BRIMONIDINE AND NEUROPROTECTION

• The main risk factor identified so far for the development and progression of glaucomatous optic nerve degeneration (GOND) is elevated intra-ocular pressure (IOP).

• It is also known that non-pressure dependent mechanisms may play a significant role in the etiopathogenesis of glaucoma. This is seen in normal tension glaucoma (NTG) and those individuals in whom IOP is presumably controlled to statistically acceptable levels.

• Management strategies for glaucoma are focusing on neuro-modulation, neuro-protection and neuro-regeneration.

• Brimonidine tartarate 0.15% (BT) reduces IOP by decreasing aqueous production (inflow) as well as by increasing uveo-scleral aqueous outflow. This molecule is also being investigated for its role in neuroprotection.

• BT is a third-generation alpha-2 adrenergic agonist. It has >1000-fold selectivity for alpha-2 receptors (compared to alpha-1 receptors).

•  BT acts initially by reducing aqueous production and on chronic use increases uveo-scleral outflow.

• Neuroprotection refers to the ability to preserve anatomic and functional integrity of the retinal ganglion cells (RGC), without the role of lowered IOP, thus preserving the visual field.

• The retina contains alpha-2 receptors primarily in the ganglion cell layer and inner nuclear layer.

• BT requires an in vivo concentration of 2 Nm to activate alpha-2 receptors significantly.

• In a study, the drug was instilled prior to vitrectomy and vitreous samples collected intra-operatively. The mean BT concentration was 185 Nm, high enough to reach the retina. Therefore, topical BT is presumed to be effective in the retina adequately.

• The Low-Pressure Glaucoma Treatment Study (LoGTS) reported progression of visual fields was reduced by 9.1% in eyes treated with timolol and by 39.1% in eyes treated with BT, after 2 years of follow-up.

• In a chronic ocular hypertension rat model, subcutaneous injection of BT and timolol were studied. BT treated eyes had 50% less RGC degeneration compared to timolol treated eyes. Similar results were obtained on intra-peritoneal injection of BT in rat models of glaucoma. Ischemia induced and crush injury models also showed enhanced RGC survival and preserved ERG b wave following administration of BT.

• Patients undergoing laser treatment for choroidal neovascularization were treated with BT 4-48 hours prior to the procedure and continued treatment for one-month post-laser. BT treated eyes had better visual acuity preservation. This was attributed to the protective effect of BT on the neuroretina from laser-induced collateral damage.

• In a study of ocular hypertension patients, BT and timolol were compared for their effects on retinal nerve fiber layer (RNFL) thickness. Scanning laser polarimetry (GDx) showed less progression of RNFL thinning in eyes treated with BT over a 12-month follow-up.

• Another study compared BT with 360-degree argon laser trabeculoplasty (ALT).  Although IOP reduction was comparatively less in BT treated eyes, visual field progression was slower.

• BT treated eyes have also shown improved contrast sensitivity.

• BT is presumed to act through alpha-receptor stimulation which inhibits the signals triggering apoptotic cascade in the RGCs.

 

• The mechanism of proposed brimonidine neuroprotection is unclear. In one study of ischemic injury to the retina in a rat model, brimonidine was shown to lower glutamate concentrations in the vitreous humor. Based on these results, it has been suggested that brimonidine might be neuroprotective because it prevents glutamate-associated excitotoxicity. Alternatively, it has been suggested that brimonidine may directly inhibit apoptotic pathways.

• Further studies are required to confirm the suitability of BT as a neuro-protective agent.

FURTHER READING:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2709013/ 

PROTECT THE NERVE