[Characteristics of N-methyl-N-nitrosourea-induced retinal degeneration in animals and application for the therapy of human retinitis pigmentosa].

Abstract

BACKGROUND:

Retinitis pigmentosa(RP) is a human disease characterized by loss of photoreceptor cells, especially rods, leading to visual disturbance and eventually to blindness. Effective treatment for RP control is still unavailable. The establishment of reliable animal models is essential for a better understanding of this disease, and for the development of therapeutic intervention. Here we summarize the establishment of N-methyl-N-nitrosourea (MNU)-induced retinal degeneration in animals, and success in disease control using this model.

RESULTS:

Retinal damage induced by MNU was highly reproducible and involved photoreceptor cell loss. It was obvious in all animals at approximately 7 days following a single systemic administration of MNU to adult mice (60 mg/kg), rats (60-75 mg/kg), hamsters (90 mg/kg), shrews (65 mg/kg), and monkeys (40 mg/kg). Extensive investigation in the rats revealed that MNU-induced photoreceptor cell loss was due to apoptosis with a decrease of Bcl-2 protein, increase of Bax protein, and activation of caspase families. Therapeutic to control MNU-induced photoreceptor cell loss in rats was evaluated with caspase-3 inhibitor (Ac-DEVD-CHO), nicotinamide(NAM), and docosahexaenoic acid(DHA); 4,000ng Ac-DEVD-CHO injected intravitreally 0 and 10 h after MNU suppressed disease progression, 25-1,000 mg/kg NAM subcutaneously injected concurrently or subsequently to MNU reversed retinal damage, and dietary supplementation of 9.5% DHA counteracted photoreceptor cell loss.

CONCLUSION:

Although the mechanisms triggering pathogenesis and the apoptotic cascade may differ between animals and humans, MNU-induced retinal degeneration is caused by photoreceptor cell apoptosis. Thus, suppression of MNU-induced photoreceptor cell apoptosis in animals may provide therapeutic information for RP control in humans.

• Authors: Katsuhiko Yoshizawa, Airo Tsubura
• Journal: Nippon Ganka Gakkai zasshi (Nippon Ganka Gakkai Zasshi) Vol. 109 Issue 6 Pg. 327-37 (Jun 2005) ISSN: 0029-0203 [Print] Japan
• PMID: 16047940 (Publication Type: English Abstract, Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• BAX protein, human
• Bax protein, mouse
• Bax protein, rat
• Oligopeptides
• Proto-Oncogene Proteins c-bcl-2
• acetyl-aspartyl-glutamyl-valyl-aspartal
• bcl-2-Associated X Protein
• Docosahexaenoic Acids
• Niacinamide
• Methylnitrosourea
• Caspases

Topics

• Animals
• Apoptosis (genetics)
• Caspases (metabolism)
• Cricetinae
• Disease Models, Animal
• Docosahexaenoic Acids (administration & dosage)
• Humans
• Methylnitrosourea
• Mice
• Niacinamide (administration & dosage)
• Oligopeptides (administration & dosage)
• Photoreceptor Cells (cytology, pathology)
• Proto-Oncogene Proteins c-bcl-2
• Rats
• Retinal Degeneration (chemically induced)
• Retinitis Pigmentosa (etiology, therapy)
• bcl-2-Associated X Protein