Neuroprotective effects of benzatropine on rat model of nonarteritic anterior ischemic optic neuropathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Gan Linyang , Cui Jiantao , Chou Yuyu , Wang Yuhan , Du Hong , Li Donghui , Dai Wei , Zhang Hong , Zhang Dong , Ma Jin ,  Zhong Yong

Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China;

Corresponding author：

Zhong Yong, Email: yzhong_eye@163.com

Keywords：

Optic neuropathy, ischemic; Retinal ganglion cells; Disease models, animal

DOI：

10.3760/cma.j.issn.1005-1015.2019.03.010

Video：

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Objective To investigate the neuroprotective effect of Benztropine on retinal ganglion cells (RGCs) death and optic nerve injury in rats model of non-arteritis anterior ischemic optic neuropathy (rNAION).Methods A total of 25 Sprague-Dawley rats were randomly divided into Benztropine treatment group (n=13) and PBS control group (n=12). The right eye was set as the experimental eye. rNAION model was established by using rose Bengal combined with laser photodynamic method. The rats in the Benztropine treatment group were received intraperitoneal injection with Benztropine 10 mg/kg (0.2 ml) daily for 3 weeks, while the rats in the PBS control group were received intraperitoneal injection with an equal volume of PBS. At 1, 3 and 7 days after modeling, the retinal and optic disc conditions of the rats were observed by direct ophthalmoscopy. Retrograde labeling, fluorescence microscopy and transmission electron microscopy were used to observe the survival of RGCs and the damage of the optic nerve myelin and axon at 4 weeks after modeling. The RGCs density and survival rate of the two groups were compared by One-Way Anova.Results At 1 and 3 days after modeling, the optic disc edema was observed in the rats of rNAION model group. At 7 days after modeling, the optic disc edema decreased and the boundary was blurred compared with 3 days after modeling.After 4 weeks, the RGCs density in the PBS group was 308±194/mm² and the survival rate was 13.7%. The density of RGCs in the Benztropine group was 1173+868/mm² and the survival rate was 47.6%. The differences of RGCs density and survival rate were significant between the two groups (F=7.552, 8.184; P=0.015, 0.012). Myelin disintegration, axon degeneration, onion-like body and gliosis were observed in the optic nerve sections of rNIAON in the PBS group, while the damage of axon and myelin structure in the Benztropine group was significantly less than that in the PBS group.Conclusions Benztropine group showed higher RGC survival rate, less damage of axon and myelin structure on rNAION model. This study explored the potential neuroprotective effect of Benztropine.

Citation： Gan Linyang, Cui Jiantao, Chou Yuyu, Wang Yuhan, Du Hong, Li Donghui, Dai Wei, Zhang Hong, Zhang Dong, Ma Jin, Zhong Yong. Neuroprotective effects of benzatropine on rat model of nonarteritic anterior ischemic optic neuropathy. Chinese Journal of Ocular Fundus Diseases, 2019, 35(3): 259-262. doi: 10.3760/cma.j.issn.1005-1015.2019.03.010 Copy

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8.	Deshmukh VA, Tardif V, Lyssiotis CA, et al. A regenerative approach to the treatment of multiple sclerosis[J]. Nature, 2013, 502(7471): 327-332. DOI: 10.1038/nature12647.
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11.	陈婷, 马瑾, 王一玮, 等. 大鼠非动脉炎性前部缺血性视神经病变模型视神经与视网膜的形态学观察[J]. 中华眼科杂志, 2015, 51(8): 592-596. DOI: 10.3760/cma.j.issn.0412-4081.2015.08.009.Chen T, Ma J, Wang YW, et al. Morphological evaluation of the optic nerve and retina in the rat model of non-arteritic anterior ischemic optic neuropathy[J]. Chin J Ophthalmol, 2015, 51(8): 592-596. DOI: 10.3760/cma.j.issn.0412-4081.2015.08.009.
12.	Zhang C, Guo Y, Slater BJ, et al. Axonal degeneration, regeneration and ganglion cell death in a rodent model of anterior ischemic optic neuropathy (rAION)[J]. Exp Eye Res, 2010, 91(2): 286-292. DOI: 10.1016/j.exer.2010.05.021.
13.	Dutta R, Trapp BD. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis[J]. Prog Neurobiol, 2011, 93(1): 1-12. DOI: 10.1016/j.pneurobio.2010.09.005.
14.	Dziedzic T, Metz I, Dallenga T, et al. Wallerian degeneration: a major component of early axonal pathology in multiple sclerosis[J]. Brain Pathol, 2010, 20(5): 976-985. DOI: 10.1111/j.1750-3639.2010.00401.x.
15.	Wakatsuki S, Furuno A, Ohshima M, et al. Oxidative stress-dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration[J]. J Cell Biol, 2015, 211(4): 881-896. DOI: 10.1083/jcb.201506102.
16.	Lee GH, Stanford MP, Shariati MA, et al. Severe, early axonal degeneration following experimental anterior ischemic optic neuropathy[J]. Invest Ophthalmol Vis Sci, 2014, 55(11): 7111-7118. DOI: 10.1167/iovs.14-14603.
17.	Knox DL, Kerrison JB, Green WR. Histopathologic studies of ischemic optic neuropathy[J]. Trans Am Ophthalmol Soc, 2000, 98: 203-220.
18.	Levin LA, Louhab A. Apoptosis of retinal ganglion cells in anterior ischemic optic neuropathy[J]. Arch Ophthalmol, 1996, 114(4): 488-491. DOI: 10.1001/archopht.1996.01100130484027.

1. Goldenberg-Cohen N, Guo Y, Margolis F, et al. Oligodendrocyte dysfunction after induction of experimental anterior optic nerve ischemia[J]. Invest Ophthalmol Vis Sci, 2005, 46(8): 2716-2725. DOI: 10.1167/iovs.04-0547.
2. Albrecht May C. Comparative anatomy of the optic nerve head and inner retina in non-primate animal models used for glaucoma research[J]. Open Ophthalmol J, 2008, 2: 94-101. DOI: 10.2174/1874364100802010094.
3. Bernstein SL, Guo Y, Kelman SE, et al. Functional and cellular responses in a novel rodent model of anterior ischemic optic neuropathy[J]. Invest Ophthalmol Vis Sci, 2003, 44(10): 4153-4162. DOI: 10.1167/iovs.03-0274.
4. Bernstein SL, Johnson MA, Miller NR. Nonarteritic anterior ischemic optic neuropathy (NAION) and its experimental models[J]. Prog Retin Eye Res, 2011, 30(3): 167-187. DOI: 10.1016/j.preteyeres.2011.02.003.
5. Peeler C, Cestari DM. Non-arteritic anterior ischemic optic neuropathy (NAION): a review and update on animal models[J]. Semin Ophthalmol, 2016, 31(1-2): 99-106. DOI: 10.3109/08820538.2015.1115248.
6. 王一玮, 陈婷, 马瑾, 等. 大鼠非动脉炎性前部缺血性视神经病变模型RGC及视神经损伤的特点[J]. 中华眼科杂志, 2016, 52(12): 918-923. DOI: 10.3760/cma.j.issn.0412-4081.2016.12.009.Wang YW, Chen T, Ma J, et al. Temporal and spatial characteristics of RGC death and axon degeneration in the rat model of nonarteritic anterior ischemic optic neuropathy[J]. Chin J Ophthalmol, 2016, 52(12): 918-923. DOI: 10.3760/cma.j.issn.0412-4081.2016.12.009.
7. 王文娟, 马伟娜. 非动脉炎性前部缺血性视神经病变动物模型的制备[J]. 中华实验眼科杂志, 2013, 31(1): 91-95. DOI: 10.3760/cma.j.issn.2095-0160.2013.01.022.Wang WJ, Ma WN. Establish of animal model of nonarteritic anterior ischemic optic neuropathy[J]. Chin J Exp Ophthalmol, 2013, 31(1): 91-95. DOI: 10.3760/cma.j.issn.2095-0160.2013.01.022.
8. Deshmukh VA, Tardif V, Lyssiotis CA, et al. A regenerative approach to the treatment of multiple sclerosis[J]. Nature, 2013, 502(7471): 327-332. DOI: 10.1038/nature12647.
9. Salgado C, Vilson F, Miller NR, et al. Cellular inflammation in nonarteritic anterior ischemic optic neuropathy and its primate model[J]. Arch Ophthalmol, 2011, 129(12): 1583-1591. DOI: 10.1001/archophthalmol.2011.351.
10. Ma J, Jiang L, Zhong Y, et al. Neuroprotective effect on retinal ganglion cells by transpupillary laser irradiation of the optic nerve head[J]. Neurosci Lett, 2010, 476(1): 3-8. DOI: 10.1016/j.neulet.2010.01.001.
11. 陈婷, 马瑾, 王一玮, 等. 大鼠非动脉炎性前部缺血性视神经病变模型视神经与视网膜的形态学观察[J]. 中华眼科杂志, 2015, 51(8): 592-596. DOI: 10.3760/cma.j.issn.0412-4081.2015.08.009.Chen T, Ma J, Wang YW, et al. Morphological evaluation of the optic nerve and retina in the rat model of non-arteritic anterior ischemic optic neuropathy[J]. Chin J Ophthalmol, 2015, 51(8): 592-596. DOI: 10.3760/cma.j.issn.0412-4081.2015.08.009.
12. Zhang C, Guo Y, Slater BJ, et al. Axonal degeneration, regeneration and ganglion cell death in a rodent model of anterior ischemic optic neuropathy (rAION)[J]. Exp Eye Res, 2010, 91(2): 286-292. DOI: 10.1016/j.exer.2010.05.021.
13. Dutta R, Trapp BD. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis[J]. Prog Neurobiol, 2011, 93(1): 1-12. DOI: 10.1016/j.pneurobio.2010.09.005.
14. Dziedzic T, Metz I, Dallenga T, et al. Wallerian degeneration: a major component of early axonal pathology in multiple sclerosis[J]. Brain Pathol, 2010, 20(5): 976-985. DOI: 10.1111/j.1750-3639.2010.00401.x.
15. Wakatsuki S, Furuno A, Ohshima M, et al. Oxidative stress-dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration[J]. J Cell Biol, 2015, 211(4): 881-896. DOI: 10.1083/jcb.201506102.
16. Lee GH, Stanford MP, Shariati MA, et al. Severe, early axonal degeneration following experimental anterior ischemic optic neuropathy[J]. Invest Ophthalmol Vis Sci, 2014, 55(11): 7111-7118. DOI: 10.1167/iovs.14-14603.
17. Knox DL, Kerrison JB, Green WR. Histopathologic studies of ischemic optic neuropathy[J]. Trans Am Ophthalmol Soc, 2000, 98: 203-220.
18. Levin LA, Louhab A. Apoptosis of retinal ganglion cells in anterior ischemic optic neuropathy[J]. Arch Ophthalmol, 1996, 114(4): 488-491. DOI: 10.1001/archopht.1996.01100130484027.

Chinese Journal of Ocular Fundus Diseases

Neuroprotective effects of benzatropine on rat model of nonarteritic anterior ischemic optic neuropathy

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