Brimonidine promotes axon growth after optic nerve injury through Erk phosphorylation

Y Fujita,T Yamashita,A Sato

doi:10.1038/cddis.2013.298

Y Fujita, T Yamashita + Show 1 more

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https://doi.org/10.1038/cddis.2013.298

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Abstract

It is well known that axons of the adult mammalian central nervous system have a very limited ability to regenerate after injury. Therefore, the neurodegenerative process of glaucoma results in irreversible functional deficits, such as blindness. Brimonidine (BMD) is an alpha2-adrenergic receptor agonist that is used commonly to lower intraocular pressure in glaucoma. Although it has been suggested that BMD has neuroprotective effects, the underlying mechanism remains unknown. In this study, we explored the molecular mechanism underlying the neuroprotective effect of BMD in an optic nerve injury (ONI) model. BMD treatment promoted optic nerve regeneration by inducing Erk1/2 phosphorylation after ONI. In addition, an Erk1/2 antagonist suppressed BMD-mediated axonal regeneration. A gene expression analysis revealed that the expression of the neurotrophin receptor gene p75 was increased and that the expression of the tropomyosin receptor kinase B (TrkB) gene was decreased after ONI. BMD treatment abrogated the changes in the expression of these genes. These results indicate that BMD promotes optic nerve regeneration via the activation of Erk1/2.

Highlights

Brimonidine (BMD) is a selective alpha2-adrenergic receptor agonist that is known for its role in reducing intraocular pressure (IOP) in the treatment of ocular hypertension and glaucoma.[1]
Several clinical studies have reported its safety in lowering IOP:[2,3,4] recent experiments suggest that it has a neuroprotective effect after various types of injury in animal models, such as optic neuropathy including optic nerve injury (ONI),[5,6] ischemia,[7,8] and experimental glaucoma.[9,10,11]
The regenerating fibers of retinal ganglion cells (RGCs) were traced by injecting cholera toxin subunit B (CTB) conjugated to Alexa Fluor 555 into the vitreous of the retina 12 days after the crush injury (Figure 1a)

Summary

Introduction

Brimonidine (BMD) is a selective alpha2-adrenergic receptor agonist that is known for its role in reducing intraocular pressure (IOP) in the treatment of ocular hypertension and glaucoma.[1]. It has been suggested that BMD exerts its neuroprotective effects on RGCs via the upregulation of neurotrophic growth factors, such as FGF213,14 and BDNF.[15] We reported previously that the activation of the tropomyosin receptor kinase B (TrkB) receptor—a BDNF receptor—is required for the promotion of optic nerve regeneration, as well as the inhibition of the myelin signaling pathway.[16] These findings suggest that neurotrophin receptors have roles in axon regeneration after optic nerve crush injury. We reported previously that the inhibition of the p75 neurotrophin receptor causes the activation of TrkB, leading to optic nerve regeneration.[19] In this study, we assessed the manner via which BMD promotes optic nerve regeneration via neurotrophin signaling

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Conclusion