Effects of phenylalanine on the survival and neurite outgrowth of rat cortical neurons in primary cultures: possible involvement of brain-derived neurotrophic factor

Phenylketonuria (PKU) is characterized by elevated levels of phenylalanine (Phe) in plasma and cerebrospinal fluid of PKU patients, leading to mental retardation. The developmental delay in the cerebral cortex is one of the characteristic pathologic changes in untreated phenylketonuria patients. This is thought to be due to the toxic effects of Phe and/or its metabolites; however, the underlying mechanisms are as yet unknown. In this study, using a model system in which cultured cortical neurons were induced with Phe, we observed that Phe inhibited the longest neurite outgrowth and induced the neuronal death. We further demonstrated that the expression of BDNF mRNA and protein was significantly decreased by Phe, together with a decrease in extracellular signal-regulated kinase (ERK) and Akt phosphorylation activity. There was no change in expression of TrkB mRNA and protein. Considering the important role of BDNF in normal brain development and function, these l-Phe-induced changes in BDNF in PKU brain may be a critical element of the neurological symptoms of PKU.