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Editors Selection IGR 11-3

Medical Treatment: Neuroprotection

Comment by David Calkins on:

54546 Brimonidine promotes axon growth after optic nerve injury through Erk phosphorylation, Fujita Y; Sato A; Yamashita T, Cell Death and Disease, 2013; 4: e763

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Vision loss in optic neuropathy and injury arises from the limited neuroregenerative capacity of the retina and optic projection. This reduced capacity is due in part to neuronal reprogramming from a growth-associated state. Targets that could facilitate regrowth therefore are of tremendous therapeutic value, especially those with known neuroprotective properties. Several common compounds used to lower ocular pressure in glaucoma are themselves neuroprotective independent of their hypotensive effects.¹ For example, brimonidine (brimonidine tartrate) is a selective alpha-2-adrenergic receptor agonist that is directly neuroprotective of retinal ganglion cell neurons in various disease-relevant models. While brimonidine can exert a protective effect by modulating NMDA glutamate receptors in the retina, the drug is also associated with upregulation of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF). In this study, Yamashita's team injured the optic nerve by crush ‐ a common model for studying ganglion cell axons ‐ and measured how daily application of 1% brimonidine tartrate solution for two weeks influenced recovery. The team found that treatment increased the number of axons in the optic nerve capable of transporting cholera toxin b out of the retina and into the nerve, a typical assay for studying axon recovery. The team also found that brimonidine upregulated in the retina expression of the TrkB receptor, which promotes neuronal survival upon binding BDNF by activation of intracellular Erk1/2 (extracellular signal-regulated kinase). Co-treatment with an Erk1/2 antagonist suppressed the protective effect of brimonidine, suggesting a causal role for TrkB-Erk1/2 signaling. While crush is doubtlessly injurious, an important next step is to test whether brimonidine can truly regenerate ganglion cell axons that have been disconnected from the nerve or from central brain targets.

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