Increase of Tryptophan and 5-Hydroxyindole Acetic Acid in the Brain of Ornithine Carbamoyltransferase Deficient Sparse-Fur Mice

Abstract

Summaryeated in that complex model (1 1). For this reason we used a Sparse-fur mice, 28 d of age with the x-chromosomal inherited defect of ornithine carbamoyltransferase, were used to investigate if tryptophan and the serotonin pathway in the brain are affected in this animal model which closely resembles the human inborn error of metabolism. Increased concentrations of tryptophan and 5-hydroxyindole acetic acid were found in forebrain and brainstem. Application of probenecid, which blocks the efflux of 5-hydroxyindole acetic acid from the brain, led to an augmented accumulation of this serotonin metabolite in the affected males. We conclude that the increased concentration of tryptophan in brain and the subsequent increased flux through the serotonin pathway are a consequence of hyperammone@a in this inherited defect of urea synthesis. Surprisingly, increased carbamoylphosphate synthetase was found in the liver of the male sparse-fur mice. Abbreviations CPS, carbamoylphosphate synthetase HIAA, 5-hydroxyindole acetic acid HT, 5-hydroxytryptamine NAGS, N-acetylglutamate synthetase OCT, ornithine carbamoyltransferase spf, sparse-fur TRP, tryptophan Sparse-fur (spf) mice have a x-chromosomal inherited defect of OCT (E C 2.3.3.1 1). In affected males this leads to hyperammonemia (10, 17) as in the human variant of OCT deficiency, an inborn error of metabolism which presents with neurologic symptoms (1, 23). These are presumably mediated by changes of neurotransmitters in brain. We chose to investigate metabolites of the serotonin pathway in spf mice, because TRP and HIAA were increased in two animal models where hyperammonemia is present. Studies with rats subjected to portacaval shunting have repeatedly led to the conclusion that chronic liver insufficiency (with hyperammonemia) increases the brain concentration of TRP, the precursor of serotonin (HT), and of HIAA, the main metabolite of HT (1 1). Because of the multiple metabolic changes encountered in portacaval anastomosis, the particular role of hyperammonemia has not been clearly delinsimpler set-up and injected rats with urease. We found that the transport of TRP into the brain was enhanced and that the concentrations of TRP and HIAA in forebrain and brainstem were higher than in pair-fed controls (3).The following investigations were performed to find out if an inherited defect of an urea cycle enzyme leads to comparable changes in the serotonin pathway. We examined if, in the spf mouse model, the affected males (spf/Y) had increased concentrations of TRP, HT, and HIAA in brain as compared with their unaffected littermates (+/Y). In order to detect if the flux through the serotonin pathway is altered in spf mice, the indole metabolites were determined also after injection of probenecid, an inhibitor of HIAA transport out of the brain. MATERIALS AND METHODSSpf-females (spf/+) from the Oak Ridge National Laboratory (Oak Ridge, TN) were mated with C57BL*BALBc males (Jackson Lab, Bar Harbour, ME). The offspings were used for the experiments. These were camed ou...

Quinolinate in Brain and Cerebrospinal Fluid in Rat Models of Congenital Hyperammonemia

“…We have documented 2-to 10-fold increases of QUIN in CSF of comatose children and 2-to 4-fold increases of QUIN in CSF of clinically stable children with congenital hyperammonemia (1 1). Previous studies have also documented increased levels of the serotonin metabolite, 5-HIAA, in CSF and/or brain of children with congenital hyperammonemia, adults with hepatic encephalopathy, and animal models of these diseases (7,8,(22)(23)(24). Some studies (9,10) suggest that augmented transport of Trp into the CNS leads to this increase in serotonin turnover (Fig.…”

Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis

“…In the present experiments the brain concentrations of ammonia were high enough to inhibit the Cl-pump and, at least in principle, cause neurons to become more easily excited (Raabe, 1982 (Raabe, 1989b It is well established that hyperammonaemia, whether caused by portacaval shunting or by artificial means, leads to a much greater activity of the carrier system that transports neutral amino acids across the blood-brain barrier, as well as to a rise in the brain content of aromatic amino acids (James et al, 1976(James et al, , 1978Mans et al, 1979Mans et al, , 1982Mans et al, , 1983aMans et al, , 1984Bachmann & Colombo, 1984;Jonung et al, 1984;Jeppsson et al, 1985;Bachmann et al, 1986;Jessy et al, 1990). The permeability of the blood-brain barrier to neutral amino acids and the accumulation of aromatic amino acids are both closely correlated with brain glutamine content (Jeppsson et al, 1985;Jessy et al, 1990).…”

Ammonia toxicity to the brain and creatine

“…The increase of tryptophan leads to an increased synthesis and release of serotonine and thus might induce anorexia [11,12]; this symptom often found in UCD patients renders them prone to chronic catabolism and malnutrition and thus to increased ammonia load resulting in a vicious cycle.…”