N-Methyl-N-Nitrosourea-Induced Photoreceptor Degeneration Is Inhibited by Nicotinamide via the Blockade of Upstream Events before the Phosphorylation of Signalling Proteins
Open accessAbstract
N-methyl-N-nitrosourea (MNU), a known carcinogen, is generally used in animal models to chemically induce photoreceptor degeneration. It has been reported that nicotinamide (NAM) exerts a protective effect on MNU-induced photoreceptor degeneration. We investigated the molecular mechanisms on MNU-induced photoreceptor degeneration. Intraperitoneal MNU injection (75 mg/kg) in rats induced selective photoreceptor degeneration in 7 days. NAM administration completely inhibited photoreceptor degeneration. Photoreceptor layer abnormality was observed within 6 hours after MNU injection, whereas it was restored in the NAM-treated retina, as detected by optical coherence tomography. One day following MNU administration, phosphorylation of the cell death-associated signalling proteins c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38) increased, while the apoptosis-related proteins, full-length poly(ADP-ribose) polymerase (PARP) and apoptosis-inducing factor (AIF), were depleted. These changes were not observed in the NAM-treated retinas. Cell survival signalling, such as extracellular signal-regulated kinase (ERK), Akt, and cAMP response element binding protein (CREB) phosphorylation, increased in the MNU- but not in the NAM-treated rat retinas. Increased phosphorylated ERK (p-ERK) levels were observed within 6 hours after MNU administration, suggestive of cell survival signalling activation. This did not occur in NAM-treated retinas. These results indicate that NAM regulates upstream cellular events prior to the activation of cell death-related signalling events, such as JNK and p38 phosphorylation.
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- Authors
- Sugano, E., Tabata, K., Takezawa, T., Shiraiwa, R., Muraoka, H., Metoki, T., Kudo, A., Iwama, Y., Nakazawa, M., & Tomita, H.
- Affiliations
- Iwate University (JP)
- Laboratory of Visual Neuroscience, Graduate Course in Biological Sciences, Iwate University Division of Science and Engineering, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan
- Hirosaki University (JP)
- Corresponding author
- Tomita, Hiroshi
- Venue
- BioMed Research International
- Publisher
- Wiley
- Published
- 2019-04-23
- Volume
- 2019
- Pages
- 1-10
- ISSN
- 1110-7243 (ISSN-L)
- 2314-6133
- 2314-6141
- PMC
- PMC6507250
- OpenAlex
- W2941988698
- Cited by
- 9
- References
- 34
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 1
- FWCI
- 0.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- BioMed Research International (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (16H05485, 16K11314, 18K09433, 17H06330)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Drug-Induced Ocular Toxicity
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- N-methyl-N-nitrosourea, photoreceptor degeneration, nicotinamide, retinal protection, c-Jun N-terminal kinase, p38 MAPK, ERK signaling, Akt signaling, CREB phosphorylation, apoptosis, cell survival signaling, photoreceptor layer, retinal degeneration
- MeSH terms
- Animals, Eye Proteins, Male, Methylnitrosourea, Niacinamide, Phosphorylation, Retinal Degeneration, Rats, Sprague-Dawley, Photoreceptor Cells, Vertebrate, MAP Kinase Signaling System, Rats
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