Ammonium alters creatine transport and synthesis in a 3D culture of developing brain cells, resulting in secondary cerebral creatine deficiency.

Hyperammonemic disorders in pediatric patients lead to poorly understood irreversible effects on the developing brain that may be life-threatening. We showed previously that some of these NH4+-induced irreversible effects might be due to impairment of axonal growth that can be protected under ammonium exposure by creatine co-treatment. The aim of the present work was thus to analyse how the genes of arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), allowing creatine synthesis, as well as of the creatine transporter SLC6A8, allowing creatine uptake into cells, are regulated in rat brain cells under NH4+ exposure. Reaggregated brain cell three-dimensional cultures exposed to NH4Cl were used as an experimental model of hyperammonemia in the developing central nervous system (CNS). We show here that NH4+ exposure differentially alters AGAT, GAMT and SLC6A8 regulation, in terms of both gene expression and protein activity, in a cell type-specific manner. In particular, we demonstrate that NH4+ exposure decreases both creatine and its synthesis intermediate, guanidinoacetate, in brain cells, probably through the inhibition of AGAT enzymatic activity. Our work also suggests that oligodendrocytes are major actors in the brain in terms of creatine synthesis, trafficking and uptake, which might be affected by hyperammonemia. Finally, we show that NH4+ exposure induces SLC6A8 in astrocytes. This suggests that hyperammonemia increases blood-brain barrier permeability for creatine. This is normally limited due to the absence of SLC6A8 from the astrocyte feet lining microcapillary endothelial cells, and thus creatine supplementation may protect the developing CNS of hyperammonemic patients.

Tasavallan Presidentin tervehdyssanat Euroopan turvallisuus- ja yhteistyökonferenssin avajaisissa Helsingissä 3.7.1973 = speech of welcome by the President of the Republic, Dr. Urho Kekkonen, at the inaugural session of CSCE in Helsinki, July 3rd, 1973

Puhe

Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence

Schizophrenia is a complex multifactorial brain disorder with a genetic component. Convergent evidence has implicated oxidative stress and glutathione (GSH) deficits in the pathogenesis of this disease. The aim of the present study was to test whether schizophrenia is associated with a deficit of GSH synthesis. Cultured skin fibroblasts from schizophrenia patients and control subjects were challenged with oxidative stress, and parameters of the rate-limiting enzyme for the GSH synthesis, the glutamate cysteine ligase (GCL), were measured. Stressed cells of patients had a 26% (P = 0.002) decreased GCL activity as compared with controls. This reduction correlated with a 29% (P < 0.001) decreased protein expression of the catalytic GCL subunit (GCLC). Genetic analysis of a trinucleotide repeat (TNR) polymorphism in the GCLC gene showed a significant association with schizophrenia in two independent case-control studies. The most common TNR genotype 7/7 was more frequent in controls [odds ratio (OR) = 0.6, P = 0.003], whereas the rarest TNR genotype 8/8 was three times more frequent in patients (OR = 3.0, P = 0.007). Moreover, subjects with disease-associated genotypes had lower GCLC protein expression (P = 0.017), GCL activity (P = 0.037), and GSH contents (P = 0.004) than subjects with genotypes that were more frequent in controls. Taken together, the study provides genetic and functional evidence that an impaired capacity to synthesize GSH under conditions of oxidative stress is a vulnerability factor for schizophrenia.

Speech prognosis and need of pharyngeal flap for non syndromic vs syndromic Pierre Robin Sequence

BACKGROUND: The aim of this retrospective study was to evaluate speech outcome and need of a pharyngeal flap in children born with nonsyndromic Pierre Robin Sequence (nsPRS) vs syndromic Pierre Robin Sequence (sPRS). METHODS: Pierre Robin Sequence was diagnosed when the triad microretrognathia, glossoptosis, and cleft palate were present. Children were classified at birth in 3 categories depending on respiratory and feeding problems. The Borel-Maisonny classification was used to score the velopharyngeal insufficiency. RESULTS: The study was based on 38 children followed from 1985 to 2006. For the 25 nsPRS, 9 (36%) pharyngeal flaps were performed with improvements of the phonatory score in the 3 categories. For the 13 sPRS, 3 (23%) pharyngeal flaps were performed with an improvement of the phonatory scores in the 3 children. There was no statistical difference between the nsPRS and sPRS groups (P = .3) even if we compared the children in the 3 categories (P = .2). CONCLUSIONS: Children born with nsPRS did not have a better prognosis of speech outcome than children born with sPRS. Respiratory and feeding problems at birth did not seem to be correlated with speech outcome. This is important when informing parents on the prognosis of long-term therapy