Nicotinamide Prevents N-Methyl-N-nitrosourea Induced Photoreceptor Cell Apoptosis in Rats and Mice

Abstract

Abstract: : Purpose: A single systemic administration of N-methyl-N-nitrosourea (MNU) to rats and mice results retinal degeneration in all treated animals over a 7-day period. Retinal degeneration was due to photoreceptor cell apoptosis that was identical to human retinitis pigmentosa. In this study, the effect of nicotinamide (NAM), a water-soluble B-group vitamin (vitamin B₃), was examined in this MNU model. Method: MNU dissolved in physiological saline containing 0.05% acetic acid (Rats, 60 mg/kg; Mice, 50 mg/kg) or vehicle (physiological saline containing 0.05% acetic acid) was administered once by an intraperitoneal route. NAM was dissolved in physiological saline and injected subcutaneously at a dose of 0 to 1000 mg/kg, 0 to 12 hrs after MNU administration, and animals were sacrificed 7days after MNU injection and compared with age-matched controls. Some rats were observed for 35-day period. Retinas of animals were examined histologically, immunohistochemically, and by TUNEL method. Results: In rats, a dose of NAM ≷25 mg/kg completely suppressed photoreceptor cell loss when administered simultaneously with MNU. While in mice, doses of 1000 mg/kg and ≷100 mg/kg were needed for complete and partial suppression, respectively; rats were more responsive to NAM than mice. The retinoprotective effect of 1000 mg/kg NAM lasted throughout the 35-day observation period, with no apparent toxicity. In rats, 1000 mg/kg NAM completely suppressed photoreceptor cell loss when administered up to 4 hrs after MNU treatment, and partially suppressed photoreceptor cell loss when administered 6 hrs after MNU treatment. In mice, administration of NAM 2 to 6 hrs after MNU resulted in partial suppression. NAM did not reduce levels of 7-methyldeoxyguanosine DNA adduct as detected immunohistochemically, but did reduce photoreceptor cell apoptosis as evaluated by TUNEL method. Conclusion: NAM may be a potential therapeutic agent for the treatment of retinal degeneration.

Keywords: 323 apoptosis/cell death • 506 pathology: experimental • 517 photoreceptors