Impaired cognitive performance in ornithine transcarbamylase-deficient mice on arginine-free diet

D’Hooge, Rudi; Marescau, B.; Qureshi, Ijaz A.; Deyn, Peter Paul De

doi:10.1016/s0006-8993(00)02589-0

Cited by 13 publications

(7 citation statements)

References 19 publications

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“…When eating an arginine-free diet susceptible animals became hyperammonemic. An arginine-free diet had been used to cause HA in other mammals (Stewart et al, 1981), and it was previously used by D'Hooge et al (2000) to render spf mice hyperammonemic. We observed a severe clinical effect of the arginine-free diet within 24 hr (mice sitting stiff and still in their cage) in weaned 25-day-old affected mice (carrying or not carrying the EGFP trans-gene) after weaning.…”

Section: Induction Of Hamentioning

confidence: 99%

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

Lichter‐Konecki

Mangin

Gordish‐Dressman

et al. 2008

Glia

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Acute hyperammonemia (HA) causes cerebral edema and brain damage in children with urea cycle disorders (UCDs) and in patients in acute liver failure. Chronic HA is associated with developmental delay and mental retardation in children with UCDs, and with neuropsychiatric symptoms in patients with chronic liver failure. Astrocytes are a major cellular target of hyperammonemic encephalopathy, and changes occurring in these cells are thought to be causally related to the brain edema of acute HA. To study the effect of HA on astrocytes in vivo, we crossed the Otc spf mouse, a mouse with the X-linked UCD ornithine transcarbamylase (OTC) deficiency, with the hGFAP-EGFP mouse, a mouse selectively expressing green fluorescent protein in astrocytes. We used FACS to purify astrocytes from the brains of hyperammonemic and healthy Otc spf /GFAP-EGFP mice. RNA isolated from these astrocytes was used in microarray expression analyses and qRT-PCR. When compared with healthy littermates, we observed a significant downregulation of the gap-junction channel connexin 43 (Cx43) the water channel aquaporin 4 (Aqp4) genes, and the astrocytic inward-rectifying potassium channel (Kir) genes Kir4.1 and Kir5.1 in hyperammonemic mice. Aqp4, Cx43, and Kir4.1/ Kir5.1 are co-localized to astrocytic end-feet at the brain vasculature, where they regulate potassium and water transport.Since, ions can permeate water and K + -channels, downregulation of these three channels may be a direct effect of elevated blood ammonia levels. Our results suggest that alterations in astrocyte-mediated water and potassium homeostasis in brain may be key to the development of the brain edema.

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Section: Induction Of Hamentioning

confidence: 99%

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

Lichter‐Konecki

Mangin

Gordish‐Dressman

et al. 2008

Glia

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“…[6][7][8][9] Animal models used in studying hyperammonemic disorders are multiple: fulminant hepatic failure, 10 chronic liver failure, 11 or urea cycle deficiency. 12 Ammonia is produced by many tissues but its major external source results from deaminase and urease activities of the gut flora. Although its absorption occurs through the intestinal epithelium, ammonia is carried by the portal vein into the liver where it is metabolized into urea.…”

mentioning

confidence: 99%

“…In this study, ammonia absorption was modulated in the gut by the administration of a wild-type strain of L. plantarum, NCIMB8826, and a genetically engineered ammonia hyperconsuming L. plantarum strain, able to efficiently convert ammonia to alanine in three rodent models of hyperammonemia. [10][11][12] An L. plantarum strain deficient for the ammonium transporter was also constructed in order to evaluate its implication in ammonia metabolism and consumption.…”

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confidence: 99%

Control of acute, chronic, and constitutive hyperammonemia by wild-type and genetically engineered Lactobacillus plantarum in rodents

et al. 2008

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Hyperammonemia is a common complication of acute and chronic liver diseases. Often accompanied with side effects, therapeutic interventions such as antibiotics or lactulose are generally targeted to decrease the intestinal production and absorption of ammonia. In this study, we aimed to modulate hyperammonemia in three rodent models by administration of wild-type Lactobacillus plantarum, a genetically engineered ammonia hyperconsuming strain, and a strain deficient for the ammonia transporter. Wild-type and metabolically engineered L. plantarum strains were administered in ornithine transcarbamoylase-deficient Sparse-fur mice, a model of constitutive hyperammonemia, in a carbon tetrachloride rat model of chronic liver insufficiency and in a thioacetamide-induced acute liver failure mice model. Constitutive hyperammonemia in Sparse-fur mice and hyperammonemia in a rat model of chronic hepatic insufficiency were efficiently decreased by Lactobacillus administration. In a murine thioacetamide-induced model of acute liver failure, administration of probiotics significantly increased survival and decreased blood and fecal ammonia. The ammonia hyperconsuming strain exhibited a beneficial effect at a lower dose than its wild-type counterpart. Improved survival in the acute liver failure mice model was associated with lower blood ammonia levels but also with a decrease of astrocyte swelling in the brain cortex. Modulation of ammonia was abolished after administration of the strain deficient in the ammonium transporter. Intestinal pH was clearly lowered for all strains and no changes in gut flora were observed. Conclusion: Hyperammonemia in constitutive model or after acute or chronic induced liver failure can be controlled by the administration of L. plantarum with a significant effect on survival. The mechanism involved in this ammonia decrease implicates direct ammonia consumption in the gut. (HEPATOLOGY 2008;48:1184-1192 H yperammonemia (HA) is a well-known complication of acute and chronic liver diseases and plays a central role in the pathogenesis of hepatic encephalopathy (HE). [1][2][3][4][5] This neurological dysfunction results, at least in part, from an increase in plasma ammonia level and the severity of the symptoms correlates with blood ammonia level. 6-9 Animal models used in studying hyperammonemic disorders are multiple: fulminant hepatic failure, 10 chronic liver failure, 11 or urea cycle deficiency. 12 Ammonia is produced by many tissues but its major external source results from deaminase and urease activities of the gut flora. Although its absorption occurs through the intestinal epithelium, ammonia is carried by the portal vein into the liver where it is metabolized into urea. 13 Classical treatments of HE, except through liver transplantation and liver replacement therapies, consist in decreasing the ammonia production of urease-positive bacteria by antibiotics or decreasing the ammonia absorption into the gut by acidifying the colon content with nonabsorbable sugars such as lactulose. 4,[13][14][1...

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“…The mouse has to be stressed to ensure that it is hyperammonaemic at the time of the experiment. A proven method of stressing the urea synthesis capacity of the spf mouse is feeding it an arginine-free diet (D_Hooge et al 2000). spf mice will be hyperammonaemic after a defined time on the diet because the arginine deficiency further compromises their urea cycle function by decreasing the amount of arginine available as ornithine precursor, with ornithine necessary for normal urea cycle function.…”

Section: Previously Used Research Toolsmentioning

confidence: 99%

Profiling of astrocyte properties in the hyperammonaemic brain: Shedding new light on the pathophysiology of the brain damage in hyperammonaemia

Lichter‐Konecki

2008

J of Inher Metab Disea

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Acute hyperammonaemia (HA) causes cerebral oedema and severe brain damage in patients with urea cycle disorders (UCDs) or acute liver failure (ALF). Chronic HA is associated with developmental delay and intellectual disability in patients with UCDs and with neuropsychiatric symptoms in patients with chronic liver failure. Treatment often cannot prevent severe brain injury and neurological sequelae. The causes of the brain oedema in hyperammonaemic encephalopathy (HAE) have been subject of intense controversy among physicians and scientists working in this field. Currently favoured hypotheses are astrocyte swelling due to increased intracellular glutamine content and neuronal cell death due to excitotoxicity caused by elevated extracellular glutamate levels. While many researchers focus on these mechanisms of cytotoxicity, others emphasize vascular causes of brain oedema. New data gleaned from expression profiling of astrocytes acutely isolated from hyperammonaemic mouse brains point to disturbed water and potassium homeostasis as regulated by astrocytes at the brain microvasculature and in the perisynaptic space as a potential mechanism of brain oedema development in hyperammonaemia.

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Impaired cognitive performance in ornithine transcarbamylase-deficient mice on arginine-free diet

Cited by 13 publications

References 19 publications

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

Control of acute, chronic, and constitutive hyperammonemia by wild-type and genetically engineered Lactobacillus plantarum in rodents

Profiling of astrocyte properties in the hyperammonaemic brain: Shedding new light on the pathophysiology of the brain damage in hyperammonaemia

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