Reisenhofer M H, Balmer J M, Enzmann V
Department of Ophthalmology, Bern University Hospital, Inselspital, University of Bern, Bern. Switzerland.
Division of Veterinary Anatomy, Vetsuisse Faculty, University of Bern, Bern. Switzerland.
Curr Mol Med. 2017;17(2):100-107. doi: 10.2174/1566524017666170331162048.
Animal models with pharmacologically induced retinal degeneration including sodium iodate (NaIO3) and N-methyl-N-nitrosourea (MNU) have been extensively used in ophthalmic research to investigate retinal degeneration. NaIO3 induces degeneration of the retinal pigment epithelium (RPE) followed by photoreceptor (PRC) cell death, mimicking features of age-related macular degeneration. In contrast, MNU leads to rapid destruction of the PRCs only, enabling the use of the MNU model to investigate degeneration induced in retinitis pigmentosa. It has been shown that multiple cell death pathways are involved in the cell-specific effects of the toxins. Necrosis has been identified as the cause of the NaIO3-induced RPE loss. PRC degeneration in the described models is mainly induced by programmed cell death, indicated by the upregulation of conventional apoptosis initiator and effector caspases. However, recent research points to the additional involvement of caspase-independent processes as endoplasmic reticulum stress and calpain activation. Since there is still a substantial amount of contradictory hypotheses concerning triggers of cell death, the use of pharmacological models is controversial. Thereby, the advantages of such models like the application reaching across species and strains as well as modulation of onset and severity of damage are not exploited to a full extent. Thus, the present review aims to give more insight into the involved cell death pathways and discusses recent findings in the most widely used retinal degeneration models. It might facilitate further studies aiming to develop putative therapeutic approaches for retinal degenerative diseases including combinatory treatment with cell death inhibitors and cell transplantation therapy.
具有药理学诱导视网膜变性的动物模型，包括碘酸钠（NaIO3）和N-甲基-N-亚硝基脲（MNU），已广泛用于眼科研究以探究视网膜变性。NaIO3诱导视网膜色素上皮（RPE）变性，随后光感受器（PRC）细胞死亡，模拟年龄相关性黄斑变性的特征。相比之下，MNU仅导致PRC迅速破坏，使得MNU模型可用于研究色素性视网膜炎中诱导的变性。已表明多种细胞死亡途径参与毒素的细胞特异性作用。坏死已被确定为NaIO3诱导的RPE损失的原因。所述模型中的PRC变性主要由程序性细胞死亡诱导，表现为传统凋亡起始和效应半胱天冬酶的上调。然而，最近的研究指出，半胱天冬酶非依赖性过程如内质网应激和钙蛋白酶激活也参与其中。由于关于细胞死亡触发因素仍有大量相互矛盾的假说，药理学模型的使用存在争议。因此，此类模型的优势，如跨物种和品系的应用以及损伤发生和严重程度的调节，并未得到充分利用。因此，本综述旨在更深入地了解所涉及的细胞死亡途径，并讨论最广泛使用的视网膜变性模型中的最新发现。它可能有助于进一步研究，旨在开发针对视网膜退行性疾病的推定治疗方法，包括与细胞死亡抑制剂联合治疗和细胞移植治疗。
