Spermidine Attenuates High Glucose-Induced Oxidative Damage in Retinal Pigment Epithelial Cells by Inhibiting Production of ROS and NF-κB/NLRP3 Inflammasome Pathway

Abstract

Diabetic retinopathy (DR) is the leading cause of vision loss and a critical complication of diabetes with a very complex etiology. The build-up of reactive oxygen species (ROS) due to hyperglycemia is recognized as a primary risk factor for DR. Although spermidine, a naturally occurring polyamine, has been reported to have antioxidant effects, its effectiveness in DR has not yet been examined. Therefore, in this study, we investigated whether spermidine could inhibit high glucose (HG)-promoted oxidative stress in human retinal pigment epithelial (RPE) cells. The results demonstrated that spermidine notably attenuated cytotoxicity and apoptosis in HG-treated RPE ARPE-19 cells, which was related to the inhibition of mitochondrial ROS production. Under HG conditions, interleukin (IL)-1β and IL-18’s release levels were markedly increased, coupled with nuclear factor kappa B (NF-κB) signaling activation. However, spermidine counteracted the HG-induced effects. Moreover, the expression of nucleotide-binding oligomerization domain-like receptor (NLR) protein 3 (NLRP3) inflammasome multiprotein complex molecules, including TXNIP, NLRP3, ASC, and caspase-1, increased in hyperglycemic ARPE-19 cells, but spermidine reversed these molecular changes. Collectively, our findings demonstrate that spermidine can protect RPE cells from HG-caused injury by reducing ROS and NF-κB/NLRP3 inflammasome pathway activation, indicating that spermidine could be a potential therapeutic compound for DR treatment.

Spermidine Synthase Localization in Retinal Layers: Early Age Changes

“…Catabolic PA degradation [ 7 , 31 , 32 , 33 , 34 , 35 , 36 ], oxidation, and the production of toxic acrolein [ 36 , 37 ] can lead to multiple CNS diseases such as Parkinson’s [ 38 , 39 , 40 ], Alzheimer’s, [ 41 , 42 ], and Huntington’s [ 43 ], and PAs are also key players in EAST/SeSAME, Snyder–Robinson, Down, and Rett syndromes [ 11 , 44 , 45 ]. However, unmodified PAs (i) protect against oxidative stress [ 46 , 47 , 48 ], (ii) glutamate toxicity [ 33 ], and (iii) DNA damage [ 36 , 49 ], and serve in (iv) improving memory [ 50 , 51 ] and (v) increasing longevity [ 52 , 53 , 54 , 55 , 56 ].…”