Top

BMC Ophthalmology

Published in:

Open Access 01-12-2018 | Research article

A rodent model of anterior ischemic optic neuropathy (AION) based on laser photoactivation of verteporfin

Authors: Jing-yu Min, Yanan Lv, Lei Mao, Yuan-yuan Gong, Qing Gu, Fang Wei

Published in: BMC Ophthalmology | Issue 1/2018

Abstract

Background

A rodent model of photodynamic AION resulting from intravenous verteporfin is presented. The analysis of the morphological function, the pathological changes and the potential mechanism of action were further investigated.

Methods

Photodynamic treatment was conducted on the optic nerve head (ONH) following administration of the photosensitizer. The fellow eye was considered as sham control. Fundus Fluorescein angiography (FFA), spectral domain optical coherence tomography (SD-OCT) and Flash-visual evoked potential (F-VEP) recordings were conducted at different time points. Immunohistochemistry was used to observe apoptotic cell death (TUNEL) and macrophage infiltration (ED-1/Iba-1). Retrograde labeling of retinal ganglion cells (RGCs) was used to evaluate the loss of RGCs.

Results

After laser treatment, SD-OCT indicated optic nerve edema, while FFA indicated late leakage of the ONH. F-VEPs were distinctly reduced compared to control eyes. The number of apoptotic RGCs peaked on day 14 (5.71 ± 0.76, p < 0.01). The infiltration of ED-1 and Iba-1 increased on the 3rd day following PDT, while it peaked on day 14 (67.5 ± 9.57 and 77.5 ± 12.58 respectively, p < 0.01). Following 3 weeks of AION, the densities of RGCs in the central retinas of the normal and AION eyes were 3075 ± 298/mm² and 2078 ± 141/mm² (p < 0.01), respectively.

Conclusions

Verteporfin photodynamic treatment on rodents ONH can lead to functional, histological, and pathological changes. This type of animal model of AION is easy to establish and stable. It can be used for studying the mechanism and neuroprotective medicine of AION injury.

Biousse V, Newman NJ. Ischemic optic neuropathies. N Engl J Med. 2015;372:2428–36. https://doi.org/10.1056/NEJMra1413352.CrossRefPubMed

Xu L, Wang Y, Jonas JB. Incidence of nonarteritic anterior ischemic optic neuropathy in adult Chinese: the Beijing eye study. Eur J Ophthalmol. 2007;17:459–60.CrossRef

Hayreh SS. Management of ischemic optic neuropathies. Indian J Ophthalmol. 2011;59:123–36. https://doi.org/10.4103/0301-4738.77024.CrossRefPubMedPubMedCentral

Bernstein SL, Guo Y, Kelman SE, Flower RW, Johnson MA. Functional and cellular responses in a novel rodent model of anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci. 2003;44:4153–62.CrossRef

Wen YT, Huang TL, Huang SP, Chang CH, Tsai RK. Early applications of granulocyte colony-stimulating factor (G-CSF) can stabilize the blood-optic-nerve barrier and ameliorate inflammation in a rat model of anterior ischemic optic neuropathy (rAION). Dis Model Mech. 2016;9:1193–202. https://doi.org/10.1242/dmm.025999.CrossRefPubMedPubMedCentral

Huang TL, Wen YT, Chang CH, Chang CW, Lin KH, Tsai RK. Efficacy of intravitreal injections of triamcinolone Acetonide in a rodent model of Nonarteritic anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci. 2016;57:1878–84. https://doi.org/10.1167/iovs.15-19023.CrossRefPubMed

Mathews MK, Guo Y, Langenberg P, Bernstein SL. Ciliary neurotrophic factor (CNTF)-mediated ganglion cell survival in a rodent model of non-arteritic anterior ischaemic optic neuropathy (NAION). Br J Ophthalmol. 2015;99:133–7. https://doi.org/10.1136/bjophthalmol-2014-305969.CrossRefPubMed

Huang TL, Huang SP, Chang CH, Lin KH, Chang SW, Tsai RK. Protective effects of systemic treatment with methylprednisolone in a rodent model of non-arteritic anterior ischemic optic neuropathy (rAION). Exp Eye Res. 2015;131:69–76. https://doi.org/10.1016/j.exer.2014.12.014.CrossRefPubMed

Mantopoulos D, Bouzika P, Tsakris A, Pawlyk BS, Sandberg MA, Miller JW, Rizzo Iii JF, Vavvas DG, Cestari DM. (TUNEL!!!) an experimental animal model of photodynamic optic nerve head injury (PONHI). Curr Eye Res. 2016:1–9. https://doi.org/10.3109/02713683.2015.1135960.CrossRef

10.

Zacks DN, Ezra E, Terada Y, Michaud N, Connolly E, Gragoudas ES, Miller JW. Verteporfin photodynamic therapy in the rat model of choroidal neovascularization: angiographic and histologic characterization. Invest Ophthalmol Vis Sci. 2002;43:2384–91.PubMed

11.

Denny CA, Alroy J, Pawlyk BS, Sandberg MA, d’Azzo A, Seyfried TN. Neurochemical, morphological, and neurophysiological abnormalities in retinas of Sandhoff and GM1 gangliosidosis mice. J Neurochem. 2007;101:1294–302. https://doi.org/10.1111/j.1471-4159.2007.04525.x.CrossRefPubMed

12.

Jiang B, Zhang P, Zhou D, Zhang J, Xu X, Tang L. Intravitreal transplantation of human umbilical cord blood stem cells protects rats from traumatic optic neuropathy. PLoS One. 2013;8:e69938. https://doi.org/10.1371/journal.pone.0069938.CrossRefPubMedPubMedCentral

13.

Xiong S, Xu Y, Ma M, Wang H, Wei F, Gu Q, Xu X. Neuroprotective effects of a novel peptide, FK18, under oxygen-glucose deprivation in SH-SY5Y cells and retinal ischemia in rats via the Akt pathway. Neurochem Int. 2017. https://doi.org/10.1016/j.neuint.2017.02.015.CrossRef

14.

Chen YJ, Huang YS, Chen JT, Chen YH, Tai MC, Chen CL, Liang CM. Protective effects of glucosamine on oxidative-stress and ischemia/reperfusion-induced retinal injury. Invest Ophthalmol Vis Sci. 2015;56:1506–16. https://doi.org/10.1167/iovs.14-15726.CrossRefPubMed

15.

Touitou V, Johnson MA, Guo Y, Miller NR, Bernstein SL. Sustained neuroprotection from a single intravitreal injection of PGJ2 in a rodent model of anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci. 2013;54:7402–9. https://doi.org/10.1167/iovs.13-12055.CrossRefPubMedPubMedCentral

16.

Huang SP, Tsai RK. Efficacy of granulocyte-colony stimulating factor treatment in a rat model of anterior ischemic optic neuropathy. Neural Regen Res. 2014;9:1502–5. https://doi.org/10.4103/1673-5374.139472.CrossRefPubMedPubMedCentral

17.

Fard MA, Ebrahimi KB, Miller NR. RhoA activity and post-ischemic inflammation in an experimental model of adult rodent anterior ischemic optic neuropathy. Brain Res. 2013;1534:76–86. https://doi.org/10.1016/j.brainres.2013.07.053.CrossRefPubMed

18.

Bernstein SL, Guo Y. Changes in cholinergic amacrine cells after rodent anterior ischemic optic neuropathy (rAION). Invest Ophthalmol Vis Sci. 2011;52:904–10. https://doi.org/10.1167/iovs.10-5247.CrossRefPubMedPubMedCentral

19.

Klaassen CD. Pharmacokinetics of rose bengal in the rat, rabbit, dog and Guinea pig. Toxicol Appl Pharmacol. 1976;38:85–100.CrossRef

20.

She H, Nakazawa T, Matsubara A, Connolly E, Hisatomi T, Noda K, Kim I, Gragoudas ES, Miller JW. Photoreceptor protection after photodynamic therapy using dexamethasone in a rat model of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2008;49:5008–14. https://doi.org/10.1167/iovs.07-1154.CrossRefPubMed

21.

Renno RZ, Terada Y, Haddadin MJ, Michaud NA, Gragoudas ES, Miller JW. Selective photodynamic therapy by targeted verteporfin delivery to experimental choroidal neovascularization mediated by a homing peptide to vascular endothelial growth factor receptor-2. Arch Ophthalmol. 2004;122:1002–11. https://doi.org/10.1001/archopht.122.7.1002.CrossRefPubMed

22.

Matsubara A, Nakazawa T, Noda K, She H, Connolly E, Young TA, Ogura Y, Gragoudas ES, Miller JW. Photodynamic therapy induces caspase-dependent apoptosis in rat CNV model. Invest Ophthalmol Vis Sci. 2007;48:4741–7. https://doi.org/10.1167/iovs.06-1534.CrossRefPubMed

23.

Hedges TR 3rd, Vuong LN, Gonzalez-Garcia AO, Mendoza-Santiesteban CE, Amaro-Quierza ML. Subretinal fluid from anterior ischemic optic neuropathy demonstrated by optical coherence tomography. Arch Ophthalmol. 2008;126:812–5. https://doi.org/10.1001/archopht.126.6.812.CrossRefPubMed

24.

Yu C, Ho JK, Liao YJ. Subretinal fluid is common in experimental non-arteritic anterior ischemic optic neuropathy. Eye (Lond). 2014;28:1494–501. https://doi.org/10.1038/eye.2014.220.CrossRef

25.

Zhang C, Guo Y, Slater BJ, Miller NR, Bernstein SL. Axonal degeneration, regeneration and ganglion cell death in a rodent model of anterior ischemic optic neuropathy (rAION). Exp Eye Res. 2010;91:286–92. https://doi.org/10.1016/j.exer.2010.05.021.CrossRefPubMedPubMedCentral

26.

Slater BJ, Mehrabian Z, Guo Y, Hunter A, Bernstein SL. Rodent anterior ischemic optic neuropathy (rAION) induces regional retinal ganglion cell apoptosis with a unique temporal pattern. Invest Ophthalmol Vis Sci. 2008;49:3671–6. https://doi.org/10.1167/iovs.07-0504.CrossRefPubMedPubMedCentral

27.

Tsai RK, Chang CH, Wang HZ. Neuroprotective effects of recombinant human granulocyte colony-stimulating factor (G-CSF) in neurodegeneration after optic nerve crush in rats. Exp Eye Res. 2008;87:242–50. https://doi.org/10.1016/j.exer.2008.06.004.CrossRefPubMed

28.

Salgado C, Vilson F, Miller NR, Bernstein SL. Cellular inflammation in nonarteritic anterior ischemic optic neuropathy and its primate model. Arch Ophthalmol. 2011;129:1583–91. https://doi.org/10.1001/archophthalmol.2011.351.CrossRefPubMedPubMedCentral

29.

Yin Y, Henzl MT, Lorber B, Nakazawa T, Thomas TT, Jiang F, Langer R, Benowitz LI. Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. Nat Neurosci. 2006;9:843–52. https://doi.org/10.1038/nn1701.CrossRefPubMed

30.

Zhang C, Guo Y, Miller NR, Bernstein SL. Optic nerve infarction and post-ischemic inflammation in the rodent model of anterior ischemic optic neuropathy (rAION). Brain Res. 2009;1264:67–75. https://doi.org/10.1016/j.brainres.2008.12.075.CrossRefPubMedPubMedCentral

31.

Bernstein SL, Johnson MA, Miller NR. Nonarteritic anterior ischemic optic neuropathy (NAION) and its experimental models. Prog Retin Eye Res. 2011;30:167–87. https://doi.org/10.1016/j.preteyeres.2011.02.003.CrossRefPubMedPubMedCentral

32.

Slater BJ, Vilson FL, Guo Y, Weinreich D, Hwang S, Bernstein SL. Optic nerve inflammation and demyelination in a rodent model of nonarteritic anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci. 2013;54:7952–61. https://doi.org/10.1167/iovs.13-12064.CrossRefPubMedPubMedCentral

Title: A rodent model of anterior ischemic optic neuropathy (AION) based on laser photoactivation of verteporfin
Authors: Jing-yu Min
Yanan Lv
Lei Mao
Yuan-yuan Gong
Qing Gu
Fang Wei
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Ophthalmology / Issue 1/2018
Electronic ISSN: 1471-2415
DOI: https://doi.org/10.1186/s12886-018-0937-5

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

A rodent model of anterior ischemic optic neuropathy (AION) based on laser photoactivation of verteporfin

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2018

A clinical analysis of vitrectomy for severe vitreoretinopathy in patients with chronic renal

Predictive multi-imaging biomarkers relevant for visual acuity in idiopathic macular telangiectasis type 1

Management of refractory macular hole with blood and gas-assisted autologous neurosensory retinal free flap transplantation: a case report

Microglia enhanced the angiogenesis, migration and proliferation of co-cultured RMECs

Prevalence and risk factors of retinopathy of prematurity in Iran: a systematic review and meta-analysis

Effect of dexamethasone intravitreal implant (Ozurdex®) on corneal endothelium in retinal vein occlusion patients