Maki Kuro

N -ethyl- N -nitrosourea induces retinal photoreceptor damage in adult rats.

Seven-week-old male Lewis rats received a single intraperitoneal injection of N-ethyl-N-nitrosourea (ENU) (100, 200, 400 or 600 mg/kg), and retinal damage was evaluated 7 days after the treatment. Sequential morphological features of the retina and retinal DNA damage, as determined by a TUNEL assay and phospho-histone H2A.X (γ-H2AX), were analyzed 3, 6, 12, 24 and 72 hr, 7 days, and/or 30 days after 400 mg/kg ENU treatment. Activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP) was analyzed immunohistochemically by poly (ADP-ribose) (PAR) expression in response to DNA damage of the retina. All rats that received ≥ 400 mg/kg of ENU developed retinal degeneration characterized by the loss of photoreceptor cells in both the central and peripheral retina within 7 days. In the 400 mg/kg ENU-treated rats, TUNEL-positive signals were only located in the photoreceptor cells and peaked 24 hr after ENU treatment. The γ-H2AX signals in inner retinal cells appeared at 24 hr and peaked at 72 hr after ENU treatment, and the PAR signals selectively located in the photoreceptor cell nuclei appeared at 12 hr and peaked at 24 hr after ENU treatment. However, degeneration was restricted to photoreceptor cells, and no degenerative changes in inner retinal cells were seen at any time points. Retinal thickness and the photoreceptor cell ratio in the central and peripheral retina were significantly decreased, and the retinal damage ratio was significantly increased 7 days after ENU treatment. In conclusion, ENU induced retinal degeneration in adult rats that was characterized by photoreceptor cell apoptosis through PARP activity.

Arachidonic acid supplementation during gestational, lactational and post-weaning periods prevents retinal degeneration induced in a rodent model

Fatty acids and their derivatives play a role in the response to retinal injury. The effects of dietary arachidonic acid (AA) supplementation on N-methyl-N-nitrosourea (MNU)-induced retinal degeneration was investigated in young Lewis rats during the gestational, lactational and post-weaning periods. Dams were fed 0·1, 0·5 or 2·0% AA diets or a basal (< 0·01% AA) diet. On postnatal day 21 (at weaning), male pups received a single intraperitoneal injection of 50 mg MNU/kg or vehicle, and were fed the same diet as their mother for 7 d. Retinal apoptosis was analysed by the terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick-end labelling (TUNEL) assay 24 h after the MNU treatment, and retinal morphology was examined 7 d post-MNU. Histologically, all rats that received MNU and were fed the basal and 0·1% AA diets developed retinal degeneration characterised by the loss of photoreceptor cells (disappearance of the outer nuclear layer and the photoreceptor layer) in the central retina. The 0·5 and 2·0% AA diets rescued rats from retinal damage. Morphometrically, in parallel with the AA dose (0·5 and 2·0% AA), the photoreceptor ratio significantly increased and the retinal damage ratio decreased in the central retina, compared with the corresponding ratios in basal diet-fed rats. In parallel with the increase in serum and retinal AA levels and the AA:DHA ratio, the apoptotic index in the central retina was dose-dependently decreased in rats fed the 0·5 and 2·0% AA diets. In conclusion, an AA-rich diet during the gestation, lactation and post-weaning periods rescued young Lewis rats from MNU-induced retinal degeneration via the inhibition of photoreceptor apoptosis. Therefore, an AA-enriched diet in the prenatal and postnatal periods may be an important strategy to suppress the degree of photoreceptor injury in humans.

N -Methyl- N -Nitrosourea Animal Models for Retinitis Pigmentosa

Abstract Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases in humans characterized by the loss of photoreceptor cells leading to a reduction of the peripheral visual field (known as tunnel vision) and eventually to blindness. N -Methyl- N -nitrosourea (MNU) is an alkylating agent that exhibits its toxicity by transferring its methyl group to nucleobases in nucleic acids. A single systemic administration of MNU causes retinal degeneration in various animal species. The retinal degeneration is highly reproducible, and the photoreceptor cell loss occurs within a week when a suitable dose of MNU is administered. Photoreceptor cell loss occurs via apoptosis, which resembles human RP. Decreased levels of basal autophagy concomitantly occur during the course of apoptosis progression. The time-course progression of the disease, the molecular mechanisms of the disease, and the therapeutic trials against MNU-induced photoreceptor cell apoptosis are described.

Chapter 5 – N-Methyl-N-Nitrosourea Animal Models for Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases in humans characterized by the loss of photoreceptor cells leading to a reduction of the peripheral visual field (known as tunnel vision) and eventually to blindness. N-Methyl-N-nitrosourea (MNU) is an alkylating agent that exhibits its toxicity by transferring its methyl group to nucleobases in nucleic acids. A single systemic administration of MNU causes retinal degeneration in various animal species. The retinal degeneration is highly reproducible, and the photoreceptor cell loss occurs within a week when a suitable dose of MNU is administered. Photoreceptor cell loss occurs via apoptosis, which resembles human RP. Decreased levels of basal autophagy concomitantly occur during the course of apoptosis progression. The time-course progression of the disease, the molecular mechanisms of the disease, and the therapeutic trials against MNU-induced photoreceptor cell apoptosis are described.

Case of Primary Intraocular Lymphoma with Extraocular Extension

Purpose: To describe a case of primary intraocular lymphoma (PIOL) with an extension through the sclera that was confirmed to be part of the PIOL by histopathological examinations. Case: An 89-year-old woman was referred to a local clinic with a 1-year history of persistent blurred vision in her left eye. After 2 years without aggressive treatments, she had a marked reduction of vision and pain in her left eye. The clinical diagnosis was panophthalmitis, and the eye was enucleated and submitted for histopathological study. Results: Light microscope examination showed that atypical lymphocytic cells had infiltrated into both the intraocular and extraocular areas. The anterior chamber angle was blocked by infiltrating tumor cells, which were also detected around the optic nerve. The tumor cells destroyed Bruchs membrane and infiltrated around the perineural and perivascular areas within the sclera. Immunohistochemistry showed that the tumor cells were positive for B-lymphocyte surface antigen (CD20), B-cell antigen receptor complex-associated protein alpha chain (CD79-alpha), and had a high positive rate for anti-Ki-67 antibody. Conclusion: The finding in our case indicates that early diagnosis and treatment are important for eyes with PIOL because the tumor can spread and penetrate the sclera and invade extraocular tissues.