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Cited by 10Retinal Development and DisordersOcular and Laser Science ResearchRetinal Diseases and Treatments

Effect of Phosphorylated-Extracellular Regulated Kinase 1/2 Inhibitor on Retina from Light-induced Photoreceptor Degeneration

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Ding, Xin-Yi, Gu, Rui-Ping, Tang, Wen-Yi, Shu, Qin-Meng, Xu, Ge-Zhi, Zhang, Meng·2018·Chinese Medical Journal
DOI 10.4103/0366-6999.246064PMC PMC6278201
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Abstract

Background: The demonstrated role of mitogen-activated protein kinase (MAPK) in both cell apoptosis and the inflammation pathway makes it an attractive target for photoreceptor protection. The aim of this study was to investigate the protective effects of MAPK antagonists against photoreceptor degeneration and retinal inflammation in a rat model of light-induced retinal degeneration. Methods: Sprague Dawley rats were treated with intravitreal injections of MAPK antagonists, inhibitors of p-P38, phosphorylated-extracellular regulated kinase (p-ERK) 1/2, and p-c-Jun N-terminal kinase (JNK) just before they were assigned to dark adaptation. After dark adaptation for 24 h, rats were exposed to blue light (2500 lux) in a light box for 24 h, and then returned to the normal 12-h light/12-h dark cycle. Samples were collected at different time points. MAPK expression during light exposure was examined with immunofluorescence. Photoreceptor death was detected with histopathology and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The expression of retinal p-ERK1/2, caspase 3, activated caspase 3, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β was examined by Western blotting. Differences between groups were evaluated using unpaired one-way analysis of variance and least significant difference post hoc tests. Results: MAPKs (P38, ERK1/2, and p-JNK) were phosphorylated and activated in the light injury groups, compared with normal group, and their expressions were mainly elevated in the outer nuclear layer (ONL). Among the selected MAPK antagonists, only the p-ERK1/2 inhibitor attenuated the loss of photoreceptors and the thinning of ONL in light injury groups. Besides, p-ERK1/2 inhibitor refrained light-induced photoreceptor apoptosis, which was presented by TUNEL positive cells. Light injury significantly increased the expression of p-ERK1/2 (1.12 ± 0.06 vs. 0.57 ± 0.08, t = 9.99, P < 0.05; 1.23 ± 0.03 vs. 0.57 ± 0.08, t = 11.90, P < 0.05; and 1.12 ± 0.12 vs. 0.57 ± 0.08, t = 9.86, P < 0.05; F = 49.55, P < 0.001), and induced caspase 3 activating (0.63 ± 0.06 vs. 0.14 ± 0.05, t = 13.67, P < 0.05; 0.74 ± 0.05 vs. 0.14 ± 0.05, t = 16.87, P < 0.05; and 0.80 ± 0.05 vs. 0.14 ± 0.05, t = 18.57, P < 0.05; F = 100.15, P < 0.001), compared with normal group. The p-ERK1/2 inhibitor significantly reduced p-ERK1/2 overexpression (0.61 ± 0.06 vs. 1.12 ± 0.06, t = −9.26, P < 0.05; 0.77 ± 0.06 vs. 1.23 ± 0.03, t = −8.29, P < 0.05; and 0.68 ± 0.03 vs. 1.12 ± 0.12, t = −7.83, P < 0.05; F = 49.55, P < 0.001) and downregulated caspase 3 activating (0.23 ± 0.04 vs. 0.63 ± 0.06, t = −11.24, P < 0.05; 0.43 ± 0.03 vs. 0.74 ± 0.05, t = −8.86, P < 0.05; and 0.58 ± 0.03 vs. 0.80 ± 0.05, t = −6.17, P < 0.05; F = 100.15, P < 0.001), compared with light injury group. No significant change in the total level of caspase 3 was seen in different groups ( F = 0.56, P = 0.75). As for inflammation, light injury significantly increased the expression of TNF-α (0.42 ± 0.04 vs. 0.25 ± 0.05, t = 5.99, P < 0.05; 0.65 ± 0.03 vs. 0.25 ± 0.05, t = 14.87, P < 0.05; and 0.86 ± 0.04 vs. 0.25 ± 0.05, t = 22.58, P < 0.05; F = 160.27, P < 0.001) and IL-1β (0.24 ± 0.01 vs. 0.19 ± 0.02, t = 2.33, P < 0.05; 0.35 ± 0.02 vs. 0.19 ± 0.02, t = 7.97, P < 0.05; and 0.48 ± 0.04 vs. 0.19 ± 0.02, t = 14.69, P < 0.05; F = 77.29, P < 0.001), compared with normal group. P-ERK1/2 inhibitor significantly decreased the overexpression of TNF-α (0.22 ± 0.02 vs. 0.42 ± 0.04, t = −7.40, P < 0.05; 0.27 ± 0.02 vs. 0.65 ± 0.03, t = −14.27, P < 0.05; and 0.33 ± 0.03 vs. 0.86 ± 0.04, t = −19.58, P < 0.05; F = 160.27, P < 0.001) and IL-1β (0.13 ± 0.03 vs. 0.24 ± 0.01, t = −5.77, P < 0.05; 0.17 ± 0.01 vs. 0.22 ± 0.02, t = −9.18, P < 0.05; and 0.76 ± 0.05 vs. 0.48 ± 0.04, t = −13.12, P < 0.05; F = 77.29, P < 0.001), compared with light injury group. Conclusion: The p-ERK1/2 inhibitor might protect the retina from light-induced photoreceptor degeneration and retinal inflammation.

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  • In this rat model, only the p-ERK1/2 inhibitor attenuated the progressive photoreceptor loss and thinning of the ONL and protected the retina from photoreceptor degeneration and inflammation, while p38 and JNK inhibitors had no such effect.

    “In this model though, only the p-ERK1/2 inhibitor attenuated the progressive photoreceptor loss and thinning of the ONL and protected the retina from photoreceptor degeneration and inflammation, while p38 and JNK inhibitors had no such effect.”

    From MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges (2023) · cites this paper as [64]

    The Results (Figure 2; page not supplied) say that only the p-ERK1/2 inhibitor reduced photoreceptor loss and ONL thinning among the three inhibitors. The Discussion (Figure 5; page not supplied) reports an anti-inflammatory effect of the p-ERK1/2 inhibitor, but does not establish that the p38 and JNK inhibitors lacked such an effect on inflammation. (LLM, conf=0.84)

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  • In a rat model of light-induced retinal degeneration, ERK1/2, p38 and JNK were phosphorylated and activated, mainly in the retinal outer nuclear layer (ONL).

    “In a rat model of light-induced retinal degeneration, ERK1/2, p38 and JNK were phosphorylated and activated, mainly in the retinal outer nuclear layer (ONL) [ 64 ].”

    From MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges (2023) · cites this paper as [64]

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Authors
Ding, X.-Y., Gu, R.-P., Tang, W.-Y., Shu, Q.-M., Xu, G.-Z., & Zhang, M.
Affiliations
Shanghai Medical College of Fudan University (CN)
Corresponding author
Zhang, Meng
Venue
Chinese Medical Journal
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-12-05
Volume
131
Issue
23
Pages
2836-2843
ISSN
0366-6999 (ISSN-L)
DOI
10.4103/0366-6999.246064
PMC
PMC6278201
OpenAlex
W2980645727
Cited by
10
References
4
Citations by year
2025: 1 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 1 · 2019: 1
FWCI
0.18
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Chinese Medical Journal (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • PubMed
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Health Sciences › Medicine › Ophthalmology › Ocular and Laser Science Research
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Keywords
ERK1/2 inhibitor, retinal degeneration, MAPK signaling, photoreceptor apoptosis, retinal inflammation, TNF-α, IL-1β, p38 MAPK, JNK, outer nuclear layer, photoprotection, intravitreal injection
MeSH terms
Animals, Light, Male, Phosphorylation, Retina, Retinal Degeneration, Tumor Necrosis Factor-alpha, Blotting, Western, Rats, Sprague-Dawley, In Situ Nick-End Labeling, Mitogen-Activated Protein Kinases, Rats, Interleukin-1beta

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