Biochemical and neurological effects of an experimental phenylketonuria-like condition in infant rats during the first 2 weeks after birth

An experimental phenylketonuria (PKU)-like rat model developed in this laboratory should be useful to determine the mechanism of brain damage in PKU. Using this procedure the primary biochemical characteristic of PKU, i.e., elevated levels of plasma phenylalanine relative to tyrosine with ratios of phenylalanine to tyrosine ranging from 4.7 at 6 days to 12.6 at 14 days, has been induced in rats during the first 2 wk postnatally. This has been accomplished by stomach intubation of l-phenylalanine along with low doses of phenylalanine hydroxylase inhibitors, amethopterin and p-chlorophenylalanine. Use of low doses of inhibitors minimizes their toxicity and the inhibitory effect of amethopterin on neurotransmitter synthesis. The effect of the PKU-like condition on brain cellular development was measured by both biochemical and histological means. Treatment with phenylalanine and inhibitors produces progressive elevations of plasma phenylalanine/tyrosine ratios at 6, 10 and 14 days after birth with values ranging up to 12.6, well above the normal value of one. Brain weights negatively correlate with phenylalanine/tyrosine ratios and are lowest in the 14-day-old experimental PKU-like rats. The same is true of the reduced levels of DNA, RNA, and protein which are found in brain at 6, 10, and 14 days after birth while protein/ DNA ratios remain constant, indicating the PKU-like condition adversely affects cell number but not cell size. Microscopic examination of the cerebellum confirms biochemical findings in that fewer cells are present in the proliferative zone and a greater reduction and/or delayed myelination occurs in the experimental PKU-like rats than in any of the control animals of the same age.