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N-Methyl-D-aspartate receptor activation, novel mechanism of homocysteine-induced blood–retinal barrier dysfunction

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Abstract

Elevated levels of amino acid homocysteine (Hcy) recognized as hyperhomocysteinemia (HHcy) was reported in several human visual disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Breakdown of blood–retinal barrier (BRB) is concomitant with vision loss in DR and AMD. We previously reported that HHcy alters BRB. Here, we tested the hypothesis that HHcy alters BRB via activation of N-methyl-D-aspartate receptor (NMDAR). Human retinal endothelial cells subjected to high level of Hcy and mouse model of HHcy were used. We injected Hcy intravitreal and used a mouse model of HHcy that lacks cystathionine-β-synthase (CBS). RT-PCR, western blot, and immunofluorescence showed that retinal endothelial cells (RECs) express NMDAR at the gene and protein levels both in vitro and in vivo and this was increased by HHcy. We assessed BRB function and retinal morphology using fluorescein angiogram and optical coherence tomography (OCT) under HHcy with and without pharmacological inhibition of NMDAR by (MK801) or in mice lacking endothelial NMDAR (NMDARE−/− mouse). Additionally, retinal albumin leakage and tight junction proteins ZO-1 and occludin were assessed by western blotting analysis. Inhibition or elimination of NMDAR was able to improve the altered retinal hyperpermeability and morphology under HHcy as indicated by significant decrease in retinal albumin leakage and restoration of tight junction proteins ZO-1 and occludin. Our findings underscore a potential role for endothelial NMDAR in mediating Hcy-induced breakdown of BRB and subsequently as a potential therapeutic target in retinal diseases associated with HHcy such as DR and AMD.

Key messages

• Elevated levels of homocysteine (Hcy) are defined as hyperhomocysteinemia (HHcy).

• HHcy is implicated in diabetic retinopathy and age-related macular degeneration.

• HHcy alters BRB via activation of N-methyl-D-aspartate receptor.

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Data availability

Data and material are available in request to corresponding author.

References

  1. Malaguarnera G, Gagliano C, Salomone S, Giordano M, Bucolo C, Pappalardo A, Drago F, Caraci F, Avitabile T, Motta M (2015) Folate status in type 2 diabetic patients with and without retinopathy. Clin Ophthalmol 9:1437–1442

    CAS  PubMed  PubMed Central  Google Scholar 

  2. McCully KS (1969) Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56:111–128

    CAS  PubMed  PubMed Central  Google Scholar 

  3. McCully KS, Ragsdale BD (1970) Production of arteriosclerosis by homocysteinemia. Am J Pathol 61:1–11

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Karger AB, Steffen BT, Nomura SO, Guan W, Garg PK, Szklo M, Budoff MJ, Tsai MY (2020) Association between homocysteine and vascular calcification incidence, prevalence, and progression in the MESA cohort. J Am Heart Assoc 9:e013934

    PubMed  PubMed Central  Google Scholar 

  5. Zhou H, Huang C, Liu R, Liu C, Ma C, Ren X (2019) Lack of association between serum homocysteine level and middle cerebral artery stenosis. Brain Behav 9:e01297

    PubMed  PubMed Central  Google Scholar 

  6. Bossenmeyer-Pourie C, Smith AD, Lehmann S, Deramecourt V, Sablonniere B, Camadro JM, Pourie G, Kerek R, Helle D, Umoret R, Gueant-Rodriguez RM, Rigau V, Gabelle A, Sequeira JM, Quadros EV, Daval JL, Gueant JL (2019) N-homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer’s disease and vascular dementia. J Pathol 248:291

    CAS  PubMed  Google Scholar 

  7. Ajith TA, Ranimenon (2015) Homocysteine in ocular diseases. Clin Chim Acta 450:316–321

    CAS  PubMed  Google Scholar 

  8. Dong N, Shi H, Tang X (2018) Plasma homocysteine levels are associated with macular thickness in type 2 diabetes without diabetic macular edema. Int Ophthalmol 38:737–746

    PubMed  Google Scholar 

  9. Lei X, Zeng G, Zhang Y, Li Q, Zhang J, Bai Z, Yang K (2018) Association between homocysteine level and the risk of diabetic retinopathy: a systematic review and meta-analysis. Diabetol Metab Syndr 10:61

    PubMed  PubMed Central  Google Scholar 

  10. Lei XW, Li Q, Zhang JZ, Zhang YM, Liu Y, Yang KH (2019) The protective roles of folic acid in preventing diabetic retinopathy are potentially associated with suppressions on angiogenesis, inflammation, and oxidative stress. Ophthalmic Res 62:1–13

    Google Scholar 

  11. Malaguarnera G, Gagliano C, Giordano M, Salomone S, Vacante M, Bucolo C, Caraci F, Reibaldi M, Drago F, Avitabile T, Motta M (2014) Homocysteine serum levels in diabetic patients with non proliferative, proliferative and without retinopathy. Biomed Res Int 2014:191497

    PubMed  PubMed Central  Google Scholar 

  12. Gopinath B, Flood VM, Rochtchina E, Wang JJ, Mitchell P (2013) Homocysteine, folate, vitamin B-12, and 10-y incidence of age-related macular degeneration. Am J Clin Nutr 98:129–135

    CAS  PubMed  Google Scholar 

  13. Christen WG, Cook NR, Chiuve SE, Ridker PM, Gaziano JM (2018) Prospective study of plasma homocysteine, its dietary determinants, and risk of age-related macular degeneration in men. Ophthalmic Epidemiol 25:79–88

    PubMed  Google Scholar 

  14. Christen WG, Chasman DI, Cook NR, Chiuve SE, Ridker PM, Buring JE (2018) Homocysteine, B vitamins, mthfr genotype, and incident age-related macular degeneration. Ophthalmol Retina 2:508–510

    PubMed  PubMed Central  Google Scholar 

  15. Rochtchina E, Wang JJ, Flood VM, Mitchell P (2007) Elevated serum homocysteine, low serum vitamin B12, folate, and age-related macular degeneration: the Blue Mountains Eye Study. Am J Ophthalmol 143:344–346

    CAS  PubMed  Google Scholar 

  16. Beard RS Jr, Reynolds JJ, Bearden SE (2011) Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions. Blood 118:2007–2014

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Yang G, Lu J, Pan C (2002) The impact of plasma homocysteine level on development of retinopathy in type 2 diabetes mellitus. Zhonghua Nei Ke Za Zhi 41:34–38

    CAS  PubMed  Google Scholar 

  18. Vaccaro O, Perna AF, Mancini FP, Iovine C, Cuomo V, Sacco M, Tufano A, Rivellese AA, Ingrosso D, Riccardi G (2000) Plasma homocysteine and microvascular complications in type 1 diabetes. Nutr Metab Cardiovasc Dis 10:297–304

    CAS  PubMed  Google Scholar 

  19. Ukinc K, Ersoz HO, Karahan C, Erem C, Eminagaoglu S, Hacihasanoglu AB, Yilmaz M, Kocak M (2009) Methyltetrahydrofolate reductase C677T gene mutation and hyperhomocysteinemia as a novel risk factor for diabetic nephropathy. Endocrine 36:255–261

    CAS  PubMed  Google Scholar 

  20. Aydin E, Demir HD, Ozyurt H, Etikan I (2008) Association of plasma homocysteine and macular edema in type 2 diabetes mellitus. Eur J Ophthalmol 18:226–232

    CAS  PubMed  Google Scholar 

  21. Cheng Z, Yang X, Wang H (2009) Hyperhomocysteinemia and endothelial dysfunction. Curr Hypertens Rev 5:158–165

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Tawfik A, Al-Shabrawey M, Roon P, Sonne S, Covar JA, Matragoon S, Ganapathy PS, Atherton SS, El-Remessy A, Ganapathy V, Smith SB (2013) Alterations of retinal vasculature in cystathionine-beta-synthase mutant mice, a model of hyperhomocysteinemia. Invest Ophthalmol Vis Sci 54:939–949

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Tawfik A, Markand S, Al-Shabrawey M, Mayo JN, Reynolds J, Bearden SE, Ganapathy V, Smith SB (2014) Alterations of retinal vasculature in cystathionine-beta-synthase heterozygous mice: a model of mild to moderate hyperhomocysteinemia. Am J Pathol 184:2573–2585

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Mohamed R, Sharma I, Ibrahim AS, Saleh H, Elsherbiny NM, Fulzele S, Elmasry K, Smith SB, Al-Shabrawey M, Tawfik A (2017) Hyperhomocysteinemia alters retinal endothelial cells barrier function and angiogenic potential via activation of oxidative stress. Sci Rep 7:11952

    PubMed  PubMed Central  Google Scholar 

  25. Ibrahim AS, Mander S, Hussein KA, Elsherbiny NM, Smith SB, Al-Shabrawey M, Tawfik A (2016) Hyperhomocysteinemia disrupts retinal pigment epithelial structure and function with features of age-related macular degeneration. Oncotarget 7:8532–8545

    PubMed  PubMed Central  Google Scholar 

  26. Elmasry K, Mohamed R, Sharma I, Elsherbiny NM, Liu Y, Al-Shabrawey M, Tawfik A (2018) Epigenetic modifications in hyperhomocysteinemia: potential role in diabetic retinopathy and age-related macular degeneration. Oncotarget 9:12562–12590

    PubMed  PubMed Central  Google Scholar 

  27. Elsherbiny NM, Sharma I, Kira D, Alhusban S, Samra YA, Jadeja R, Martin P, Al-Shabrawey M, Tawfik A (2020) Homocysteine induces inflammation in retina and brain. Biomolecules 10:393

    CAS  PubMed Central  Google Scholar 

  28. Shakib M, Cunha-Vaz JG (1966) Studies on the permeability of the blood-retinal barrier. IV. Junctional complexes of the retinal vessels and their role in the permeability of the blood-retinal barrier. Exp Eye Res 5:229–234

    CAS  PubMed  Google Scholar 

  29. Cunha-Vaz JG (1976) The blood-retinal barriers. Doc Ophthalmol 41:287–327

    CAS  PubMed  Google Scholar 

  30. Cunha-Vaz J (2017) The blood-retinal barrier in the management of retinal disease: EURETINA award lecture. Ophthalmologica 237:1–10

    CAS  PubMed  Google Scholar 

  31. Schultz H, Song Y, Baumann BH, Kapphahn RJ, Montezuma SR, Ferrington DA, Dunaief JL (2019) Increased serum proteins in non-exudative AMD retinas. Exp Eye Res 186:107686

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634

    CAS  PubMed  Google Scholar 

  33. Li J, McRoberts JA, Ennes HS, Trevisani M, Nicoletti P, Mittal Y, Mayer EA (2006) Experimental colitis modulates the functional properties of NMDA receptors in dorsal root ganglia neurons. Am J Physiol Gastrointest Liver Physiol 291:G219–G228

    CAS  PubMed  Google Scholar 

  34. Patton AJ, Genever PG, Birch MA, Suva LJ, Skerry TM (1998) Expression of an N-methyl-D-aspartate-type receptor by human and rat osteoblasts and osteoclasts suggests a novel glutamate signaling pathway in bone. Bone 22:645–649

    CAS  PubMed  Google Scholar 

  35. Singh J, Kaur G (2009) Transcriptional regulation of PSA-NCAM expression by NMDA receptor activation in RA-differentiated C6 glioma cultures. Brain Res Bull 79:157–168

    CAS  PubMed  Google Scholar 

  36. LeMaistre JL, Sanders SA, Stobart MJ, Lu L, Knox JD, Anderson HD, Anderson CM (2012) Coactivation of NMDA receptors by glutamate and D-serine induces dilation of isolated middle cerebral arteries. J Cereb Blood Flow Metab 32:537–547

    CAS  PubMed  Google Scholar 

  37. Reijerkerk A, Kooij G, van der Pol SM, Leyen T, Lakeman K, van Het Hof B, Vivien D, de Vries HE (2010) The NR1 subunit of NMDA receptor regulates monocyte transmigration through the brain endothelial cell barrier. J Neurochem 113:447–453

    CAS  PubMed  Google Scholar 

  38. Krizbai IA, Deli MA, Pestenacz A, Siklos L, Szabo CA, Andras I, Joo F (1998) Expression of glutamate receptors on cultured cerebral endothelial cells. J Neurosci Res 54:814–819

    CAS  PubMed  Google Scholar 

  39. Sharp CD, Hines I, Houghton J, Warren A, Jackson THT, Jawahar A, Nanda A, Elrod JW, Long A, Chi A, Minagar A, Alexander JS (2003) Glutamate causes a loss in human cerebral endothelial barrier integrity through activation of NMDA receptor. Am J Physiol Heart Circ Physiol 285:H2592–H2598

    CAS  PubMed  Google Scholar 

  40. Liu X, Hunter C, Weiss HR, Chi OZ (2010) Effects of blockade of ionotropic glutamate receptors on blood-brain barrier disruption in focal cerebral ischemia. Neurol Sci 31:699–703

    PubMed  Google Scholar 

  41. Paul C, Bolton C (2002) Modulation of blood-brain barrier dysfunction and neurological deficits during acute experimental allergic encephalomyelitis by the N-methyl-D-aspartate receptor antagonist memantine. J Pharmacol Exp Ther 302:50–57

    CAS  PubMed  Google Scholar 

  42. Ganapathy PS, White RE, Ha Y, Bozard BR, McNeil PL, Caldwell RW, Kumar S, Black SM, Smith SB (2011) The role of N-methyl-D-aspartate receptor activation in homocysteine-induced death of retinal ganglion cells. Invest Ophthalmol Vis Sci 52:5515–5524

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Gunasekar PG, Kanthasamy AG, Borowitz JL, Isom GE (1995) NMDA receptor activation produces concurrent generation of nitric oxide and reactive oxygen species: implication for cell death. J Neurochem 65:2016–2021

    CAS  PubMed  Google Scholar 

  44. McCully KS (2009) Chemical pathology of homocysteine. IV. Excitotoxicity, oxidative stress, endothelial dysfunction, and inflammation. Ann Clin Lab Sci 39:219–232

    CAS  PubMed  Google Scholar 

  45. Domagala TB, Undas A, Libura M, Szczeklik A (1998) Pathogenesis of vascular disease in hyperhomocysteinaemia. J Cardiovasc Risk 5:239–247

    CAS  PubMed  Google Scholar 

  46. Moustafa AA, Hewedi DH, Eissa AM, Frydecka D, Misiak B (2014) Homocysteine levels in schizophrenia and affective disorders-focus on cognition. Front Behav Neurosci 8:343

    PubMed  PubMed Central  Google Scholar 

  47. Tomiyama M, Furusawa K, Kamijo M, Kimura T, Matsunaga M, Baba M (2005) Upregulation of mRNAs coding for AMPA and NMDA receptor subunits and metabotropic glutamate receptors in the dorsal horn of the spinal cord in a rat model of diabetes mellitus. Brain Res Mol Brain Res 136:275–281

    CAS  PubMed  Google Scholar 

  48. Rodman MJ (1989) Your guide to the newest drugs. RN 52:61–76

    CAS  PubMed  Google Scholar 

  49. Watanabe M, Osada J, Aratani Y, Kluckman K, Reddick R, Malinow MR, Maeda N (1995) Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia. Proc Natl Acad Sci U S A 92:1585–1589

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ju P, Cui D (2016) The involvement of N-methyl-D-aspartate receptor (NMDAR) subunit NR1 in the pathophysiology of schizophrenia. Acta Biochim Biophys Sin Shanghai 48:209–219

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Ramsey AJ (2009) NR1 knockdown mice as a representative model of the glutamate hypothesis of schizophrenia. Prog Brain Res 179:51–58

    CAS  PubMed  Google Scholar 

  52. Tawfik A, Mohamed R, Elsherbiny NM, DeAngelis MM, Bartoli M, Al-Shabrawey M (2019) Homocysteine: a potential biomarker for diabetic retinopathy. J Clin Med 8

  53. Remtulla S, Hallett PE (1985) A schematic eye for the mouse, and comparisons with the rat. Vis Res 25:21–31

    CAS  PubMed  Google Scholar 

  54. Kuhlmann CR, Zehendner CM, Gerigk M, Closhen D, Bender B, Friedl P, Luhmann HJ (2009) MK801 blocks hypoxic blood-brain-barrier disruption and leukocyte adhesion. Neurosci Lett 449:168–172

    CAS  PubMed  Google Scholar 

  55. Minniti G, Calevo MG, Giannattasio A, Camicione P, Armani U, Lorini R, Piana G (2014) Plasma homocysteine in patients with retinal vein occlusion. Eur J Ophthalmol 24:735–743

    PubMed  Google Scholar 

  56. Homme RP, Singh M, Majumder A, George AK, Nair K, Sandhu HS, Tyagi N, Lominadze D, Tyagi SC (2018) Remodeling of retinal architecture in diabetic retinopathy: disruption of ocular physiology and visual functions by inflammatory gene products and pyroptosis. Front Physiol 9:1268

    PubMed  PubMed Central  Google Scholar 

  57. Booth GL, Wang EE (2000) Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events. CMAJ 163:21–29

    CAS  PubMed  PubMed Central  Google Scholar 

  58. McCully KS (2017) Hyperhomocysteinemia, suppressed immunity, and altered oxidative metabolism caused by pathogenic microbes in atherosclerosis and dementia. Front Aging Neurosci 9:324

    PubMed  PubMed Central  Google Scholar 

  59. Dong Y, Kalueff AV, Song C (2017) N-methyl-d-aspartate receptor-mediated calcium overload and endoplasmic reticulum stress are involved in interleukin-1beta-induced neuronal apoptosis in rat hippocampus. J Neuroimmunol 307:7–13

    CAS  PubMed  Google Scholar 

  60. Glynn-Servedio BE, Ranola TS (2017) AChE inhibitors and NMDA receptor antagonists in advanced Alzheimer’s disease. Consult Pharm 32:511–518

    PubMed  Google Scholar 

  61. Merello M, Nouzeilles MI, Cammarota A, Leiguarda R (1999) Effect of memantine (NMDA antagonist) on Parkinson’s disease: a double-blind crossover randomized study. Clin Neuropharmacol 22:273–276

    CAS  PubMed  Google Scholar 

  62. Hallett PJ, Standaert DG (2004) Rationale for and use of NMDA receptor antagonists in Parkinson’s disease. Pharmacol Ther 102:155–174

    CAS  PubMed  Google Scholar 

  63. Kamat PK, Kyles P, Kalani A, Tyagi N (2016) Hydrogen sulfide ameliorates homocysteine-induced Alzheimer’s disease-like pathology, blood-brain barrier disruption, and synaptic disorder. Mol Neurobiol 53:2451–2467

    CAS  PubMed  Google Scholar 

  64. Poddar R, Paul S (2009) Homocysteine-NMDA receptor-mediated activation of extracellular signal-regulated kinase leads to neuronal cell death. J Neurochem 110:1095–1106

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Deep SN, Mitra S, Rajagopal S, Paul S, Poddar R (2019) GluN2A-NMDA receptor-mediated sustained Ca(2+) influx leads to homocysteine-induced neuronal cell death. J Biol Chem 294:11154–11165

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Jindal A, Rajagopal S, Winter L, Miller JW, Jacobsen DW, Brigman J, Allan AM, Paul S, Poddar R (2019) Hyperhomocysteinemia leads to exacerbation of ischemic brain damage: Role of GluN2A NMDA receptors. Neurobiol Dis 127:287–302

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Sibarov DA, Abushik PA, Giniatullin R, Antonov SM (2016) GluN2A subunit-containing NMDA receptors are the preferential neuronal targets of homocysteine. Front Cell Neurosci 10:246

    PubMed  PubMed Central  Google Scholar 

  68. Moore P, El-sherbeny A, Roon P, Schoenlein PV, Ganapathy V, Smith SB (2001) Apoptotic cell death in the mouse retinal ganglion cell layer is induced in vivo by the excitatory amino acid homocysteine. Exp Eye Res 73:45–57

    CAS  PubMed  Google Scholar 

  69. Pang X, Liu J, Zhao J, Mao J, Zhang X, Feng L, Han C, Li M, Wang S, Wu D (2014) Homocysteine induces the expression of C-reactive protein via NMDAr-ROS-MAPK-NF-kappaB signal pathway in rat vascular smooth muscle cells. Atherosclerosis 236:73–81

    CAS  PubMed  Google Scholar 

  70. Diaz-Coranguez M, Ramos C, Antonetti DA (2017) The inner blood-retinal barrier: cellular basis and development. Vis Res 139:123–137

    PubMed  Google Scholar 

  71. Campbell M, Cassidy PS, O'Callaghan J, Crosbie DE, Humphries P (2018) Manipulating ocular endothelial tight junctions: applications in treatment of retinal disease pathology and ocular hypertension. Prog Retin Eye Res 62:120–133

    CAS  PubMed  Google Scholar 

  72. Qureshi I, Chen H, Brown AT, Fitzgerald R, Zhang X, Breckenridge J, Kazi R, Crocker AJ, Stuhlinger MC, Lin K, Cooke JP, Eidt JF, Moursi MM (2005) Homocysteine-induced vascular dysregulation is mediated by the NMDA receptor. Vasc Med 10:215–223

    PubMed  Google Scholar 

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Funding

The authors received the fund provided by the American Heart Association (AHA) Scientist Development Grant award #16SDG3070001, and NEI grant awards 1R01EY029751-02, 1R01EY030054-01A1, and P30EY031631

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Authors and Affiliations

  1. Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, 1120 15th Street, CB 1114, Augusta, GA, 30912-2000, USA

    Amany Tawfik, Dina Kira, Suhib Alhusban & Mohamed Al-Shabrawey

  2. James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, 30912, USA

    Amany Tawfik, Dina Kira, Suhib Alhusban & Mohamed Al-Shabrawey

  3. Department of Cellular Biology and Anatomy, Medical College of Georgia (MCG), Augusta University, Augusta, GA, 30912, USA

    Amany Tawfik & Mohamed Al-Shabrawey

  4. Department of Ophthalmology, Medical College of Georgia (MCG), Augusta University, Augusta, GA, 30912, USA

    Amany Tawfik & Mohamed Al-Shabrawey

  5. Department of Physiology Medical College of Georgia (MCG), Augusta University, Augusta, GA, 30912, USA

    Riyaz Mohamed

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  1. Amany Tawfik
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Contributions

Conceptualization: Amany Tawfik. Methodology: Riyaz Mohamed, Dina Kira, Suhib Alhusban , Mohamed Al-Shabrawey. Formal analysis and investigation: Amany Tawfik, Mohamed Al-Shabrawey. Writing—original draft preparation: Amany Tawfik. Writing—review and editing: Amany Tawfik, Mohamed Al-Shabrawey. Funding acquisition: Amany Tawfik. Supervision: Amany Tawfik.

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Correspondence to Amany Tawfik.

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All experiments with animals conformed to the ARVO Statement for Use of Animals in Ophthalmic and Vision Research and were done following our animal protocol approved by the Institute for Animal Care and Use Committee (IACUC) and Augusta University policies (protocol number AUP 2014-0683).

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Tawfik, A., Mohamed, R., Kira, D. et al. N-Methyl-D-aspartate receptor activation, novel mechanism of homocysteine-induced blood–retinal barrier dysfunction. J Mol Med 99, 119–130 (2021). https://doi.org/10.1007/s00109-020-02000-y

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