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

Agmatine in diabetic retinopathy

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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.

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Authors and Affiliations

  1. Physiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt

    Rehab E. Abo El Gheit, Nermin M Madi, Mervat H El-Saka & Marwa N. Emam

  2. Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta, Egypt

    Nema A. Soliman

  3. Pharmacology and Toxicology Department, Faculty of Pharmacy and Pharmaceutical Industries, Sinai University, El-Arish, Egypt

    Ghada A. Badawi

  4. Histology Departments, Tanta University, Tanta, Egypt

    Shimaa M. Badr

Authors
  1. Rehab E. Abo El Gheit
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  2. Nema A. Soliman
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  3. Ghada A. Badawi
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  4. Nermin M Madi
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  5. Mervat H El-Saka
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  7. Marwa N. Emam
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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.

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Correspondence to Rehab E. Abo El Gheit.

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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.

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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 77, 305–320 (2021). https://doi.org/10.1007/s13105-021-00799-9

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  • DOI: https://doi.org/10.1007/s13105-021-00799-9

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