臺灣博碩士論文加值系統

前部非動脈炎性缺血性視神經病變(NAION) 是成人最常見視神經有關的急性視力喪失。非動脈炎性前部缺血性視神經病變發病機制及其治療一直是有爭議的話題。有關急性 NAION的臨床典型表現為單眼無痛性視力模糊，發病後無任何治療四至六周後視神經盤會變成節段性或彌漫的蒼白。我們認為NAION視力損傷最可能的原因是前部視神經的血流減少進而導致視神經缺血及後續的發炎反應，導致視網膜神經節細胞次發性死亡。因此，建立一個可信賴的大白鼠的前缺血視神經病變動物模式(rAION)來研究致病機轉與治療效果有其必要性。
實驗動物與研究方法是利用雷射來誘導Wistar大白鼠在視神經盤產生微血管梗塞。主要的實驗評估方法包括回朔標記視網膜節細胞的密度分析(retrograde FluoroGoldTM label)、視覺誘導電位(FVEP)、視網膜節細胞層細胞凋零分析Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)、 細胞免疫染色ED1陽性細胞在視神經的浸潤數量。
第一階段，我們在2015年Exp Eye Res發表全身類固醇Methylprednisolone (MP)對大白鼠的前缺血視神經病變有視神經保護效果，結果包含視網膜節細胞存活數量與視覺誘導電位神經傳導功能的增加，且降低發炎細胞的浸潤與減少凋亡細胞的數量。第二階段實驗是針對類固醇藥物給予的途徑研究；針對三個時間點:在立即注射TA組與一星期後、二星期後注射TA，前兩組結果都比兩星期後治療組更有視神經保護效果且證實局部注射的治療也產生保護效果，此結果於2016 IOVS刊登發表。第三階段我們針對玻璃體注射抗血管內皮細胞增生因子藥物，結果顯示抗血管內皮細胞增生因子藥物注射並不會有視神經保護效果；且缺血視神經病變的大白鼠視網膜中的血管內皮細胞增生因子VEGF含量，在急性期並無增加，此結果已於2015 IOVS刊登發表。接下來第四階段我們試圖找出血液-視神經屏障的恢復與神經保護效果的分子生物機轉，探討全身類固醇治療的治療黃金期。結果發現全身類固醇治療MP在立即治療組及1天後開始治療組它們的視神經血管的通透性有顯著性的降低與相對應大幅度降低發炎細胞因子的濃度，且發現此兩組時間對神經保護效果顯著高於其他組別，此篇論文已於2017 IOVS年刊登。
類固醇治療及其抗發炎機制在大鼠非動脈炎性前缺血視神經病變的研究結果顯示類固醇治療不論局部注射或系統性注射對視網膜神經節細胞的存活率及視覺傳導功能皆有保護效果，且有降低發炎細胞因子濃度與發炎細胞於視神經的浸潤數量與減少視網膜節細胞的凋亡。且類固醇治療與降低血管通透性與視神經血液屏障的恢復機制呈現高度相關，所以針對急性期大鼠非動脈炎性前缺血視神經病變給予系統性類固醇治療，須於缺血視神經病變傷害一天之內給予MP的治療，保護效果為最顯著。

Non-arterial anterior ischemic optic neuropathy (NAION) is the most common optic neuropathy in aged adult. The pathogenesis and treatments of NAION have been controversial topics. We supposed key mechanism is that reduction of blood flow around optic nerve (ON) head then lead to subsequent inflammation over ON head and secondary progressive death of retinal ganglion cells (RGCs). Setting up one reliable animal model in order to study the pathogenesis and potential treatment of NAION is the most critical method to get answers. In our experimental design of anterior ischemic optic neuropathy in rat (rAION), we mainly applied lasers on the ON head of rats immediately after intravenous injection of photosensitizer. The mainstay of analysis experiments included retrograde labeling of RGCs with FluoroGoldTM and morphometry of the RGCs, electrophysiological visual function by flash visual-evoked potentials, apoptosis assays by TUNEL and ED1 staining of the ONs.
In the first experiment, we gave systemic corticosteroid (Methylprednisolone (MP)) after induced rAION and investigated the protective effects of MP on both ON and RGCs. The results showed MP in rAION indeed had protective effects on survival number of RGC as well as improvement of FVEP. TUNEL assays showed a significant decrease in the number of apoptotic cells and significantly decreased in ED1 positive cells in the MP group. The second experiment, we wanted to clarify whether local intravitreous injection of corticosteroid had neuroprotective effects. The results showed that treatment of IVI of TA within 7- day post-infarct in rAION had neuroprotective effects as well as anti-inflammatory effect. We had the third experiment to show that early IVI of anti-VEGF agent did not have protective effects on RGCs and ONs. In addition, there was no change in concentration of VEGF in retina in rAION.
In the fourth experiment, we proved that macrophage recruitment in the ON was significantly reduced after MP treatment starting on 0-day and 1-d post-insult, which was compatible with the change of reduction in ON vascular leakage by Evans blue stain and correspondent reduction in expression of TNF-α and IL-1β. The therapeutic time of MP in rAION demonstrated optimal neuroprotective effect and anti-inflammation within one day after injury.
In summary, corticosteroids treatment regarding local or systemic injection, both have neuroprotection on survival of RGCs as well as amplitudes of FVEP. Giving MP treatment within one day after injury will significantly lessen of infiltration of macrophage and reduced vascular leakage in ON head. The very narrow therapeutic time associated with the quick stabilization of the disrupted barrier in acute ischemic optic neuropathy.

Acknowledgements II
Abstract III-VII
Chinese III-IV
English V-VII
Content VIII-IX
List of Figures X-XI
List of abbreviations XII
Chapter 1 Introduction 1-5
Chapter 2 Hypothesis 6-7
Chapter 3 Materials and Methods 8-26
Methods of rAION 8-9
Animals and retinal /ON samples preparations 10-11
Study design 12-13
Dose of MP 14
Retrograde labeling of RGCs with FluorogoldTM 14-15
Flash visual-evoked potentials (FVEP) 16
Immunohistochemistry (IHC) of ED1 in the ONs 17
In situ nick end-labeling (TUNEL) assay 17-18
IVI-TA study 19-20
IVI-VEGF study 21-22
Study for therapeutic window of MP 23
Evan's Blue Dye Extravasation 23-24
IL-1ß and TNF-α mRNA by qRT-PCR 25
Statistical analysis 26
Chapter 4 Results 27-50
MP study 27-31
IVI-TA study 32-36
IVI-Anti- VEGF agent study 37-43
BOB and Therapeutic window of MP and study 44-50
Chapter 5 Discussion 51-55
Chapter 6 Conclusion 56
Chapter 7 Prospects 57
References 58-64
Appendix 65
 

References

1.Biousse V, Newman NJ. Ischemic Optic Neuropathies. N Engl J Med. 2015;372:2428-2436.
2.Kerr NM, Chew SS, Danesh-Meyer HV. Non-arteritic anterior ischaemic optic neuropathy: a review and update. J Clin Neurosci. 2009;16:994-1000.
3.Arnold AC. Pathogenesis of nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2003;23:157-163.
4.Hayreh SS, Zimmerman MB. Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol. 2008;246:1029-1046.
5.Hayreh SS, Zimmerman MB. Optic disc edema in non-arteritic anterior ischemic optic neuropathy. Graefes Arch Clin Exp Ophthalmol. 2007;245:1107-1121.
6.Rebolleda G, Perez-Lopez M, Casas LP, Contreras I, Munoz-Negrete FJ. Visual and anatomical outcomes of non-arteritic anterior ischemic optic neuropathy with high-dose systemic corticosteroids. Graefes Arch Clin Exp Ophthalmol. 2013;251:255-260.
7.Knox DL, Kerrison JB, Green WR. Histopathologic studies of ischemic optic neuropathy. Trans Am Ophthalmol Soc. 2000;98:203-220; discussion 221-202.
8.Tesser RA, Niendorf ER, Levin LA. The morphology of an infarct in nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 2003;110:2031-2035.
9.Salgado C, Vilson F, Miller NR, Bernstein SL. Cellular inflammation in nonarteritic anterior ischemic optic neuropathy and its primate model. Arch Ophthalmol. 2011;129:1583-1591.
10.Bernstein SL, Johnson MA, Miller NR. Nonarteritic anterior ischemic optic neuropathy (NAION) and its experimental models. Prog Retin Eye Res. 2011;30:167-187.
11.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;87:242-250.
12.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;9:1193-1202.
13.Chang CH, Huang TL, Huang SP, Tsai RK. Neuroprotective effects of recombinant human granulocyte colony-stimulating factor (G-CSF) in a rat model of anterior ischemic optic neuropathy (rAION). Exp Eye Res. 2014;118:109-116.
14.Jiang W, Xia F, Han J, Wang J. Patterns of Nogo-A, NgR, and RhoA expression in the brain tissues of rats with focal cerebral infarction. Translational Research. 154:40-48.
15.Fard MA, Ebrahimi KB, Miller NR. RhoA activity and post-ischemic inflammation in an experimental model of adult rodent anterior ischemic optic neuropathy. Brain Research. 2013;1534:76-86.
16.Sugiyama T, Shibata M, Kajiura S, et al. Effects of fasudil, a Rho-associated protein kinase inhibitor, on optic nerve head blood flow in rabbits. Invest Ophthalmol Vis Sci. 2011;52:64-69.
17.Nicholson JD, Puche AC, Guo Y, Weinreich D, Slater BJ, Bernstein SL. PGJ(2) provides prolonged CNS stroke protection by reducing white matter edema. PLoS One. 2012;7:e50021.
18.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;54:7402-7409.
19.Ou Z, Zhao X, Labiche LA, et al. Neuronal expression of peroxisome proliferator-activated receptor-gamma (PPARgamma) and 15d-prostaglandin J2--mediated protection of brain after experimental cerebral ischemia in rat. Brain Res. 2006;1096:196-203.
20.Giri S, Rattan R, Singh AK, Singh I. The 15-deoxy-delta12,14-prostaglandin J2 inhibits the inflammatory response in primary rat astrocytes via down-regulating multiple steps in phosphatidylinositol 3-kinase-Akt-NF-kappaB-p300 pathway independent of peroxisome proliferator-activated receptor gamma. J Immunol. 2004;173:5196-5208.
21.Modarres M, Falavarjani KG, Nazari H, et al. Intravitreal erythropoietin injection for the treatment of non-arteritic anterior ischaemic optic neuropathy. Br J Ophthalmol. 2011;95:992-995.
22.Zhong L, Bradley J, Schubert W, et al. Erythropoietin promotes survival of retinal ganglion cells in DBA/2J glaucoma mice. Invest Ophthalmol Vis Sci. 2007;48:1212-1218.
23.Weishaupt JH, Rohde G, Polking E, Siren AL, Ehrenreich H, Bahr M. Effect of erythropoietin axotomy-induced apoptosis in rat retinal ganglion cells. Invest Ophthalmol Vis Sci. 2004;45:1514-1522.
24.Ahmed Z, Kalinski H, Berry M, et al. Ocular neuroprotection by siRNA targeting caspase-2. Cell Death Dis. 2011;2:e173.
25.Agudo M, Perez-Marin MC, Lonngren U, et al. Time course profiling of the retinal transcriptome after optic nerve transection and optic nerve crush. Mol Vis. 2008;14:1050-1063.
26.Morimoto T, Miyoshi T, Sawai H, Fujikado T. Optimal parameters of transcorneal electrical stimulation (TES) to be neuroprotective of axotomized RGCs in adult rats. Exp Eye Res. 2010;90:285-291.
27.Hayreh SS. Management of non-arteritic anterior ischemic optic neuropathy. Graefes Arch Clin Exp Ophthalmol. 2009;247:1595-1600.
28.Foulds WS. Visual disturbances in systemic disorders. Optic neuropathy and systemic disease. Trans Ophthalmol Soc U K. 1970;89:125-146.
29.Arnold AC. The 14th Hoyt Lecture: Ischemic Optic Neuropathy: The Evolving Profile, 1966-2015. J Neuroophthalmol. 2016;36:208-215.
30.Atkins EJ, Bruce BB, Newman NJ, Biousse V. Treatment of nonarteritic anterior ischemic optic neuropathy. Surv Ophthalmol. 2010;55:47-63.
31.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;49:3671-3676.
32.Duh EJ. A novel mechanism for glucocorticoid-induced tightening of endothelial barriers. Invest Ophthalmol Vis Sci. 2013;54:4016.
33.Keil JM, Liu X, Antonetti DA. Glucocorticoid Induction of Occludin Expression and Endothelial Barrier Requires Transcription Factor p54 NONO. Invest Ophthalmol Vis Sci. 2013;54:4007-4015.
34.Felinski EA, Cox AE, Phillips BE, Antonetti DA. Glucocorticoids induce transactivation of tight junction genes occludin and claudin-5 in retinal endothelial cells via a novel cis-element. Exp Eye Res. 2008;86:867-878.
35.Goldenberg-Cohen N, Guo Y, Margolis F, Cohen Y, Miller NR, Bernstein SL. Oligodendrocyte dysfunction after induction of experimental anterior optic nerve ischemia. Invest Ophthalmol Vis Sci. 2005;46:2716-2725.
36.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;91:286-292.
37.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.
38.Bernstein SL, Guo Y. Changes in cholinergic amacrine cells after rodent anterior ischemic optic neuropathy (rAION). Invest Ophthalmol Vis Sci. 2011;52:904-910.
39.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;54:7952-7961.
40.Osako T, Chuman H, Maekubo T, Ishiai M, Kawano N, Nao IN. Effects of steroid administration and transcorneal electrical stimulation on the anatomic and electrophysiologic deterioration of nonarteritic ischemic optic neuropathy in a rodent model. Jpn J Ophthalmol. 2013;57:410-415.
41.Jonas JB, Spandau UH, Harder B, Sauder G. Intravitreal triamcinolone acetonide for treatment of acute nonarteritic anterior ischemic optic neuropathy. Graefes Arch Clin Exp Ophthalmol. 2007;245:749-750.
42.Lee Y-C, Huang T-L, Sheu M-M, Liu P-K, Tsai R-K. Intravitreal injection of triamcinolone acetonide in nonarteritic anterior ischemic optic neuropathy. Taiwan Journal of Ophthalmology. 4:86-89.
43.Radoi C, Garcia T, Brugniart C, Ducasse A, Arndt C. Intravitreal triamcinolone injections in non-arteritic anterior ischemic optic neuropathy. Graefes Arch Clin Exp Ophthalmol. 2014;252:339-345.
44.Johnson KS, Chu DS. Evaluation of sub-Tenon triamcinolone acetonide injections in the treatment of scleritis. Am J Ophthalmol. 2010;149:77-81.
45.Grover D, Li TJ, Chong CC. Intravitreal steroids for macular edema in diabetes. Cochrane Database Syst Rev. 2008;CD005656.
46.Shields CL, Demirci H, Marr BP, et al. Intravitreal triamcinolone acetonide for acute radiation papillopathy. Retina. 2006;26:537-544.
47.Wirostko B, Wong TY, Simo R. Vascular endothelial growth factor and diabetic complications. Prog Retin Eye Res. 2008;27:608-621.
48.Kelman SE. Intravitreal triamcinolone or bevacizumab for nonarteritic anterior ischemic optic neuropathy: do they merit further study? J Neuroophthalmol. 2007;27:161-163.
49.Jeong SJ, Han SH, Kim CO, Choi JY, Kim JM. Anti-vascular endothelial growth factor antibody attenuates inflammation and decreases mortality in an experimental model of severe sepsis. Crit Care. 2013;17:R97.
50.Bennett JL, Thomas S, Olson JL, Mandava N. Treatment of nonarteritic anterior ischemic optic neuropathy with intravitreal bevacizumab. J Neuroophthalmol. 2007;27:238-240.
51.Prescott CR, Sklar CA, Lesser RL, Adelman RA. Is intravitreal bevacizumab an effective treatment option for nonarteritic anterior ischemic optic neuropathy? J Neuroophthalmol. 2012;32:51-53.
52.Entezari M, Ramezani A, Pakravan M, Mahmoodi A, Hassanpour H, Yaseri M. Anterior ischemic optic neuropathy. Ophthalmology. 2012;119:879-880.
53.Bernstein SL, Miller NR. Ischemic optic neuropathies and their models: disease comparisons, model strengths and weaknesses. Jpn J Ophthalmol. 2015;59:135-147.
54.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.
55.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;49:3671-3676.
56.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;44:4153-4162.
57.Cui Q, Yin Y, Benowitz LI. The role of macrophages in optic nerve regeneration. Neuroscience. 2009;158:1039-1048.
58.Dickstein JB, Moldofsky H, Hay JB. Brain-blood permeability: TNF-alpha promotes escape of protein tracer from CSF to blood. Am J Physiol Regul Integr Comp Physiol. 2000;279:R148-151.
59.Levin LA, Danesh-Meyer HV. Hypothesis: a venous etiology for nonarteritic anterior ischemic optic neuropathy. Arch Ophthalmol. 2008;126:1582-1585.
60.Huang TL, Huang SP, Chang CH, Lin KH, Sheu MM, Tsai RK. Factors influencing the retrograde labeling of retinal ganglion cells with fluorogold in an animal optic nerve crush model. Ophthalmic Res. 2014;51:173-178.
61.Levkovitch-Verbin H, Quigley HA, Martin KR, Zack DJ, Pease ME, Valenta DF. A model to study differences between primary and secondary degeneration of retinal ganglion cells in rats by partial optic nerve transection. Invest Ophthalmol Vis Sci. 2003;44:3388-3393.
62.Ohlsson M, Westerlund U, Langmoen IA, Svensson M. Methylprednisolone treatment does not influence axonal regeneration or degeneration following optic nerve injury in the adult rat. J Neuroophthalmol. 2004;24:11-18.
63.Gao H, Qiao X, Gao R, Mieler WF, McPherson AR, Holz ER. Intravitreal triamcinolone does not alter basal vascular endothelial growth factor mRNA expression in rat retina. Vision Res. 2004;44:349-356.
64.Berkowitz BA, Lukaszew RA, Mullins CM, Penn JS. Impaired hyaloidal circulation function and uncoordinated ocular growth patterns in experimental retinopathy of prematurity. Invest Ophthalmol Vis Sci. 1998;39:391-396.
65.Huang TL, Chang CH, Lin KH, Sheu MM, Tsai RK. Lack of protective effect of local administration of triamcinolone or systemic treatment with methylprednisolone against damages caused by optic nerve crush in rats. Exp Eye Res. 2011;92:112-119.
66.Derevjanik NL, Vinores SA, Xiao WH, et al. Quantitative assessment of the integrity of the blood-retinal barrier in mice. Invest Ophthalmol Vis Sci. 2002;43:2462-2467.
67.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 further ameliorate optic nerve inflammation in a rat model of anterior ischemic optic neuropathy (rAION). Dis Model Mech. 2016.
68.Xu Q, Qaum T, Adamis AP. Sensitive blood-retinal barrier breakdown quantitation using Evans blue. Invest Ophthalmol Vis Sci. 2001;42:789-794.
69.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;57:1878-1884.
70.Huang TL, Wen YT, Chang CH, Chang SW, Lin KH, Tsai RK. Early Methylprednisolone Treatment Can Stabilize the Blood-Optic Nerve Barrier in a Rat Model of Anterior Ischemic Optic Neuropathy (rAION). Invest Ophthalmol Vis Sci. 2017;58:1628-1636.
71.Macky TA, Helmy D, El Shazly N. Retinal toxicity of triamcinolone's vehicle (benzyl alcohol): an electrophysiologic and electron microscopic study. Graefes Arch Clin Exp Ophthalmol. 2007;245:817-824.
72.Ruiz-Moreno JM, Montero JA, Bayon A, Rueda J, Vidal M. Retinal toxicity of intravitreal triamcinolone acetonide at high doses in the rabbit. Exp Eye Res. 2007;84:342-348.
73.Vingrys AJ, Bui BV. Development of postreceptoral function in pigmented and albino guinea pigs. Vis Neurosci. 2001;18:605-613.
74.Heiduschka P, Schraermeyer U. Comparison of visual function in pigmented and albino rats by electroretinography and visual evoked potentials. Graefes Arch Clin Exp Ophthalmol. 2008;246:1559-1573.
75.Chen CS, Johnson MA, Flower RA, Slater BJ, Miller NR, Bernstein SL. A primate model of nonarteritic anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci. 2008;49:2985-2992.
76.Ohlsson M, Mattsson P, Svensson M. A temporal study of axonal degeneration and glial scar formation following a standardized crush injury of the optic nerve in the adult rat. Restor Neurol Neurosci. 2004;22:1-10.
77.Zhang C, Lam TT, Tso MO. Heterogeneous populations of microglia/macrophages in the retina and their activation after retinal ischemia and reperfusion injury. Exp Eye Res. 2005;81:700-709.
78.Pannicke T, Iandiev I, Wurm A, et al. Diabetes alters osmotic swelling characteristics and membrane conductance of glial cells in rat retina. Diabetes. 2006;55:633-639.
79.Zhang X, Bao S, Lai D, Rapkins RW, Gillies MC. Intravitreal triamcinolone acetonide inhibits breakdown of the blood-retinal barrier through differential regulation of VEGF-A and its receptors in early diabetic rat retinas. Diabetes. 2008;57:1026-1033.
80.Popovich PG, Guan Z, McGaughy V, Fisher L, Hickey WF, Basso DM. The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation. J Neuropathol Exp Neurol. 2002;61:623-633.
81.Ghosh M, Xu Y, Pearse DD. Cyclic AMP is a key regulator of M1 to M2a phenotypic conversion of microglia in the presence of Th2 cytokines. Journal of Neuroinflammation. 2016;13:9.
82.Benveniste EN. Inflammatory cytokines within the central nervous system: sources, function, and mechanism of action. Am J Physiol. 1992;263:C1-16.
83.Abcouwer SF, Lin CM, Wolpert EB, et al. Effects of ischemic preconditioning and bevacizumab on apoptosis and vascular permeability following retinal ischemia-reperfusion injury. Invest Ophthalmol Vis Sci. 2010;51:5920-5933.
84.Goldenberg-Cohen N, Dadon-Bar-El S, Hasanreisoglu M, et al. Possible neuroprotective effect of brimonidine in a mouse model of ischaemic optic neuropathy. Clin Experiment Ophthalmol. 2009;37:718-729.
85.Dratviman-Storobinsky O, Hasanreisoglu M, Offen D, Barhum Y, Weinberger D, Goldenberg-Cohen N. Progressive damage along the optic nerve following induction of crush injury or rodent anterior ischemic optic neuropathy in transgenic mice. Mol Vis. 2008;14:2171-2179.
86.Ubogu EE. Inflammatory neuropathies: pathology, molecular markers and targets for specific therapeutic intervention. Acta Neuropathol. 2015;130:445-468.
87.Rhodes KE, Raivich G, Fawcett JW. The injury response of oligodendrocyte precursor cells is induced by platelets, macrophages and inflammation-associated cytokines. Neuroscience. 2006;140:87-100.
88.Orihuela R, McPherson CA, Harry GJ. Microglial M1/M2 polarization and metabolic states. Br J Pharmacol. 2016;173:649-665.
89.Mills EL, O'Neill LA. Reprogramming mitochondrial metabolism in macrophages as an anti-inflammatory signal. Eur J Immunol 2016;46:13-21.