1. N -Methyl- N -Nitrosourea-Induced Photoreceptor Degeneration Is Inhibited by Nicotinamide via the Blockade of Upstream Events before the Phosphorylation of Signalling Proteins.
- Author
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Sugano E, Tabata K, Takezawa T, Shiraiwa R, Muraoka H, Metoki T, Kudo A, Iwama Y, Nakazawa M, and Tomita H
- Subjects
- Animals, Male, Phosphorylation drug effects, Photoreceptor Cells, Vertebrate pathology, Rats, Rats, Sprague-Dawley, Eye Proteins metabolism, MAP Kinase Signaling System drug effects, Methylnitrosourea toxicity, Niacinamide pharmacology, Photoreceptor Cells, Vertebrate metabolism, Retinal Degeneration chemically induced, Retinal Degeneration drug therapy, Retinal Degeneration metabolism, Retinal Degeneration pathology
- Abstract
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.
- Published
- 2019
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