C. Stephen Foster, MD


July 20, 2012

Glaucoma: A Neurodegenerative Disease

Glaucoma is increasingly recognized as a neurodegenerative disease, and substantial numbers of patients experience progressive loss of vision from glaucoma, despite medical, laser, and surgical therapy that results in normal or even subnormal intraocular pressure. Patient and physician frustration have prompted increasing interest in therapeutic targets other than intraocular pressure in patients with glaucoma. A major focus of the glaucoma presentations at the 2012 Association for Research in Vision and Ophthalmology (ARVO) meeting was neuroprotection, at the levels of molecular mechanisms and disease-modifying treatments.

Targeting the Inner Mitochondrial Membrane

Osborne[1] reported on the complex interactions among blood flow dynamics in the region of the optic nerve head, energy requirements of the retinal ganglion cells, anatomy of the lamina cribrosa, and influence of microglia and astrocytes in the retina. They hypothesize that after the onset of glaucoma, ganglion cell apoptosis is initiated by both receptor and mitochondrial-mediated events, which vary for different neurons. This suggests that a neuroprotective strategy will require the use of substances with multiple modes of action, which is unlikely to be achieved with a single chemical, such as memantine.

Building on the many years of clinical and bench research into the neuroprotective capabilities of memantine, Ramirez and colleagues[2] described additional molecular mechanisms by which such protection may be provided. They studied the effects of memantine on the mitochondrial membrane potential (ΔΨm) and lactate dehydrogenase (LDH) production in ARPE-19 and Müller cells (MIO-M1) exposed to hydroquinone in vitro.

The ΔΨm for ARPE-19 cells exposed to 200 µM, 100 µM, 50 µM, and 25 µM of hydroquinone was 3770 ± 43.08, 4015 ± 66.51, 5139 ± 40.76, and 7475 ± 94.06, respectively, compared with 9097 ± 76.06 in cells treated with the highest dimethyl sulfoxide (DMSO) equivalent (200 µM). Pretreatment with 30 µM of memantine resulted in an increased ΔΨm only at the 50-µM dose of hydroquinone (6997 ± 75.45; P < .001). The values for memantine-pretreated cultures plus 200 µM, 100 µM, and 25 µM of hydroquinone were 3777 ± 23.23 (P = .88), 4181 ± 39.52 (P =.057), and 7637 ± 41.71 (P = .146), respectively.

The ΔΨm for cultures treated with MIO-M1 plus 200 µM, 100 µM, 50 µM, and 25 µM of hydroquinone were 3275 ± 81.50, 4527 ± 61.49, 5625 ± 57.80, and 7763 ± 34.77, respectively, compared with 9118 ± 45.9 in cells treated with the highest DMSO equivalent (200 µM). In cells exposed to 50 µM of hydroquinone after memantine pretreatment, the ΔΨm increased to 669 5 ± 34.03 (P < .001). No statistically significant differences were found for the other hydroquinone doses.

LDH levels for ARPE-19 cells treated with 200 µM, 100 µM, 50 µM, and 25 µM of hydroquinone were 5.50 ± 0.25, 4.8 ± 0.20, 4.16 ± 0.06, and 2.0 ± 0.10. The LDH levels were significantly reduced after pretreatment with memantine in cells exposed to 50 µM and 25 µM of hydroquinone: 2.233 ± 0.08 (P < .001) and 1.567 ± 0.12 (P < .031), respectively. MIO-M1 cells treated with the same concentrations of hydroquinone alone showed LDH levels of 6.20 ± 0.11, 5.66 ± 0.08, 5.35 ± 0.13, and 2.06 ± 0.03. The LDH level was significantly reduced after pretreatment with memantine only in cells exposed to 25 µM of hydroquinone: 1.250 ± 0.08 (P < .001).

Ramirez and colleagues concluded that memantine showed an in vitro protective effect against hydroquinone-induced toxicity by increasing the ΔΨm at a dose of 50 µM. This drug is currently being used to treat patients with various neurodegenerative disorders, and some physicians are using it off-label in patients with glaucoma, especially low- or normal-tension glaucoma.