Memantine mitigates ROS/TXNIP/NLRP3 signaling and protects against mouse diabetic retinopathy: Histopathologic, ultrastructural and bioinformatic studies

Diabetic retinopathy (DRET) triggers vision loss in adults, however, little therapeutic options are existing. Memantine is an anti-Alzheimer drug that antagonizes the activity of glutamate at N-methyl-D-aspartate (NMDA) receptors. Glutamate and thioredoxin-interacting protein (TXNIP) are known to be...

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Published in:	Biomedicine & pharmacotherapy Vol. 163; p. 114772
Main Authors:	ElSayed, Mohammed H., Elbayoumi, Khaled S., Eladl, Mohamed Ahmed, Mohamed, Abeer A.K., Hegazy, Ann, El-Sherbeeny, Nagla A., Attia, Mohammed A., Hisham, Fatma Azzahraa, Saleh, Mohamed A.K., Elaskary, Abdelhakeem, Morsi, Khaled, Mustsafa, Amna M.A., Enan, Eman T., Zaitone, Sawsan A.
Format:	Journal Article
Language:	English
Published:	France Elsevier Masson SAS 01-07-2023 Elsevier
Subjects:	Animals Carrier Proteins Diabetes Mellitus Diabetic retinopathy Diabetic Retinopathy - drug therapy Diabetic Retinopathy - metabolism Diabetic Retinopathy - prevention & control Glutamate, inflammation Glutamates Inflammasomes - metabolism Male Memantine Memantine - pharmacology Mice Mouse NLR Family, Pyrin Domain-Containing 3 Protein - metabolism NLR Proteins - metabolism Reactive Oxygen Species - metabolism ROS/TXNIP/NLRP3 Thioredoxins - metabolism ROS/TXNIP/NLRP3 Diabetic retinopathy Glutamate, inflammation Memantine Mouse
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Summary:	Diabetic retinopathy (DRET) triggers vision loss in adults, however, little therapeutic options are existing. Memantine is an anti-Alzheimer drug that antagonizes the activity of glutamate at N-methyl-D-aspartate (NMDA) receptors. Glutamate and thioredoxin-interacting protein (TXNIP) are known to be overexpressed in diabetic retinas and can produce activation of NOD-like receptor protein 3 (NLRP3) with subsequent secretion of interlukin-1β. This study repurposed memantine for its neuroprotective effect in experimental DRET and tested its impact on ROS/TXNIP/NLRP3. In addition, KEGG pathway database and STRING database identified the protein-protein interaction between glutamate receptors and TXNIP/NLRP3. Male Swiss albino mice received alloxan (180 mg/kg) to induce DRET. After 9 weeks, we divided the mice into groups: (a) saline, (ii) DRET, (iii and iv) DRET + oral memantine (5 or 10 mg per kg) for 28 days. Then, mice were euthanized, and eyeballs were removed. Retinal samples were utilized for biochemical, histopathological, and electron microscopy studies. Retinal levels of glutamate, TXNIP, NLRP3 and interlukin-1β were estimated using ELISA technique as well as retinal malondialdehyde. Histopathological and ultrastructural examination demonstrated that oral memantine attenuated vacuolization and restored normal retinal cell layers. Moreover, memantine reduced TXNIP, NLRP3, interleukin-1β and MDA concentrations. These results provide evidence demonstrating memantine' efficacy in alleviating DRET via suppressing reactive oxygen species/TXNIP/NLRP3 signaling cascade. Therefore, memantine might serve as a potential therapy for retinopathy after adequate clinical research. •Memantine antagonizes the activity of glutamate at NMDA receptors.•Retinal levels of glutamate, TXNIP, NLRP3 and interlukin-1β increased in diabetic mice.•Memantine attenuated restored normal retinal cell layers and ultrastructural pathologies.•Memantine reduced retinal TXNIP, NLRP3, interleukin-1β and MDA concentrations.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0753-3322 1950-6007
DOI:	10.1016/j.biopha.2023.114772