involves retinal neuron death, with ongoing research into therapeutic mechanisms.
Purpose of the Study:
- To review the challenges and advancements in neuroprotection, particularly in the context of glaucoma.
- To highlight the potential of agents like memantine in treating glaucoma progression.
- To discuss the theoretical benefits of neuroprotection and axoprotection for retinal ganglion cells in glaucoma.
Main Methods:
- Review of existing literature on neuroprotection and glaucoma pathology.
- Analysis of factors contributing to the low success rate of neuroprotective agents in human trials.
- Examination of the role of memantine as a neuroprotectant in glaucoma.
Main Results:
- Numerous neuroprotective agents (over 500) have been investigated with limited success in human trials.
- Key challenges include animal model limitations, disease variability, and drug efficacy issues.
- Memantine shows promise as a neuroprotectant in glaucoma, with ongoing clinical trials.
Conclusions:
- Developing effective neuroprotection for conditions like glaucoma requires overcoming significant translational hurdles.
- Targeting retinal ganglion cell survival and axonal integrity offers a theoretical therapeutic strategy for glaucoma.
- Further research into neuroprotective mechanisms and agent development is essential for treating neurodegenerative eye diseases.
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