Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study.

BACKGROUND: Retinitis pigmentosa (RP) is a kind of inherited retinal degenerative diseases characterized by the progressive loss of photoreceptors. RP has been a conundrum without satisfactory countermeasures in clinic until now. Acetaldehyde dehydrogenase 2 (ALDH2), a major enzyme involved in aldehyde detoxification, has been demonstrated to be beneficial for a growing number of human diseases, such as cardiovascular dysfunction, diabetes mellitus and neurodegeneration. However, its protective effect against RP remains unknown. Our study explored the impact of ALDH2 on retinal function and structure in N-methyl-N-nitrosourea (MNU)-induced RP rats. METHODS: Rats were gavaged with 5 mg/kg Alda-1, an ALDH2 agonist, 5 days before and 3 days after MNU administration. Assessments of retinal function and morphology as well as measurement of specific proteins expression level were conducted. RESULTS: Electroretinogram recordings showed that Alda-1 administration alleviated the decrease in amplitude caused by MNU, rendering protection of retinal function. Mitigation of photoreceptor degeneration in MNU-treated retinas was observed by optical coherence tomography and retinal histological examination. In addition, Western blotting results revealed that ALDH2 protein expression level was upregulatedwith increased expression of SIRT1 protein after the Alda-1 intervention. Besides, endoplasmic reticulum stress (ERS) was reduced according to the significant downregulation of GRP78 protein, while apoptosis was ameliorated as shown by the decreased expression of PARP1 protein. CONCLUSIONS: Together, our data demonstrated that ALDH2 could provide preservation of retinal function and morphology against MNU-induced RP, with the underlying mechanism at least partly related to the modulation of SIRT1, ERS and apoptosis.

Pigmentary Maculopathy Associated with Chronic Exposure to Pentosan Polysulfate Sodium.

PURPOSE: To describe the clinical features of a unique pigmentary maculopathy noted in the setting of chronic exposure to pentosan polysulfate sodium (PPS), a therapy for interstitial cystitis (IC). DESIGN: Retrospective case series. PARTICIPANTS: Six adult patients evaluated by a single clinician between May 1, 2015, and October 1, 2017. METHODS: Patients were identified by query of the electronic medical record system. Local records were reviewed, including results of the clinical examination, retinal imaging, and visual function assessment with static perimetry and electroretinography. Molecular testing assessed for known macular dystrophy and mitochondrial cytopathy genotypes. MAIN OUTCOME MEASURES: Mean best-corrected visual acuity (BCVA; in logarithm of the minimum angle of resolution units), median cumulative PPS exposure, subjective nature of the associated visual disturbance, qualitative examination and imaging features, and molecular testing results. RESULTS: The median age at presentation was 60 years (range, 37-62 years). All patients received PPS for a diagnosis of IC, with a median cumulative exposure of 2263 g (range, 1314-2774 g), over a median duration of exposure of 186 months (range, 144-240 months). Most patients (4 of 6) reported difficulty reading as the most bothersome symptom. Mean BCVA was 0.1±0.18 logarithm of the minimum angle of resolution. On fundus examination, nearly all eyes showed subtle paracentral hyperpigmentation at the level of the retinal pigment epithelium (RPE) with a surrounding array of vitelliform-like deposits. Four eyes of 2 patients showed paracentral RPE atrophy, and no eyes demonstrated choroidal neovascularization. Multimodal retinal imaging demonstrated abnormality of the RPE generally contained in a well-delineated area in the posterior pole. None of the 4 patients who underwent molecular testing of nuclear DNA returned a pathogenic mutation. Additionally, all 6 patients showed negative results for pathogenic variants in the mitochondrial gene MTTL1. CONCLUSIONS: We describe a novel and possibly avoidable maculopathy associated with chronic exposure to PPS. Patients reported symptoms of difficulty reading and prolonged dark adaptation despite generally intact visual acuity and subtle funduscopic findings. Multimodal imaging and functional studies are suggestive of a primary RPE injury. Additional investigation is warranted to explore causality further.

Geranylgeranylacetone Suppresses N-Methyl-N-nitrosourea-Induced Photoreceptor Cell Loss in Mice.

Retinitis pigmentosa is a disease characterized by the loss of photoreceptor cells. The N-methyl-N-nitrosourea (MNU)-induced retinal degeneration model is widely used to study the mechanism of these retinal degenerative disorders because of its selective photoreceptor cell death. As for the cell death mechanism of MNU, calcium-calpain activation and lipid peroxidation processes are involved in the initiation of this cell death. Although such molecular mechanisms of the MNU-induced cell death have been described, the total image of the cell death is still obscure. Heat shock protein 70 (HSP70) has been shown to function as a chaperon molecule to protect cells against environmental and physiological stresses. In this study, we investigated the effect of geranylgeranylacetone (GGA), an accylic polyisoprenoid, on MNU-induced photoreceptor cell loss. HSP70 induction by GGA was effective against MNU-induced photoreceptor cell loss as a result of its ability to prevent HSP70 degradation. The data indicate that GGA may help to suppress the onset and progression of retinitis pigmentosa.

Phosphodiesterase inhibition induces retinal degeneration, oxidative stress and inflammation in cone-enriched cultures of porcine retina.

Inherited retinal degenerations affecting both rod and cone photoreceptors constitute one of the causes of incurable blindness in the developed world. Cyclic guanosine monophosphate (cGMP) is crucial in the phototransduction and, mutations in genes related to its metabolism are responsible for different retinal dystrophies. cGMP-degrading phosphodiesterase 6 (PDE6) mutations cause around 4-5% of the retinitis pigmentosa, a rare form of retinal degeneration. The aim of this study was to evaluate whether pharmacological PDE6 inhibition induced retinal degeneration in cone-enriched cultures of porcine retina similar to that found in murine models. PDE6 inhibition was induced in cone-enriched retinal explants from pigs by Zaprinast. PDE6 inhibition induced cGMP accumulation and triggered retinal degeneration, as determined by TUNEL assay. Western blot analysis and immunostaining indicated that degeneration was accompanied by caspase-3, calpain-2 activation and poly (ADP-ribose) accumulation. Oxidative stress markers, total antioxidant capacity, thiobarbituric acid reactive substances (TBARS) and nitric oxide measurements revealed the presence of oxidative damage. Elevated TNF-alpha and IL-6, as determined by enzyme immunoassay, were also found in cone-enriched retinal explants treated with Zaprinast. Our study suggests that this ex vivo model of retinal degeneration in porcine retina could be an alternative model for therapeutic research into the mechanisms of photoreceptor death in cone-related diseases, thus replacing or reducing animal experiments.

A novel KCNV2 mutation in a patient taking hydroxychloroquine associated with cone dystrophy with supernormal rod response.

BACKGROUND: Cone dystrophy with supernormal rod response (CDSRR) is a rare inherited retinal degeneration. A patient superimposed with medical conditions requiring use of hydroxychloroquine (HCQ) may obscure accurate diagnosis of CDSRR. Herein, we report a referral case for HCQ retinopathy screening. Comprehensive ophthalmic examinations, however, guided the diagnosis of CDSRR from a novel mutation in potassium voltage-gated channel modifier subfamily V member 2 (KCNV2) gene. MATERIALS AND METHODS: Comprehensive ophthalmic examinations were evaluated for two patients whose parents are first cousins. Direct sanger sequencing of KCNV2 was applied to confirm the mutation. RESULTS: A 38-year-old male proband was referred for HCQ retinopathy screening after taking HCQ for systemic lupus erythematosus (SLE). Fundus examination showed bull's eye pattern, and photoreceptor loss in the foveal region of both eyes was noted on spectral domain-optical coherence tomography (SD-OCT). The full-field electroretinography (ffERG) revealed a disproportionate increase in scotopic maximal response with implicit time delay, as well as universal cone dysfunction. Proband's 24-year-old sister had similar ffERG pattern in both eyes. Direct sanger sequencing of KCNV2 gene revealed a novel homozygous mutation c.280_281 insG (p.Ala94GlyfsTer278), confirming a diagnosis of CDSRR. CONCLUSIONS: We report a novel KCNV2 mutation in a consanguineous family. The unique ffERG features of CDSRR are pathognomonic and thus crucial in guiding clinicians toward genetic testing of the KCNV2 gene. Altogether, multimodal imaging, ffERG, and detailed history taking are important diagnostic tools for differentiating between acquired and inherited retinal disorders.

Photoreceptor rescue and toxicity induced by different calpain inhibitors.

Photoreceptor degeneration is the hallmark of a group of inherited blinding diseases collectively termed retinitis pigmentosa (RP); a major cause of blindness in humans. RP is at present untreatable and the underlying neurodegenerative mechanisms are largely unknown, even though the genetic causes are often established. The activation of calpain-type proteases may play an important role in cell death in various neuronal tissues, including the retina. We therefore tested the efficacy of two different calpain inhibitors in preventing cell death in the retinal degeneration (rd1) human homologous mouse model for RP. Pharmacological inhibition of calpain activity in rd1 organotypic retinal explants had ambiguous effects on photoreceptor viability. Calpain inhibitor XI had protective effects when applied for short periods of time (16 h) but demonstrated substantial levels of toxicity in both wild-type and rd1 retina when used over several days. In contrast, the highly specific calpain inhibitor calpastatin peptide reduced photoreceptor cell death in vitro after both short and prolonged exposure, an effect that was also evident after in vivo application via intravitreal injection. These findings highlight the importance of calpain activation for photoreceptor cell death but also for photoreceptor survival and propose the use of highly specific calpain inhibitors to prevent or delay RP.

Ganoderma spore lipid inhibits N-methyl-N-nitrosourea-induced retinal photoreceptor apoptosis in vivo.

The purpose of the present study was to investigate the effect of Ganoderma spores lipid (GSL) on Bax, Bcl-xl and Caspase-3 expression in damaged retina and to address the effect of GSL on photoreceptor cell lesions induced by N-methyl-N-nitrosourea (MNU). Thirty 50-day-old female Sprague-Dawley rats were divided randomly into five groups to detect the dose-response effect of GSL by electroretinogram (ERG) analysis. Four groups received different daily GSL doses (0.5, 1, 2 and 4 g/kg, respectively) and one control group received no treatment. Sixty rats were divided randomly into an untreated MNU model control group and the GSL treatment group. Retina tissue samples were obtained sequentially 0 h before and 1, 3, 7 and 10 d after MNU injection. Expressions of Bax, Bcl-xl and Caspase-3 were detected by RT-PCR and immunofluorescence assays, then photoreceptor cell apoptosis was confirmed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling (TUNEL) signals. GSL had a dose-response effect on retina ERG and reversed retinal photoreceptor damage induced by MNU. RT-PCR analysis demonstrated that transcription levels of Bax, Bcl-xl and Caspase-3 in MNU control group and GSL treatment group were all upregulated on 1 d (p < 0.01) and peaked on 3 d (p < 0.01) after MNU injection compared to before MNU injection. GSL treatment significantly decreased mRNA levels of Bax on 1, 3, 7 and 10 d vs. MNU group (all p < 0.01) and mRNA levels of Caspase-3 on 1, 3, 7 d (p < 0.01) and 10 d (p < 0.05) vs. MNU group. Bcl-xl was clearly upregulation on 1, 3, 7 and 10 d vs. MNU group (all p < 0.01). Expression ratios of Bax/Bcl-xl were raised after MNU injection on 1 and 3 d vs. 0 h before MNU (both p < 0.01), peaked on 3 d, then dropped after GSL treatment on 1, 3, 7 and 10 d vs. MNU group (all p < 0.01). Immunofluorescence assays showed GSL decreased Bax and Caspase-3 positive staining levels in retina and increased Bcl-xl level. TUNEL-positive cells were evoked only in the outer nuclear layer and peaked on 3 d in rats receiving MNU (p < 0.01 vs. 0 h before MNU). GSL administration decreased apoptosis levels significantly, and the apoptotic indexes (AIs) of the GSL group were lower than those of MNU group on 1 and 3 d (both p < 0.01). Taken together, these data suggest that GSL may regulate the expressions of Bax, Bcl-xl and Caspases-3, inhibiting MNU-induced rat photoreceptor cell apoptosis and protecting retinal function.

Interactions between canthaxanthin and lipid membranes--possible mechanisms of canthaxanthin toxicity.

Canthaxanthin (beta, beta-carotene 4, 4' dione) is used widely as a drug or as a food and cosmetic colorant, but it may have some undesirable effects on human health, mainly caused by the formation of crystals in the macula lutea membranes of the retina. This condition is called canthaxanthin retinopathy. It has been shown that this type of dysfunction of the eye is strongly connected with damage to the blood vessels around the place of crystal deposition. This paper is a review of the experimental data supporting the hypothesis that the interactions of canthaxanthin with the lipid membranes and the aggregation of this pigment may be the factors enhancing canthaxanthin toxicity towards the macula vascular system. All the results of the experiments that have been done on model systems such as monolayers of pure canthaxanthin and mixtures of canthaxanthin and lipids, oriented bilayers or liposomes indicate a very strong effect of canthaxanthin on the physical properties of lipid membranes, which may explain its toxic action, which leads to the further development of canthaxanthin retinopathy.

[Restraining effects of acupuncture on photoreceptor cell apoptosis in rats with retinitis pigmentosa induced by N-methyl-N-nitrosourea].

OBJECTIVE: To observe the effect of acupuncture on photoreceptor cell apoptosis in rats with retinitis pigmentosa induced by N-methyl-N-nitrosourea (MNU). METHODS: Fifty-day-old female SD rats were established into model of retinitis pigmentosa by once intraperitoneal injection of 50 mg/kg MNU, and randomly grouped to the acupuncture group and the model group for observing the cell apoptosis in rats and compared with that in normal rats at the corresponding time points. RESULTS: Acupuncture showed no effect on cell apoptosis at its peak of occurring, apoptotic phenomena still could be seen on days 5 and 7, but it was significantly less in the acupuncture group than in the model group (P < 0.01). Moreover, acupuncture showed a restraining effect on the up-regulation of caspase-3 activity. CONCLUSION: Acupuncture can restrain the MNU induced apoptosis of photoreceptor cells, the effect is correlated, to a certain degree, with the status of the apoptosis occurrence.

Presumed topiramate retinopathy: a case report.

BACKGROUND: We report a case of peripheral pigmentary retinopathy and visual field loss following topiramate use for uncontrolled seizures. Such side effects have not been well documented despite the increasing use of topiramate in the past 10 years. A thorough search of available English literature revealed only a small number of reports of topiramate-induced retinopathy or visual field defects in humans. One similar case has been described. We are concerned about the possible rare instances of this occurrence in future patients and hence would like to propose a presumed correlation. CASE PRESENTATION: A 48-year-old Chinese woman developed blurred vision after 9 months of topiramate use. Her visual acuity dropped from 1.2 to 0.7 in both eyes, with bilateral diffuse pigmentary retinopathy and a constricted visual field. Despite an improvement in visual acuity after cessation of the drug, the other clinical findings remained. The temporal relationship between the initiation of topiramate and the visual disturbance suggests that topiramate could be the cause of such signs and symptoms. CONCLUSION: Topiramate potentially causes pigmentary retinopathy and constricted visual field.

The bacterial toxin CNF1 as a tool to induce retinal degeneration reminiscent of retinitis pigmentosa.

Retinitis pigmentosa (RP) comprises a group of inherited pathologies characterized by progressive photoreceptor degeneration. In rodent models of RP, expression of defective genes and retinal degeneration usually manifest during the first weeks of postnatal life, making it difficult to distinguish consequences of primary genetic defects from abnormalities in retinal development. Moreover, mouse eyes are small and not always adequate to test pharmacological and surgical treatments. An inducible paradigm of retinal degeneration potentially extensible to large animals is therefore desirable. Starting from the serendipitous observation that intraocular injections of a Rho GTPase activator, the bacterial toxin Cytotoxic Necrotizing Factor 1 (CNF1), lead to retinal degeneration, we implemented an inducible model recapitulating most of the key features of Retinitis Pigmentosa. The model also unmasks an intrinsic vulnerability of photoreceptors to the mechanism of CNF1 action, indicating still unexplored molecular pathways potentially leading to the death of these cells in inherited forms of retinal degeneration.

[Protective effect of non-mitogenic haFGF on retinal injury induced by N-methyl-N-nitrosourea in Sprague-Dawley rats].

AIM: To study the effect of non-mitogenic human acidic fibroblast growth factor (nm-haFGF) on retinal injury induced by N-methyl-N-nitrosourea (MNU) in Sprague-Dawley rats and its mechanism. METHODS: Female rats of 50-days-old were injected with MNU (60 mg x kg(-1)) intraperitoneally, and three doses of nm-haFGF (1.25 microg, 2.5 microg and 5 microg in one eye of each rat) were injected, separately, into vitreous body of one eye of each rat twice a day at 0 and 12 h after MNU treatment. 24 h later, apoptotic index of photoreceptor cells was detected by TUNEL labeling and the expressions of Bcl-2 and Bax were analyzed by Western blotting. At the 7th day, retinal injury was evaluated based on retinal thickness. RESULTS: Compared with model group, apoptotic index of photoreceptor cells was significantly reduced in nm-haFGF groups at the dose of 1.25 microg and 2.5 microg in one eye of each rat at 24 h, and the total retinal thickness as well as the outer retinal thickness markedly increased 7 days after MNU, respectively. The expressions of Bcl-2 increased and that of Bax decreased adversely after being injected with different doses of nm-haFGF. CONCLUSION: nm-haFGF partially suppressed retinal injury induced by MNU in Sprague-Dawley rats. The mechanism could be related to up-regulation of Bcl-2 and down-regulation of Bax.

Light Induces Ultrastructural Changes in Rod Outer and Inner Segments, Including Autophagy, in a Transgenic Xenopus laevis P23H Rhodopsin Model of Retinitis Pigmentosa.

PURPOSE: We previously reported a transgenic Xenopus laevis model of retinitis pigmentosa in which tadpoles express the bovine form of P23H rhodopsin (bP23H) in rod photoreceptors. In this model, retinal degeneration was dependent on light exposure. Here, we investigated ultrastructural changes that occurred in the rod photoreceptors of these retinas when exposed to light. METHODS: Tadpoles expressing bP23H in rods were transferred from constant darkness to a 12-hour light:12-hour dark (12L:12D) regimen. For comparison, transgenic tadpoles expressing an inducible form of caspase 9 (iCasp9) were reared in a 12L:12D regimen, and retinal degeneration was induced by administration of the drug AP20187. Tadpoles were euthanized at various time points, and eyes were processed for confocal light and transmission electron microscopy. RESULTS: We observed defects in outer and inner segments of rods expressing bP23H that were aggravated by light exposure. Rod outer segments exhibited vesiculations throughout and were rapidly phagocytosed by the retinal pigment epithelium. In rod inner segments, we observed autophagic compartments adjacent to the endoplasmic reticulum and extensive vesiculation at later time points. These defects were not found in rods expressing iCasp9, which completely degenerated within 36 hours after drug administration. CONCLUSIONS: Our results indicate that ultrastructural defects in outer and inner segment membranes of bP23H expressing rods differ from those observed in drug-induced apoptosis. We suggest that light-induced retinal degeneration caused by P23H rhodopsin occurs via cell death with autophagy, which may represent an attempt to eliminate the mutant rhodopsin and/or damaged cellular compartments from the secretory pathway.

The temporal topography of the N-Methyl- N-nitrosourea induced photoreceptor degeneration in mouse retina.

Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases characterized by the progressive photoreceptors apoptosis. The N-Methyl- N-nitrosourea (MNU) is an alkylating toxicant which could induce photoreceptor apoptosis resembling that of the hereditary RP. However, the detailed process pattern of this degeneration remains poorly characterized. We systemically explored the topography of the photoreceptor degeneration in the MNU treated mouse, and related these spatial data with the time-dependent characteristics of retinal pathology. These temporal topographic data delineated sequential scenes of the progressive photoreceptor degeneration in the MNU treated retinas: focal photoreceptors showed different vulnerabilities to the MNU toxicity and displayed a distinctive spatial- and time-dependent progression. Moreover, the positional asymmetry between the retinal quadrants firstly provided instructive information about the unique toxicology properties of the MNU. Further mechanism study suggested that the up-regulation of Bax and Calpain-2, rather than the Caspase-3, should be responsible for the asymmetry in the MNU induced photoreceptor degeneration. Together with the comparative sensitivities to the neurotoxicity of MNU between two photoreceptor populations, these topographic data would facilitate the standardization of analytic parameters related to the MNU induced RP model, and enhance its application in the therapeutic explorations of human RP.

Ocular adverse effects of neuropsychiatric agents. Incidence and management.

Neuropsychiatric agents may adversely affect the eye in various ways. The more frequently encountered effects include corneal oedema and pigmentary changes in the lens and cornea which are induced by phenothiazine derivatives; thioridazine-induced retinopathy; tricyclic antidepressant-induced accommodation interference and glaucoma; and lithium carbonate-induced exophthalmos and papilloedema. Several adverse effects, such as corneal oedema, retinopathy and glaucoma, are vision-threatening, and patients often fail to describe their symptoms properly. A more precise understanding of these conditions is essential for prompt diagnosis and appropriate treatment.

Functional rescue of N-methyl-N-nitrosourea-induced retinopathy by nicotinamide in Sprague-Dawley rats.

PURPOSE: A single intraperitoneal injection of 60 mg/kg body weight of N-methyl-N-nitrosourea (MNU) into rats results in retinal degeneration over a 7-day period in all treated animals. The purpose of this study was to determine whether nicotinamide (NAM) can lead to a functional rescue of the MNU-induced retinopathy. METHODS: NAM, a water-soluble B-group vitamin (vitamin B( 3)), was administered immediately after MNU injection, and retinas were examined morphologically and functionally. RESULTS: Morphologically, 1000 mg/kg NAM completely suppressed and 50 mg/kg NAM partially suppressed the photoreceptor cell loss. Functionally, scotopic and photopic electroretinographic (ERG) recordings showed that both rod and cone photoreceptor cells were well protected from MNU damage by 1000 mg/kg NAM and partially protected by 50 mg/kg NAM. CONCLUSIONS: NAM can protect photoreceptor cells from MNU-induced retinopathy both structurally and functionally.

The role of Vldlr in intraretinal angiogenesis in mice.

PURPOSE. To identify and characterize the r26 mouse line, which displays depigmented patches in the retina, and to determine the causative gene mutation and study the underlying mechanism. METHODS. Fundus examination, fluorescein angiography, histology, and immunostaining were used to determine the retinal phenotypes. Genome-wide linkage analysis, DNA sequencing, and an allelic test were used to identify the causative gene mutation. Wild-type and mutant gene products were examined by Western blot and transient transfection. RESULTS. Homozygous r26/r26 mice displayed depigmented patches in the fundus that overlapped the hyperfluorescent spots in the angiogram. Histology showed overgrown retinal vessels in the subretinal space. Immunostaining verified the presence of endothelial cells in the photoreceptor layer. Chromosome mapping and DNA sequencing revealed a point mutation, c.2239C>T, in the very-low-density lipoprotein receptor (Vldlr) gene. An allelic test in Vldlr knockout (-/-) mice confirmed that r26/(-) mice display a phenotype similar to that of r26/r26 mice. The Vldlr protein was predominantly localized at the plasma membrane of transfected cells, whereas the truncated Vldlr was diffusely expressed in the cell cytosol. The r26 truncated Vldlr was undetectable in mutant retinas by Western blot. CONCLUSIONS. The r26 is a recessive mutant caused by a missense mutation in the Vldlr gene. This results in a truncated Vldlr protein that lacks the C-terminal 127 amino acid residues including the single transmembrane domain and fails to localize at the plasma membrane. Thus, the r26 is a loss-of-function Vldlr mutation. Vldlr on the cell surface probably mediates an antiangiogenic signal to prevent retinal endothelial cells from migrating into the photoreceptor cell layer.

Review: Animal models of N-Methyl-N-nitrosourea-induced mammary cancer and retinal degeneration with special emphasis on therapeutic trials.

N-Methyl-N-nitrosourea (MNU) is a direct-acting alkylating agent that interacts with DNA. Accumulation of mutations may enhance cancer risk in target organs or cause cell death in susceptible tissues or cells when excessive DNA damage is not repaired. MNU targets various organs in a variety of animal species. MNU-induced carcinogenesis can be used as organ-specific animal models for human cancer, and MNU has been most extensively utilized for the induction of mammary cancer in rats. MNU-induced rat mammary tumors possess many similarities to those of human breast cancer, and the model is utilized for screening cancer modulators. MNU-induced cell disruption is also seen in several organs and tissues, especially when MNU is applied before maturity. However, photoreceptor cells in adults are highly sensitive to MNU, which causes cell death due to apoptosis. MNU-induced photoreceptor apoptosis mimics human retinitis pigmentosa and can be used for studies of therapeutic intervention. In this review, the targets of MNU in various animal species are described, and special emphasis is given to therapeutic trials against MNU-induced mammary cancer and retinal degeneration in animal models.