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 overexpressed in diabetic retinas and can produce activation of NOD-like receptor protein 3 (NLRP3) with subsequent secretion of interlukin-1ß. 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-1ß 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-1ß 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.

Role of Curcumin in Regulation of TNF-α Mediated Brain Inflammatory Responses.

BACKGROUND: Inflammation is a protective response of the body system that protects the body from the various kinds of external and internal insults; however, it has been found that most chronic illnesses are caused by dysregulated and excessive inflammation. Inflammation plays a major role in developing neurological diseases. In the brain cytokines, TNF-α and TNF-ß are known to mediate inflammation in many diseases. Functions of these cytokines are regulated by the activation of transcription factor NF-κb. Recent evidence suggest that curcumin has an immense therapeutic potential because of its anti-inflammatory and anti-oxidant properties. It has been tested for treating various chronic illnesses associated with the brain. OBJECTIVE: The study aims to elucidate the role of curcumin in alleviating the inflammatory reactions initiated by TNF-α and NF-κb signaling. METHODS: This study is a survey of literature from sources like PubMed central, science direct, medline and available scientific databases to determine how inflammation plays an important role in the development of neurodegenerative diseases and the role of curcumin as an anti-inflammatory agent. Looking into the importance of curcumin in alleviating inflammatory responses, several patents are filed and accepted which are referenced in this article. RESULTS: Neuro-inflammation mediated by TNF-α plays a major role in the development of pathologies like Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis etc. Curcumin appears to subside or reduce the inflammatory responses. Thus, it appears to have therapeutic potential for treating various neuroinflammatory diseases. CONCLUSION: Cytokines get upregulated during neurodegenerative diseases as a result of which inflammatory responses are initiated in the brain. Curcumin is reported to have anti-inflammatory properties and thereby its supplementation may help in reducing the inflammation. Future research on this area will further explain the mode of action of curcumin in alleviating neuroinflammation.