N-methyl-N-nitrosourea-induced photoreceptor degeneration is inhibited by nicotinamide via the blockade of upstream events before the phosphorylation of signaling proteins.
N-methyl-N-nitrosourea-induced photoreceptor degeneration is inhibited by nicotinamide via the blockade of upstream events before the phosphorylation of signaling proteins.
复制标题
烟酰胺通过在信号蛋白磷酸化之前阻断上游事件来抑制 N-甲基-N-亚硝基脲诱导的光感受器变性。
DOI：
10.1155/2019/3238719
复制
发表时间：
2019
影响因子：
--
通讯作者：
Iwama Y
中科院分区：
文献类型：
--
作者：
Sugano E;Tabata K;Takezawa T;Shiraiwa R;Muraoka H;Metoki T;Kudo A;Nakazawa M;Tomita H;Iwama Y
N-甲基-N-亚硝脲(MNU)是一种已知的致癌物，通常用于动物模型以化学诱导光感受器退化。据报道，烟酰胺(NAM)对MNU诱导的光感受器变性有保护作用。我们研究了MNU诱导的光感受器退化的分子机制。大鼠腹腔注射MNU(75 mg/kg)后7d内出现选择性光感受器变性。NAM可完全抑制光感受器退变。光学相干断层扫描显示，注射MNU后6h内可见光感受器层异常，而NAM处理组视网膜光感受层已恢复正常。MNU作用1d后，细胞死亡相关信号蛋白c-jun氨基末端激酶(JNK)和p38丝裂原活化蛋白激酶(P38)的磷酸化水平增加，而与细胞凋亡相关的蛋白全长多聚(ADP-核糖)聚合酶(PARP)和凋亡诱导因子(AIF)则被耗尽。在NAM处理的视网膜中没有观察到这些变化。细胞存活信号，如细胞外信号调节激酶(ERK)、Akt和cAMP反应元件结合蛋白(CREB)磷酸化，在MNU中增加，但在NAM处理的大鼠视网膜中不增加。MNU给药后6小时内，磷酸化ERK(p-ERK)水平升高，提示细胞存活信号被激活。这在接受NAM治疗的视网膜中不会发生。这些结果表明，NAM在激活与细胞死亡相关的信号事件之前调节上游细胞事件，如JNK和p38磷酸化。
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.