MYELINATION TRANSITION ZONE ASTROCYTES ARE CONSTITUTIVELY PHAGOCYTIC AND HAVE SYNUCLEIN DEPENDENT REACTIVITY IN GLAUCOMA1

Nguyen JV, Soto I, Kim KY, et al*

Proceedings of the National Academy of Sciences, January 2011

This article identified a new degradation pathway that might be responsible for the axonal degeneration we see in glaucoma. This mechanism matches the characteristic pattern of glaucomatous damage, reflects an ability to be modulated by IOP increases, and has inborn genetic variability.

Supportive Astrocytes Gone Wild

Optic nerve head (ONH) astrocytes are capable of phagocytosis and do not have a purely supportive func- tion. Nguyen et al demonstrated that astrocytes in healthy mice have a constitutive expression of Mac-2, a “clean-up” gene, which is normally only present in specialized phago- cytic cells. There was histological evidence of destruction of the ONH, with ingested portions of neuronal axons found inside astrocytic cells. The expression of Mac-2 and largest cellular fragments were primarily found in a specific area of the retro-laminar ONH where myelination of the optic nerve begins. This so-called myelin transition zone has constitutive internalization of axonal material, whereas the surrounding cells only become phagocytic after dam- age to the nerve has occurred. The authors pointed out that the unique properties of this anatomic location could lead to the striking arcuate pattern of damage that is typi- cal for retinal nerve fiber loss in glaucoma.

Increased IOP Causes Astrocytes to Digest the Optic Nerve

The authors found that increased IOP caused astro- cytes outside the myelin transition zone to become pha- cocytic through increased Mac-2 expression. This pro- vides a plausible mechanism by which glaucomatous damage could begin during a patient's lifetime and would fit with our knowledge that lowering IOP with medication/surgery is an effective way to reduce glauco- matous progression. Remarkably, this change in gene expression was specific to pressure increase and did not occur with other manipulations of the nerve (eg, optic nerve crush).

Genetic Variation in Astrocyte Phagocytosis due to Gamma Synuclein

These results suggest that failure to clear axon-derived material (one of them being gamma synuclein) at the myelin transition zone may contribute to axonal loss in glaucoma. The findings indicate that there are protease- resistant forms of gamma synuclein in glaucoma that are similar to Parkinson disease. There are different types and amounts of gamma synuclein; the DBA/2J glaucoma mouse model has a large amount of digestion-resistant gamma synuclein when compared with control mice.

Discovering the genetic and molecular triggers for glaucomatous damage has inherent appeal. The ability to modulate these triggers could lead to a very effective new class of medications that would treat the neuronal damage itself instead of a risk factor.

*Financial disclosures: The authors stated that they hold no proprietary interest in the materials discussed herein.

DIURNAL AND NOCTURNAL EFFECTS OF BRIMONIDINE MONOTHERAPY ON INTRAOCULAR PRESSURE2

Liu JH, Medeiros FA, Slight JR, Weinreb RN*

Ophthalmology, November 2011

This study looked at the 24-hour pressure-lowering effect of brimonidine, which was especially interesting given that brimonidine is known to work through two mechanisms, reducing aqueous humor production and increasing uveoscleral outflow. Other medications that reduce aqueous humor production such as ß-blockers have been found to be ineffective at reducing IOP overnight, whereas prostaglandin analogues, which increase uveoscleral out- flow, have been found to reduce IOP throughout the day and night.3,4

Brimonidine Does Not Lower IOP at Night

The authors showed that brimonidine monotherapy lowered IOP effectively during daytime hours but not during the night. The study recruited 40- to 70-year-old, newly diagnosed, untreated glaucoma or ocular hyperten- sive patients. Each patient received baseline 24-hour IOP measurements followed by a second 24-hour series after 1 month of treatment with brimonidine three times a day. Interestingly, this reduction in IOP after treatment could be observed even when it was measured while patients were in the supine position during the day, showing that simple postural changes were not responsible. Heart rate, mean arterial pressure, and ocular perfusion pressure were measured before and after brimonidine treatment to ensure that topical brimonidine treatment did not affect these cardiovascular factors. In addition, the study was administered under strict laboratory conditions, with regulated hours of light and dark and monitored adminis- tration of eye drops at set 8-hour intervals.

Use Brimonidine Only Before Breakfast and Lunch

The authors stated that there is a plausible physio- logical rationale to explain the daytime-only IOP- reducing effects of brimonidine as well as ß-blockers. Both classes of drugs act to suppress the endogenous ß-adrenergic stimulus to produce aqueous that is only present during the daytime. Blocking this signal when it is not present, whether at the presynaptic α2 receptor or at the postsynaptic ß receptor, does not lead to an appreciable change. It remains unknown why increases in uveoscleral outflow were not appreciable at night with brimonidine therapy as opposed to prostaglandin agonist therapy. The authors pointed out that, because brimonidine does not lower IOP during nighttime hours, the third dose of brimonidine taken at bedtime is unnecessary, adds to the cost, and reduces rates of compliance.

*Financial disclosures: The authors stated that they hold no proprietary interest in the materials discussed herein.

A RANDOMIZED TRIAL OF BRIMONIDINE VERSUS TIMOLOL IN PRESERVING VISUAL FUNCTION: RESULTS FROM THE LOW- PRESSURE GLAUCOMA TREATMENT STUDY5

Krupin T, Liebman JM, Greenfield DS, et al*

American Journal of Ophthalmology, April 2011

This study followed patients with primary open-angle glaucoma in the low pressure range. They were measured during daytime visits. Twice-daily treatments with an α-agonist, brimonidine, were compared to an inexpensive and widespread ß-blocker, timolol. The different outcomes spur discussion of postulated secondary mechanisms (neuroprotection) and side effects (reduced perfusion) and may require many to rethink their prescribing practice.

Brimonidine but Not Timolol Prevents Progression in Low-Pressure Glaucoma

Patients with low-pressure glaucoma were randomly assigned to twice-daily monotherapy with either brimonidine tartrate 0.2% or timolol maleate 0.5%. They were observed for 4 years to detect visual field progres- sion shown by a decrease of greater than 1 dB per year in the same three or more points shown on three con- secutive tests. Subjects and physicians were blind to the medication assigned. Subjects were assigned in blocks of seven such that four patients received brimonidine and three received timolol, since the discontinuation rate for brimonidine is generally greater than that for timolol. Ninety-nine patients were randomized to bri- monidine, and 79 were randomized to timolol.

Significantly fewer subjects treated with brimonidine (nine subjects, 9.1%) were found to have progressed than those treated with timolol (31 subjects, 28.3%) at the endpoint of the study, despite similar IOP values at all time points. A greater percentage of subjects assigned to brimonidine (28 subjects, 28.3%) withdrew from the study than patients assigned to timolol (nine subjects, 11.4%). The most common reason for with- drawal was localized ocular allergy, which occurred in 20 patients using brimonidine and three patients using timolol. Careful analyses were performed to ensure that there was no significant difference in the patients who discontinued treatment as opposed to subjects who remained in the study to ensure that the difference seen between treatment groups was not due to self-selection bias.

Brimonidine Neuroprotection or Damaging Reduction of Perfusion With Timolol?

Since brimonidine and timolol have very similar IOP- lowering profiles, this study provides an opportunity to evaluate the potential neuroprotective properties of the former. A little-known fact is that ß-adrenergic receptor blockage (timolol) and α2 adrenergic receptor stimulation (brimonidine) have the same intracellular cascade, because both cause a downregulation of adenylate cyclase with decreased cyclic adenosine monophosphate. The fewer progressors in the brimoni- dine group could be due to protection conferred by brimonidine, a risk conferred by timolol, or some com- bination of the two. A lowering in heart rate or blood pressure by timo- lol is one potential source of the greater progression amongst timolol recipients. A recent study by Quaranta et al, however, showed that treatment with brimonidine caused a greater decrease in these param- eters than treatment with timolol.6 Pressure differ- ences not captured during office visits are another potential source of this difference. Liu et al, however, indicated that brimonidine does not effectively lower IOP during the nocturnal period in primary openangle glaucoma patients; neither does timolol.1 A final explanation would relate to the different mechanisms of action of brimonidine and timolol, as brimonidine affects uveoscleral outflow in addition to aqueous production.

This well-conducted study lends support to the idea of a neuroprotective effect of brimonidine. The patients treated with this medication had less visual field loss despite similar daytime IOP values throughout the study period, with no other simple explanation for this effect. Critics of neuroprotective eye drops for humans had pointed in the past to the much larger diffusion distance in human eyes when compared with the much shorter distance in rodent eyes where neuroprotection can be demonstrated.

*Financial disclosures: The authors stated that they hold no proprietary interest in the materials discussed herein.

Section Editor James C. Tsai, MD, is the chairman and Robert R. Young professor of ophthalmology and visual sci- ence at Yale University School of Medicine in New Haven, Connecticut. He acknowledged no financial interest in the products or companies mentioned herein. Dr. Tsai may be reached at (203) 785-7233; james.tsai@yale.edu.

Sonya Thomas is a medical student and a Doris Duke clinical research fellow at Yale University School of Medicine in New Haven, Connecticut. Ms. Thomas may be reached at (203) 936-8569; sonya.thomas@yale.edu.

Nils A. Loewen, MD, PhD, is an assistant pro- fessor of ophthalmology and visual science and the director of the glaucoma section at Yale University School of Medicine in New Haven, Connecticut. Dr. Loewen may be reached at (203) 533-1004; nils.loewen@yale.edu.

  1. Nguyen JV, Soto I, Kim Ky, et al. Myelination transition zone astrocytes are constitutively phagocytic and have synuclein dependent reactivity in glaucoma. Proc Natl Acad Sci USA. 2011;108(3):1176-1181.
  2. Liu JH, Medeiros FA, Slight JR, Weinreb RN. Diurnal and nocturnal effects of brimonidine monotherapy on intraocular pressure. Ophthalmology. 2010;117(11):2075-2079.
  3. Liu JH, Kripke DF, Weinreb RN. Comparison of the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure. Am J Ophthalmol. 2004;138(3):389-395.
  4. Liu JH, Medeiros FA, Slight JR, Weinreb RN. Comparing diurnal and nocturnal effects of brinzolamide and timolol on intraocular pressure in patients receiving latanoprost monother- apy. Ophthalmology.
    5. 2009;116(3):449-454.
  5. Krupin T, Liebmann JM, Greenfield DS, et al. A randomized trial of brimonidine versus timolol in preserving visual function: results from the Low-Pressure Glaucoma Treatment Study. Am J Ophthalmol. 2011;151(4):671-681.
  6. Quaranta L, Gandolfo F, Turano R, et al. Effects of topical hypotensive drugs on circadian IOP, blood pressure, and calculated diastolic ocular perfusion pressure in patients with glau- coma. Invest Ophthalmol Vis Sci. 2006;47(7):2917-2923.