Journal of Current Glaucoma Practice

Register      Login

VOLUME 13 , ISSUE 1 ( January-April, 2019 ) > List of Articles

Original Article

A Novel Mathematical Model of Glaucoma Pathogenesis

Muneeb A Faiq, Talvir Sidhu, Rayees A Sofi, Himanshu N Singh, Rizwana Qadri

Keywords : Glaucoma, Glial activation, Inflammation, Mathematical modeling, Neuron–glia interaction, Retinal ganglion cell

Citation Information : Faiq MA, Sidhu T, Sofi RA, Singh HN, Qadri R. A Novel Mathematical Model of Glaucoma Pathogenesis. J Curr Glaucoma Pract 2019; 13 (1):3-8.

DOI: 10.5005/jp-journals-10078-1241

License: CC BY-NC 4.0

Published Online: 01-06-2018

Copyright Statement:  Copyright © 2019; The Author(s).


Background: Conventional experimental approaches to understand glaucoma etiology and pathogenesis and, consequently, predict its course of progression have not seen much success due to the involvement of numerous molecular, cellular, and other moieties. An overwhelming number of these moieties at different levels combined with numerous environmental factors further complicate the intricacy. Interaction patterns between these factors are important to understand yet difficult to probe with conservative experimental approaches. Methods: We performed a system-level analysis with mathematical modeling by developing and analyzing rate equations with respect to the cellular events in glaucoma pathogenesis. Twenty-two events were enlisted from the literature survey and were analyzed in terms of the sensitivity coefficient of retinal ganglion cells. A separate rate equation was developed for cellular stress also. The results were analyzed with respect to time, and the time course of the events with respect to various cellular moieties was analyzed. Results: Our results suggest that microglia activation is among the earliest events in glaucoma pathogenesis. This modeling method yields a wealth of useful information which may serve as an important guide to better understand glaucoma pathogenesis and design experimental approaches and also identify useful diagnostic/predictive methods and important therapeutic targets. Conclusion: We here report the first mathematical model for glaucoma pathogenesis which provides important insight into the sensitivity coefficient and glia-mediated pathology of glaucoma.

  1. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006 Mar;90(3):262–267. DOI: 10.1136/bjo.2005.081224.
  2. Faiq MA, Dada R, et al. Brain: The potential diagnostic and therapeutic target for glaucoma. CNS Neurol Disord Drug Targets 2016;15(7):839–844. DOI: 10.2174/1871527315666160321111522.
  3. Faiq MA, Dada T. Diabetes type 4: A paradigm shift in the understanding of glaucoma, the brain specific diabetes and the candidature of insulin as a therapeutic agent. Curr Mol Med 2017;17(1):46–59. DOI: 10.2174/1566524017666170206153415.
  4. Yücel Y, Gupta N. Glaucoma of the brain: A disease model for the study of transsynaptic neural degeneration. Prog Brain Res 2008;173:465–478. DOI: 10.1016/S0079-6123(08)01132-1.
  5. Gupta N, Yücel YH. What changes can we expect in the brain of glaucoma patients? Surv Ophthalmol 2007 Nov;52(Suppl 2):S122– S126. DOI: 10.1016/j.survophthal.2007.08.006.
  6. Gupta N, Yücel YH. Glaucoma as a neurodegenerative disease. Curr Opin Ophthalmol 2007 Mar;18(2):110–114. DOI: 10.1097/ICU.0b013e3280895aea.
  7. Gupta N, Yücel YH. Glaucoma in the brain: A piece of the puzzle. Can J Ophthalmol 2006 Oct;41(5):541–542. DOI: 10.1016/S0008- 4182(06)80022-0.
  8. Kasi A, Faiq MA, et al. In vivo imaging of structural, metabolic and functional brain changes in glaucoma. Neural Regen Res 2019 Mar;14(3):446–449. DOI: 10.4103/1673-5374.243712.
  9. Faiq MA. The dark matter of vision: In search of a grand unifying theory for glaucoma. Oman J Ophthalmol 2018 May–Aug;11(2):101–102. DOI: 10.4103/ojo.OJO_92_2018.
  10. Faiq MA. Vision restoration in glaucoma: Nihilism and optimism at the crossroads. Oman J Ophthalmol 2016 Sep–Dec;9(3):123–124. DOI: 10.4103/0974-620X.192260.
  11. Faiq MA, Dada R, et al. Glaucoma–diabetes of the brain: A radical hypothesis about its nature and pathogenesis. Med Hypotheses 2014 May;82(5):535–546. DOI: 10.1016/j.mehy.2014.02.005.
  12. Wostyn P, Audenaert K, et al. Alzheimer's disease and glaucoma: Is there a causal relationship? Br J Ophthalmol 2009 Dec;93(12): 1557–1559. DOI: 10.1136/bjo.2008.148064.
  13. McKinnon SJ. Glaucoma: ocular Alzheimer's disease? Front Biosci 2003 Sep 1;8:s1140.s1156. DOI: 10.2741/1172.
  14. Burgoyne CF. A biomechanical paradigm for axonal insult within the optic nerve head in aging and glaucoma. Exp Eye Res 2011 Aug;93(2):120.132. DOI: 10.1016/j.exer.2010.09.005.
  15. Puri IK, Li L. Mathematical modeling for the pathogenesis of Alzheimer's disease. PLoS One 2010 Dec 14;5(12):e15176. DOI: 10.1371/journal.pone.0015176.
  16. Sarbaz Y, Pourakbari H. A review of presented mathematical models in Parkinson's disease: black- and gray-box models. Med Biol Eng Comput 2016 Jun;54(6):855.868. DOI: 10.1007/s11517-015-1401-9.
  17. Panayidou K, Gsteiger S, et al. Get Real in mathematical modelling: a review of studies predicting drug effectiveness in the real world. Res Synth Methods 2016 Sep;7(3):264.277. DOI: 10.1002/jrsm.1202.
  18. Rachel S., Chonga RS, et al. Glial cell interactions and glaucoma. Curr Opin Ophthalmol 2015 Mar;26(2):73.77. DOI: 10.1097/ICU.0000000000000125.
  19. Vohra R, Tsai JC, et al. The role of inflammation in the pathogenesis of glaucoma. Surv Ophthalmol 2013 Jul-Aug;58(4):311.320. DOI: 10.1016/j.survophthal.2012.08.010.
  20. Clarke G, Collins RA, et al. A one-hit model of cell death in inherited neuronal degenerations. Nature 2000;406:195.199. DOI: 10.1038/35018098.
  21. Wang JW, Chen SD, et al. Retinal Microglia in Glaucoma. J Glaucoma 2016 May;25(5):459.465. DOI: 10.1097/IJG.0000000000000200.
  22. Suh HS, Zhao ML, et al. Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia: differential regulation by inflammatory mediators. J Neuroinflammation 2013;10:37. DOI: 10.1186/1742-2094-10-37.
  23. Dheen ST, Jun Y, et al. Retinoic acid inhibits expression of TNF-alpha and iNOS in activated rat microglia. Glia 2005;50:21.31. DOI: 10.1002/glia.20153.
  24. Luo C, Yang X, et al. Glaucomatous tissue stress and the regulation of immune response through glial Toll-like receptor signaling. Invest Ophthalmol Vis Sci 2010;51:5697.5707. DOI: 10.1167/iovs.10-5407.
  25. Abraham J, Fox PD, et al. Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures. Neurobiol Dis 2012;46:425.430. DOI: 10.1016/j.nbd.2012.02.006.
  26. Kohman RA, Bhattacharya TK, et al. Effects of minocycline on spatial learning, hippocampal neurogenesis and microglia in aged and adult mice. Behav Brain Res 2013;242:17.24. DOI: 10.1016/j.bbr.2012.12.032.
  27. Liu X, Su H, et al. Minocycline inhibited the proapoptotic effect of microglia on neural progenitor cells and protected their neuronal differentiation in vitro. Neurosci Lett 2013;542:30.36. DOI: 10.1016/j.neulet.2013.03.011.
  28. Hughes EH, Schlichtenbrede FC, et al. Minocycline delays photoreceptor death in the rds mouse through a microgliaindependent mechanism. Exp Eye Res 2004;78:1077.1084. DOI: 10.1016/j.exer.2004.02.002.
  29. Zhang C, Lei B, et al. Neuroprotection of photoreceptors by minocycline in light-induced retinal degeneration. Invest Ophthalmol Vis Sci 2004;45:2753.2759. DOI: 10.1167/iovs.03-1344.
  30. Hong J, Kim BK, et al. Identification and characterization of triamcinolone acetonide, a microglial-activation inhibitor. Immunopharmacol Immunotoxicol 2012;34:912.918. DOI: 10.3109/08923973.2012.671332.
  31. Corbit RM, Ferreira JF, et al. Simplified extraction of ginsenosides from American ginseng (Panax quinquefolius L.) for high-performance liquid chromatography-ultraviolet analysis. J Agric Food Chem 2005;53:9867.9873. DOI: 10.1021/jf051504p.
  32. Guo L, Xing Y, et al. Curcumin protects microglia and primary rat cortical neurons against HIV-1 gp120-mediated inflammation and apoptosis. PLoS One 2013;8:e70565. DOI: 10.1371/journal.pone.0070565.
  33. Afzal M, Al-Hadidi D, et al. Ginger: an ethnomedical, chemical and pharmacological review. Drug Metabol Drug Interact 2001;18: 159.190. DOI: 10.1515/DMDI.2001.18.3-4.159.
  34. Kim JH, Choi BY, et al. Acetylcholine precursor, citicoline (cytidine 5′Œ-diphosphocholine), reduces hypoglycaemia-induced neuronal death in rats. J Neuroendocrinol 2018 Jan;30(1):1.11. DOI: 10.1111/jne.12567.
  35. Sun GY, Chen Z, et al. Quercetin attenuates inflammatory responses in BV-2 microglial cells: role of MAPKs on the Nrf2 pathway and induction of heme oxygenase-1. PLoS One 2015;10(10):e0141509. DOI: 10.1371/journal.pone.0141509.
  36. Brabazon F, Bermudez S, et al. The effects of insulin on the inflammatory activity of BV2 microglia. PLoS One 2018 Aug 27;13(8):e0201878. DOI: 10.1371/journal.pone.0201878.
  37. Inyang KE, Szabo-Pardi T, et al. The antidiabetic drug metformin prevents and reverses neuropathic pain and spinal cord microglial activation in male but not female mice. Pharmacol Res 2018 Nov 1;139:1.16. DOI: 10.1016/j.phrs.2018.10.027.
  38. Pan Y, Sun X, et al. Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation. J Neuroinflammation 2016 Nov 17;13(1):294. DOI: 10.1186/s12974-016-0754-9.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.