Title:
Neuroprotection and optic nerve regeneration for glaucoma therapy

 

Speaker:
Takayuki Harada, M.D. Ph.D.
Department Head, Department of Sensory and Motor Systems
Project leader, Visual Research Project
Tokyo Metropolitan Institute of Medical Science

 

Abstract:
Glaucoma is the major cause of blindness, and 70% of glaucoma patients suffer from normal tension glaucoma (NTG) in Japan. In addition to high intraocular pressure, factors such as oxidative stress and glutamate neurotoxicity may be involved in the pathogenesis of retinal ganglion cell (RGC) death. Therefore, development of therapies based on neuroprotection may achieve promising results. We previously reported generation of NTG mouse models. These mice are deficient in glutamate transporters (GLAST or EAAC1) and are very useful for evaluating the effects of drugs and gene manipulations in a short period. Using these mice, we evaluated the therapeutic potential of some agents with neuroprotective properties, for example, valproic acid has antioxidant effects and protects RGCs in NTG models. For the stimulation of axon regeneration, we are interested in the function of Dock3, a member of atypical guanine exchange factors that activates the Rho GTPases Rac1. We recently showed that Dock3 plays a role in protecting RGCs from neurotoxicity and oxidative stress as well as in promoting optic nerve regeneration. Finally, I would like to introduce some of our recent progress on glaucoma research utilizing marmosets, a non-human primate.

 

References:
1.Harada T, et al. The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma. J Clinical Invest 117: 1763-1770, 2007.
2.Harada T, Harada C and Parada LF. Molecular regulation of visual system development: more than meets the eye. Genes Dev 21: 367-378, 2007.
3.Namekata K, et al. Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex. Proc Natl Acad Sci USA 107: 7586-7591, 2010.
4.Harada C, et al. ASK1 deficiency attenuates neural cell death in GLAST deficient mice, a model of normal tension glaucoma. Cell Death Differ 17: 1751-1759, 2010.　
5.Harada C, et al. Glia- and neuron-specific functions of TrkB signalling during retinal degeneration and regeneration. Nature Commun 2: 189, 2011. 　　
6.Namekata K, et al. Dock3 stimulates axonal outgrowth via GSK-3β-mediated microtubule assembly. J Neurosci 32: 264-274, 2012.
7.Namekata K, et al. Dock GEFs and their therapeutic potential: Neuroprotection and axon regeneration. Progress in Retinal and Eye Research 43: 1-16, 2014.
8.Guo X, et al. Caloric restriction promotes cell survival in a mouse model of normal tension glaucoma. Sci Rep 6, 33950: 2016.
9.Kimura A, et al. Targeting oxidative stress for treatment of glaucoma and optic neuritis. Oxidative Medicine and Cellular Longevity 2017: 2817252, 2017.
10.Akaiwa K, et al. Edaravone suppresses retinal ganglion cell death in a mouse model of normal tension glaucoma. Cell Death Dis 8: e2934, 2017.