Alpha-2 adrenergic receptor agonists are neuroprotective in experimental models of glaucoma.
OBJECTIVE
The glaucomas are characterized by chronic progressive ganglion cell loss over many years. A drug with neuroprotective activity should increase the resistance of retinal ganglion cells (RGC) to chronic stress or injury and therefore enhance survival. Brimonidine is a highly selective and potent alpha-2 adrenergic receptor agonist, which lowers intra-ocular pressure (IOP) and is neuroprotective. Immunohistochemistry data have shown that the specific receptor targets, the alpha-2 receptors, are located in the inner retina.


METHODS
Brimonidine 0.1 mg/kg given intraperitoneally promoted RGC survival compared with vehicle using the optic nerve crush model even when administered up to 24 hours before injury. Using the chronic ocular hypertensive rat model, brimonidine 1 mg/kg/day (with osmotic pump) significantly prevented the loss of RGCs when compared with vehicle or timolol. This ability was due to the neuroprotective action of brimonidine, since it did not affect IOP. In addition, brimonidine 0.1 mg/day reached concentrations in the retina of Sprague-Dawley rats within 30 minutes of injection, which was sufficient to activate the alpha-2 receptor (> or = 2 nM) and maintained these concentrations for 6 hours.


CONCLUSIONS
Having demonstrated that: a. the specific receptor target of brimonidine is located in the retina, which is important for optic neuroprotection, b. the agent shows neuroprotective ability in animal models, c. pharmacological concentrations of the drug can be reached in the retina, clinical trial has been initiated to determine whether brimonidine is neuroprotective in patients with nonarteritic ischaemic optic neuropathy.
Wheeler
L A
LA
Department of Biological Sciences, Allergan, Inc., Irvine, California 92612, USA. Wheeler_Larry@allergan.com
Woldemussie
E
E
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000627:therapeutic use*; D000818:Animals; D000068438:Brimonidine Tartrate; D002470:Cell Survival; D004195:Disease Models, Animal; D005901:Glaucoma / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D007274:Injections, Intraperitoneal; D007429:Intraocular Pressure; D009409:Nerve Crush; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020221:Optic Nerve Injuries / Q000150:complications; D011810:Quinoxalines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D012164:Retinal Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D018696:Neuroprotective Agents; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D000068438:Brimonidine Tartrate