Biochemical, Metabolic, and Behavioral Characteristics of Immature Chronic Hyperphenylalanemic Rats

Abstract

Phenylketonuria and hyperphenylalanemia are inborn errors in metabolism of phenylalanine arising from defects in steps to convert phenylalanine to tyrosine. Phe accumulation causes severe mental retardation that can be prevented by timely identification of affected individuals and their placement on a Phe-restricted diet. In spite of many studies in patients and animal models, the basis for acquisition of mental retardation during the critical period of brain development is not adequately understood. All animal models for human disease have advantages and limitations, and characteristics common to different models are most likely to correspond to the disorder. This study established similar levels of Phe exposure in developing rats between 3 and 16 days of age using three models to produce chronic hyperphenylalanemia, and identified changes in brain amino acid levels common to all models that persist for ~16h of each day. In a representative model, local rates of glucose utilization (CMRglc) were determined at 25–27 days of age, and only selective changes that appeared to depend on Phe exposure were observed. CMRglc was reduced in frontal cortex and thalamus and increased in hippocampus and globus pallidus. Behavioral testing to evaluate neuromuscular competence revealed poor performance in chronically-hyperphenylalanemic rats that persisted for at least three weeks after cessation of Phe injections and did not occur with mild or acute hyperphenylalanemia. Thus, the abnormal amino acid environment, including hyperglycinemia, in developing rat brain is associated with selective regional changes in glucose utilization and behavioral abnormalities that are not readily reversed after they are acquired.

A Retrospective Case Series Analysis of the Relationship Between Phenylalanine: Tyrosine Ratio and Cerebral Glucose Metabolism in Classical Phenylketonuria and Hyperphenylalaninemia

“…In the largest study to date, Wasserstein et al reported that plasma phenylalanine was negatively correlated with relative cerebral glucose metabolic rates, as measured via [ 18 F]fluorodeoxyglucose positron emission tomography (PET), in ten patients with classical PKU who performed a verbal learning task during the tracer uptake period. The PKU group also had lower cortical relative glucose metabolic rate than the control group, a finding that was consistent with smaller clinical (Yanai et al, 1987;Hasselbalch et al, 1996;Ficicioglu et al, 2013) and animal studies (Qin and Smith, 2007;Dienel and Cruz, 2016).…”

cAMP/PKA-CREB-BDNF signaling pathway in hippocampus of rats subjected to chemically-induced phenylketonuria

“…This finding verifies that our experimental PKU model is valid and was effective in PKU formation. There are animal models of PKU using Phe and p-Cl-Phe in the literature, and studies are related to oxidative stress (Bortoluzzi et al 2019), brain energy metabolism (Dimer et al 2018), and metabolic changes (Dienel and Cruz 2016). No studies of the BDNF-CREB pathway have been reported previously.…”

Thiol/Disulfide Balance in Induced Phenylketonuria Model

“…To establish a PKU model [15][16][17], daily injection of phenylalanine (Phe) (5.2 mmol/g body weight) was used, while the phenylalanine hydroxylase inhibitor, p-chlorophenylalanine (p-Cl-Phe) (0.9 mmol /g body weight) was administered every other day (PKU group). Saline solution (saline) was administered to the control group.…”