Protective effect of metformin on rat diabetic retinopathy involves suppression of toll-like receptor 4/nuclear factor-k B expression and glutamate excitotoxicity

Int Immunopharmacol. 2021 Jan:90:107193. doi: 10.1016/j.intimp.2020.107193. Epub 2020 Nov 25.


Microvascular complications of diabetes mellitus are progressively significant reasons for mortality. Metformin (MET) is considered as the first-line therapy for type 2 diabetes patients, and may be especially beneficial in cases of diabetic retinopathy although the precise mechanisms of MET action are not fully elucidated. The current study was designed to inspect the antioxidant and modulatory actions of MET on DRET in streptozotocin-induced diabetic rats. The effect of MET on the toll-like receptor 4/nuclear factor kappa B (TLR4/NFkB), inflammatory burden and glutamate excitotoxicity was assessed. Twenty-four male rats were assigned to four experimental groups: (1) Vehicle group, (2) Diabetic control: developed diabetes by injection of streptozotocin (60 mg/kg, i.p.). (3&4) Diabetic + MET group: diabetic rats were left for 9 weeks without treatment and then received oral MET 100 and 200 mg/kg for 6 weeks. Retinal samples were utilized in biochemical, histological, immunohistochemical and electron microscopic studies. MET administration significantly decreased retinal level of insulin growth factor and significantly suppressed the diabetic induced increase of malondialdehyde, glutamate, tumor necrosis factor-α and vascular endothelial growth factor (VEGF). Further, MET decreased the retinal mRNA expression of NFkB, tumor necrosis factor-α and TLR4 in diabetic rats. The current findings shed the light on MET's efficacy as an adjuvant therapy to hinder the development of diabetic retinopathy, at least partly, via inhibition of oxidative stress-induced NFkB/TLR4 pathway and suppression of glutamate excitotoxicity.

Keywords: Glutamate excitotoxicity; Metformin; Oxidative stress; Rat diabetic retinopathy; TLR4/NFkB.

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetic Retinopathy / etiology
  • Diabetic Retinopathy / metabolism
  • Diabetic Retinopathy / pathology
  • Diabetic Retinopathy / prevention & control*
  • Glutamic Acid / metabolism*
  • Hypoglycemic Agents / pharmacology*
  • Male
  • Metformin / pharmacology*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Oxidative Stress / drug effects
  • Rats
  • Rats, Wistar
  • Retina / drug effects*
  • Retina / metabolism
  • Retina / pathology
  • Signal Transduction
  • Streptozocin
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Endothelial Growth Factor A / metabolism


  • Hypoglycemic Agents
  • NF-kappa B
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • Glutamic Acid
  • Streptozocin
  • Metformin