title: Progressive retinal toxicity in neonatal rats treated with D,L-2-amino-3-phosphonopropionate (D,L-AP3).
abstract: D,L-2-amino-3-phosphonopropionate (D,L-AP3) has complex pharmacologic activity at central nervous system metabotropic glutamate receptors important in excitatory neurotransmission and development. Previous studies have described retinal and optic nerve atrophy in adult rats after postnatal treatment with D,L-AP3. Using neonatal male Sprague-Dawley rats, the present studies examined normal postnatal retinal development (n = 20) and the progression of retinal toxicity induced by D,L-AP3 (n = 30). Retinal development was examined by light microscopy on postnatal days (PNDs) 5, 9, 12, 16, and 22. Between PNDs 5 and 16, the retina underwent considerable postnatal differentiation. A prominent neuroblastic layer evident on PND 5 differentiated into outer retinal layers by PND 16. To examine the effects of D,L-AP3, neonatal rats were treated intraperitoneally with sterile water or 400 mg/kg/day D,L-AP3 on PNDs 3-6. On PNDs 5, 7, 10, 15, and 20, retinas were examined by light and electron microscopy. On PNDs 5 and 7, cells with swollen, pale cytoplasm were evident in the more differentiated inner nuclear layer and in the middle of the developing neuroblastic layer. Retinal toxicity rapidly progressed after treatment, because developing outer retinal layers had cytoplasmic swelling, nuclear pyknosis, and necrosis on PND 10. By PNDs 15 and 20, retinal dystrophy was severe and involved primarily outer layers. This study showed that early postnatal treatment with D,L-AP3 initiates rapidly progressing retinal toxicity, thus implicating metabotropic glutamate receptors in the postnatal retinal development of rats.
authors.affiliation: Toxicology Research Laboratories, Lilly Research Laboratories, Eli Lilly and Company, Greenfield, IN, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Fix
authors.forename: J W
authors.initials: JW
authors.lastname: Horn
authors.forename: R L
authors.initials: RL
authors.lastname: Hall
authors.forename: J A
authors.initials: JA
authors.lastname: Johnson
authors.forename: J P
authors.initials: JP
authors.lastname: Tizzano
mesh_terms: D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D003593:Cytoplasm / Q000473:pathology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D008297:Male; D008854:Microscopy, Electron; D009336:Necrosis / Q000139:chemically induced; D009412:Nerve Fibers / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000502:physiology; D012160:Retina / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D013237:Stereoisomerism; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; C000211:2-amino-3-phosphonopropionic acid; D000409:Alanine