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Effects of combined neuroprotective and regenerative agents on damaged retinal ganglion cells in vivo
Author(s) -
Oshitari Toshiyuki,
Kitamura Yuta,
Guzel Bikbova,
Baba Takayuki,
Yamamoto Shuichi
Publication year - 2019
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/j.1755-3768.2019.5045
Subject(s) - tauroursodeoxycholic acid , axon , retina , neuroprotection , neurofilament , retinal , ciliary neurotrophic factor , chemistry , optic nerve , cornea , immunostaining , ophthalmology , anatomy , medicine , biology , pathology , pharmacology , neuroscience , neurotrophic factors , immunohistochemistry , biochemistry , apoptosis , receptor , unfolded protein response
Purpose To estimate the effectiveness of a single or combined topical neurotrophic factors on damaged retinal ganglion cells (RGCs) in optic nerve crush (OCN) rat model. Methods The left ONC was used for achieving RGC degeneration in adult SD rats. Rats were divided into 7 groups with 6 animals in each group, depending on used therapeutic agents which had been administrated by instillations of 100 m m citicoline, 100 m m tauroursodeoxycholic acid (TUDCA), 10 ng/ml neurotrophin‐4 (NT‐4), combined TUDCA/citicoline (Doublet‐1), combined TUDCA/NT‐4 (Doublet‐2), combined TUDCA/citicoline/NT‐4 (Triplet) and PBS. After 2 weeks, the number of remaining RGCs was determined by Brn3a mouse antibody immunostaining of whole‐mount retinas. To examine the regenerative effect, cryosections of optic nerve were made and immunostained for anti ‐200 kD neurofilament heavy and GAP‐43 antibodies. Results The density of RGCs in the PBS group 2 weeks after ONC was significantly less than in the normal control. The density of RGCs in citicoline, TUDCA, Doublet‐1, Doublet‐2, and Triplet groups were significantly higher than that of RGCs in the PBS group. In the Triplet group, the density of RGCs was significantly higher than that in single drug treated eyes. Compared with the PBS group, the decrease in neurofilament immunopositive axon numbers were suppressed significantly in the combination eye drop treatment groups. In the Triplet group, the number of GAP‐43 immunopositive axons was greater than that in the PBS group. Neovascularization in cornea, iris, and retina were observed in 62% of eyes in the Doublet‐1 group. Conclusions Neuroprotective and regenerative effects can be achieved with topical instillations of combinations of neurotrophic agents. Adverse effects such as neovascularizations had been observed in the Doublet‐1 group. Further studies to identify the mechanisms of neovascularization development is need to be performed.