p38 MAPK inhibitor SB202190 suppresses ferroptosis in the glutamate-induced retinal excitotoxicity glaucoma model

Lemeng Feng; Chao Wang; Cheng Zhang; Wulong Zhang; Weiming Zhu; Ye He; Zhaohua Xia; Weitao Song

doi:10.4103/1673-5374.391193

p38 MAPK inhibitor SB202190 suppresses ferroptosis in the glutamate-induced retinal excitotoxicity glaucoma model

Neural Regen Res. 2024 Oct 1;19(10):2299-2309. doi: 10.4103/1673-5374.391193. Epub 2023 Dec 21.

Authors

Lemeng Feng^{1

2

3}, Chao Wang^{1

2

3}, Cheng Zhang^{1

2

3}, Wulong Zhang^{1

2

3}, Weiming Zhu^{1

2

3}, Ye He^{1

2

3}, Zhaohua Xia^{1

2

3}, Weitao Song^{1

2

3}

Affiliations

¹ National Clinical Research Center for Geriatric Diseases, Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
² Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
³ Hunan Key Laboratory of Ophthalmology, Changsha, Hunan Province, China.

Abstract

JOURNAL/nrgr/04.03/01300535-202410000-00031/figure1/v/2024-02-06T055622Z/r/image-tiff Glutamate excitotoxicity has been shown to play an important role in glaucoma, and glutamate can induce ferroptosis. The p38 mitogen-activated protein kinase (MAPK) pathway inhibitor SB202190 has a potential ability to suppress ferroptosis, and its downstream targets, such as p53, have been shown to be associated with ferroptosis. However, whether ferroptosis also occurs in retinal ganglion cells in response to glutamate excitotoxicity and whether inhibition of ferroptosis reduces the loss of retinal ganglion cells induced by glutamate excitotoxicity remain unclear. This study investigated ferroptosis in a glutamate-induced glaucoma rat model and explored the effects and molecular mechanisms of SB202190 on retinal ganglion cells. A glutamate-induced excitotoxicity model in R28 cells and an N-methyl-D-aspartate-induced glaucoma model in rats were used. In vitro experiments showed that glutamate induced the accumulation of iron and lipid peroxide and morphological changes of mitochondria in R28 cells, and SB202190 inhibited these changes. Glutamate induced the levels of p-p38 MAPK/p38 MAPK and SAT1 and decreased the expression levels of ferritin light chain, SLC7A11, and GPX4. SB202190 inhibited the expression of iron death-related proteins induced by glutamate. In vivo experiments showed that SB202190 attenuated N-methyl-D-aspartate-induced damage to rat retinal ganglion cells and improved visual function. These results suggest that SB202190 can inhibit ferroptosis and protect retinal ganglion cells by regulating ferritin light chain, SAT1, and SLC7A11/Gpx4 pathways and may represent a potential retina protectant.

Grants and funding

Funding:This work was supported by the National Natural Science Foundation of China, Nos. 81974132, 81770927; Hunan Provincial Health Commission, No. 20220702839; the Natural Science Foundation of Hunan Province of China, No. 2022JJ30076; National Key R&D Program of China, No. 2021YFA1101202 (all to WS).