Retinoprotective effect of agmatine in streptozotocin-induced diabetic rat model: avenues for vascular and neuronal protection

Agmatine in diabetic retinopathy

Abstract

Diabetic retinopathy (DR) is the most common diabetic neurovascular complication, and the leading cause of preventable blindness among working-age individuals. Recently, agmatine, the endogenous decarboxylated L-arginine, has gained attention as a pleiotropic agent that modulates the diabetes-associated decline in quality of life, and exhibited varied protective biological effects. Diabetes was induced by a single streptozotocin (STZ, 50 mg/kg, i.p.) injection. When diabetes was verified, the animals were randomly allocated into three groups (16 rat each); diabetic, agmatine-treated diabetic (1 mg/kg, daily, for 12 weeks), and control group. Blood glucose homeostasis, retinal redox status, apoptotic parameters, nitric oxide synthase (NOS), nitric oxide (NO), vascular endothelial growth factor (VEGF), glutamate, glutamine, glutamine synthase (GS) activity, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and mitogen-activated protein kinase (MAPKs) pathways were assayed biochemically. Retinal vascular permeability was measured. Retinal morphology was evaluated by hematoxylin and eosin staining. Retinal N-methyl-D-aspartic acid receptor1 (NMDAR1) and glutamate aspartate transporter (GLAST) mRNA were quantified. Glucose transporter 1, pro-caspase3, and glial fibrillary acidic protein (GFAP) expression were quantified by immunohistochemistry. Chronic agmatine treatment abrogated STZ-induced retinal neurodegeneration features including gliosis, and neuronal apoptosis, restored retinal vascular permeability, mostly through antioxidant, anti-apoptotic capacity, abolishing glutamate excitotoxicity, modulating the activity of NMDARs, MAPKs/NFκB, and NOS/NO pathways. By restoring the molecular and functional background of retinal neurovascular homeostatic balance, agmatine would be appropriate therapeutic option acting upstream of the DR, impeding its progression.

Graphical abstract

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Abo El Gheit RE, Atef MM, Badawi GA, Elwan WM, Alshenawy HA, Emam MN (2020) Role of serine protease inhibitor, ulinastatin, in rat model of hepatic encephalopathy: aquaporin 4 molecular targeting and therapeutic implication. J Physiol Biochem 76(4):573–586. https://doi.org/10.1007/s13105-020-00762-0

    Article  PubMed  Google Scholar 

  2. 2.

    Abo El Gheit RE, Atef MM, El Deeb OS, Badawi GA, Alshenawy HA, Elwan WM, Arakeep HM, Emam MN (2020) Unique novel role of adropin in a gastric ulcer in a rotenone-induced rat model of Parkinson’s disease. ACS Chem Neurosci 11(19):3077–3088

    CAS  Article  Google Scholar 

  3. 3.

    Abo El Gheit R, Emam MN (2016) Targeting heme oxygenase-1 in early diabetic nephropathy in streptozotocin-induced diabetic rats. Physiol Int 103(4):413–427

    CAS  Article  Google Scholar 

  4. 4.

    Akasaka N, Fujiwara S (2019) The therapeutic and nutraceutical potential of agmatine, and its enhanced production using Aspergillus oryzae. Amino Acids 52:181–197

    Article  Google Scholar 

  5. 5.

    Apak R, Güçlü K, Özyürek M, Çelik SE (2008) Mechanism of antioxidant capacity assays and the CUPRAC (cupric ion reducing antioxidant capacity) assay. Microchim Acta 160(4):413–419

    CAS  Article  Google Scholar 

  6. 6.

    Atef MM, Abd-Ellatif RN, Emam MN, Abo El Gheit RE, Amer AI, Hafez YM (2019) Therapeutic potential of sodium selenite in letrozole induced polycystic ovary syndrome rat model: targeting mitochondrial approach (selenium in PCOS). Arch Biochem Biophys 671:245–254

    CAS  Article  Google Scholar 

  7. 7.

    Atef MM, El-Deeb OS, Sadek MT, Abo El Gheit RE, Emam MN, Hafez YM, El-Esawy RO (2020) Targeting ERK/COX-2 signaling pathway in permethrin-induced testicular toxicity: a possible modulating effect of matrine. Mol Biol Rep 47(1):247–259

    CAS  Article  Google Scholar 

  8. 8.

    Barua S, Kim JY, Kim JY, Kim JH, Lee JE (2019) Therapeutic effect of agmatine on neurological disease: focus on ion channels and receptors. Neurochem Res 44(4):735–750. https://doi.org/10.1007/s11064-018-02712-1

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Bredt DS, Schmidt HH (1996) The citrulline assay. In: Feelisch M, Stamler JS (eds) Methods in nitric oxide research. Wiley, New York, pp 249–270

    Google Scholar 

  10. 10.

    Conti M, Morand PC, Levillain P, Lemonnier A (1991) Improved fluorometric determination of malonaldehyde. Clin Chem 37(7):1273–1275

    CAS  Article  Google Scholar 

  11. 11.

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

    Article  Google Scholar 

  12. 12.

    Du Y, Tang J, Li G, Berti-Mattera L, Lee CA, Bartkowski D, Gale D, Monahan J, Niesman MR, Alton G, Kern TS (2010) Effects of p38 MAPK inhibition on early stages of diabetic retinopathy and sensory nerve function. Invest Ophthalmol Vis Sci 51(4):2158–2164

    Article  Google Scholar 

  13. 13.

    Fernandes R, Hosoya K, Pereira P (2011) Reactive oxygen species downregulate glucose transport system in retinal endothelial cells. American journal of physiology. Cell Physiol 300(4):C927–C936

    CAS  Article  Google Scholar 

  14. 14.

    Giove TJ, Deshpande MM, Gagen CS, Eldred WD (2009) Increased neuronal nitric oxide synthase activity in retinal neurons in early diabetic retinopathy. Mol Vis 15:2249–2258

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem 126:131–138

    CAS  Article  Google Scholar 

  16. 16.

    Gu L, Xu H, Zhang C, Yang Q, Zhang L, Zhang J (2019) Time-dependent changes in hypoxia- and gliosis-related factors in experimental diabetic retinopathy. Eye (Lond) 33(4):600–609

    CAS  Article  Google Scholar 

  17. 17.

    Han N, Yu L, Song Z, Luo LY (2015) Agmatine protects Müller cells from high-concentration glucose-induced cell damage via N-methyl-D-aspartic acid receptor inhibition. Mol Med Rep 12(1):1098–1106

    CAS  Article  Google Scholar 

  18. 18.

    Hong S, Lee JE, Kim CY, Seong GJ (2007) Agmatine protects retinal ganglion cells from hypoxia-induced apoptosis in transformed rat retinal ganglion cell line. BMC Neurosci 8:81. https://doi.org/10.1186/1471-2202-8-81

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Iizuka Y, Hong S, Kim CY, Yang WI, Lee JE, Seong GJ (2010) Protective mechanism of agmatine pretreatment on RGC-5 cells injured by oxidative stress. Braz J Med Biol Res 43(4):356–358

    CAS  Article  Google Scholar 

  20. 20.

    Jindal V (2015) Neurodegeneration as a primary change and role of neuroprotection in diabetic retinopathy. Mol Neurobiol 51(3):878–884

    CAS  Article  Google Scholar 

  21. 21.

    Jou SB, Liu IM, Cheng JT (2004) Activation of imidazoline receptor by agmatine to lower plasma glucose in streptozotocin-induced diabetic rats. Neurosci Lett 358(2):111–114

    CAS  Article  Google Scholar 

  22. 22.

    Kang S, Kim CH, Jung H, Kim E, Song HT, Lee JE (2017) Agmatine ameliorates type 2 diabetes induced-Alzheimer’s disease-like alterations in high-fat diet-fed mice via reactivation of blunted insulin signalling. Neuropharmacology 113:467–479

    CAS  Article  Google Scholar 

  23. 23.

    Kotil K, Kuscuoglu U, Kirali M, Uzun H, Akçetin M, Bilge T (2006) Investigation of the dose-dependent neuroprotective effects of agmatine in experimental spinal cord injury: a prospective randomized and placebo-control trial. J Neurosurg Spine 4(5):392–399

    Article  Google Scholar 

  24. 24.

    Kowluru RA, Engerman RL, Case GL, Kern TS (2001) Retinal glutamate in diabetes and effect of antioxidants. Neurochem Int 38(5):385–390

    CAS  Article  Google Scholar 

  25. 25.

    Kusari J, Zhou S, Padillo E, Clarke KG, Gil DW (2007) Effect of memantine on neuroretinal function and retinal vascular changes of streptozotocin-induced diabetic rats. Invest Ophthalmol Vis Sci 48(11):5152–5159

    Article  Google Scholar 

  26. 26.

    Liu IM, Cheng JT (2011) Mediation of endogenous β-endorphin in the plasma glucose-lowering action of herbal products observed in type 1-like diabetic rats. Evid Based Complement Alternat Med 2011:987876

    CAS  PubMed  Google Scholar 

  27. 27.

    Mahajan N, Arora P, Sandhir R (2019) Perturbed biochemical pathways and associated oxidative stress lead to vascular dysfunctions in diabetic retinopathy. Oxidative Med Cell Longev 2019:8458472

    Article  Google Scholar 

  28. 28.

    Moosavi M, Zarifkar AH, Farbood Y, Dianat M, Sarkaki A, Ghasemi R (2014) Agmatine protects against intracerebroventricular streptozotocin-induced water maze memory deficit, hippocampal apoptosis and Akt/GSK3β signaling disruption. Eur J Pharmacol 736:107–114

    CAS  Article  Google Scholar 

  29. 29.

    Ng YK, Zeng XX, Ling EA (2004) Expression of glutamate receptors and calcium-binding proteins in the retina of streptozotocin-induced diabetic rats. Brain Res 1018(20):66–72

    CAS  Article  Google Scholar 

  30. 30.

    Puro DG (2002) Diabetes-induced dysfunction of retinal Müller cells. Trans Am Ophthalmol Soc 43(9):3109–3116

    Google Scholar 

  31. 31.

    Regunathan S, Piletz JE (2003) Regulation of inducible nitric oxide synthase and agmatine synthesis in macrophages and astrocytes. Ann N Y Acad Sci 1009:20–29

    CAS  Article  Google Scholar 

  32. 32.

    Rondón LJ, Farges MC, Davin N, Sion B, Privat AM, Vasson MP, Eschalier A, Courteix C (2018) L-Arginine supplementation prevents allodynia and hyperalgesia in painful diabetic neuropathic rats by normalizing plasma nitric oxide concentration and increasing plasma agmatine concentration. Eur J Nutr 57(7):2353–2363

    Article  Google Scholar 

  33. 33.

    Santiago AR, Hughes JM, Kamphuis W, Schlingemann RO, Ambrósio AF (2007) Diabetes changes ionotropic glutamate receptor subunit expression level in the human retina. Brain Res 1198:153–159

    Article  Google Scholar 

  34. 34.

    Semeraro F, Morescalchi F, Cancarini A, Russo A, Rezzola S, Costagliola C (2019) Diabetic retinopathy, a vascular and inflammatory disease: therapeutic implications. Diabetes Metab 5(6):517–527

    Article  Google Scholar 

  35. 35.

    Simó R, Stitt AW, Gardner TW (2018) Neurodegeneration in diabetic retinopathy: does it really matter? Diabetologia 61(9):1902–1912

    Article  Google Scholar 

  36. 36.

    Su CH, Liu IM, Chung HH, Cheng JT (2009) Activation of I2-imidazoline receptors by agmatine improved insulin sensitivity through two mechanisms in type-2 diabetic rats. Neurosci Lett 457(3):125–128

    CAS  Article  Google Scholar 

  37. 37.

    Waataja JJ, Peterson CD, Verma H, Goracke-Postle CJ, Séguéla P, Delpire E, Wilcox GL, Fairbanks CA (2019) Agmatine preferentially antagonizes GluN2B-containing N-methyl-d-aspartate receptors in spinal cord. J Neurophysiol 121(2):662–671

    CAS  Article  Google Scholar 

  38. 38.

    Wang B, Li PK, Ma JX, Chen D (2018) Therapeutic effects of a novel phenylphthalimide analog for corneal neovascularization and retinal vascular leakage. Invest Ophthalmol Vis Sci 59(8):3630–3642

    CAS  Article  Google Scholar 

  39. 39.

    Yu X, Xu Z, Mi M, Xu H, Zhu J, Wei N, Chen K, Zhang Q, Zeng K, Wang J, Chen F, Tang Y (2008) Dietary taurine supplementation ameliorates diabetic retinopathy via anti-excitotoxicity of glutamate in streptozotocin-induced Sprague-Dawley rats. Neurochem Res 33(3):500–507

    CAS  Article  Google Scholar 

  40. 40.

    Yu XH, Zhang H, Wang YH, Liu LJ, Teng Y, Liu P (2009) Time-dependent reduction of glutamine synthetase in retina of diabetic rats. Exp Eye Res 89(6):967–971

    CAS  Article  Google Scholar 

  41. 41.

    Zhong Q, Mishra M, Kowluru RA (2013) Transcription factor Nrf2-mediated antioxidant defense system in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci 54(6):3941–3948

    CAS  Article  Google Scholar 

Download references

Funding

This work did not receive funding from any organizations.

Author information

Affiliations

Authors

Contributions

All authors contributed to research design, conception, data collection, and analysis interpretation, and shared in the critically revised process of the manuscript. Mervat H El-Saka and Nermin M Madi prepared the revised form of manuscript. All authors have approved the final manuscript version, submitted for journal publication and agree to be accountable for research aspects.

Corresponding author

Correspondence to Rehab E. Abo El Gheit.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Key points

• Agmatine effectively abrogated retinal microangiopathy and neurodegeneration in diabetic rats through modulation of NMDAR-mediated glutamate toxicity and Nrf2-mediated antioxidant capacity.

• Agmatine abrogated the NFκB/MAPK signal cascade, gliosis and restored the neurotransmitter balance, and the dysregulated neurovascular cross-talk in DR.

• Agmatine can be tooled as a neuromodulation-based therapeutic approach, to provide a safe and effective strategy for ameliorating DR.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Abo El Gheit, R.E., Soliman, N.A., Badawi, G.A. et al. Retinoprotective effect of agmatine in streptozotocin-induced diabetic rat model: avenues for vascular and neuronal protection. J Physiol Biochem (2021). https://doi.org/10.1007/s13105-021-00799-9

Download citation

Keywords

  • Agmatine diabetic retinopathy
  • Streptozotocin
  • Glutamate
  • Mitogen-activated protein kinases