The chronic
progressive loss of retinal ganglion cells (RGCs) is an important pathophysiological
mechanism in glaucoma. A growing understanding of the possible mechanism
associated with injury and death of neuronal cells provides new targets for
drug discovery and therapy. Alpha-2 receptors are present in the retina and
optic nerve. Laboratory studies show that treatment with the selective alpha-2
agonist bromonidine up-regulates an intrinsic survival pathway that protects
the retina and optic nerve after injury. Neuroprotection with brimonidine has
been observed in the nerve crush model, ocular hypertensive rat, ischemia and
light photoreceptor damage models. These data suggest that one function of
alpha-2 receptors in retina and optic nerve is to increase the resistance of
cells to stress and injury by enhancing survival pathways.
Four criteria are
proposed for assessing the likely therapeutic utility in human glaucoma of
drugs that have demonstrated neuroprotective activity in animal models. A
specific receptor target must be in the retina/optic nerve, activation of the
target must trigger pathways that enhance a neuron’s resistance to
stress/injury and/or suppresses toxic insults, the drug must reach the retina
at pharmacological doses, and the neuroprotective activity should be
demonstrated in clinical trials. Data are presented that illustrate how the
specific and potent alpha-2 agonist, brimonidine, meets these criteria.