Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering

Thrane, Vinita Rangroo; Thrane, Alexander S.; Wang, Fushun; Cotrina, Maria Luisa; Smith, Nathan A.; Chen, Michael; Xu, Qiwu; Kang, Ning; Fujita, Takumi; Nagelhus, Erlend A.

doi:10.1038/nm.3400

Cited by 219 publications

(185 citation statements)

References 53 publications

(96 reference statements)

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“…Here, ammonia may contribute to edema formation 14,33,35 and interfere with neurotransmission and astrocytic potassium handling, as is illustrated in hyperammonemic states. 14,22,34 Serum ammonia in patients with coma due to hepatic encephalopathy was 0.35 mmol/L or below. 2,32 The patients in the present study had pus ammonia levels well above that value.…”

Section: Discussion Ammonia Is High In Brain Abscesses and May Contrimentioning

confidence: 99%

“…9,15,19 Amino acids are energy substrates for bacteria, 26 and bacterial metabolism of amino acids entails formation of ammonia; 6 therefore, brain abscesses could contain ammonia. Ammonia is neurotoxic; its deleterious effects on the brain, as can be seen in hyperammonemic states, include vasogenic edema formation, 35 astrocytic swelling and alterations in neurotransmission, 14,22,33 impaired astrocytic potassium handling, 34 and a host of biochemical effects 18 that could contribute to the various symptoms of hyperammonemic disorders. 20 To see if brain abscesses contain ammonia we determined the extracellular concentration of ammonia in pus from patients with brain abscesses and, for comparison, in CSF from patients with external cerebroventricular drains.…”

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Toxic levels of ammonia in human brain abscess

Dahlberg¹,

Ivanović²,

Hassel

2016

JNS

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obJective Brain abscesses could lead to cerebral symptoms through tissue destruction, edema, changes in brain architecture, and increased intracranial pressure. However, the possibility that the pus itself could contribute to symptoms has received little attention. Brain abscesses are areas of tissue destruction, proteolysis, and formation of free amino acids, which are energy substrates for bacteria and possible sources of ammonia. Ammonia is neurotoxic, may cause brain edema, and could contribute to the symptoms of brain abscesses. methods The authors analyzed the extracellular phase of pus from 14 patients with brain abscesses with respect to ammonia and amino acids. For comparison, CSF from 10 patients undergoing external ventricular drainage was included. The ammonia-forming ability of Streptococcus intermedius and Staphylococcus aureus, two common microbial isolates in brain abscesses, was studied in vitro. results In brain abscesses ammonia was 15.5 mmol/L (median value; range 1.7-69.2 mmol/L). In CSF ammonia was 29 µmol/L (range 17-55 µmol/L; difference from value in pus: p < 0.001). The total concentration of amino acids in brain abscesses was 1.12-16 times higher than the ammonia concentration (p = 0.011). The median glucose value in pus was 0 mmol/L (range 0-2.1 mmol/L), lactate was 21 mmol/L (range 3.3-26.5 mmol/L), and pH was 6.8 (range 6.2-7.3). In vitro, S. intermedius and S. aureus formed ammonia at 6-7 mmol/L in 24 hours when incubated with 20 proteinogenic amino acids plus g-aminobutyric acid (GABA), taurine, and glutathione at 1 mmol/L. coNclusioNs Intracerebral abscesses contain toxic levels of ammonia. At the concentrations found in pus, ammonia could contribute to the brain edema and the symptoms of brain abscesses.

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Section: Discussion Ammonia Is High In Brain Abscesses and May Contrimentioning

confidence: 99%

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confidence: 99%

Toxic levels of ammonia in human brain abscess

Dahlberg¹,

Ivanović²,

Hassel

2016

JNS

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“…Ammonia is an integral constituent in cell metabolism, but its homeostasis is, due to the biological toxicity of ammonia (1)(2)(3)(4), highly regulated around 10 -35 M in plasma (5). Ammonia is a base and thus exists in two forms: NH 3 (ammonia) or NH 4 ϩ (ammonium ion).…”

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confidence: 99%

“…The sensitivity of the different experimental approaches employed to determine the NH 3 permeability is not defined, and it is possible that, as most K ϩ * The authors declare that they have no conflicts of interest with the contents of this article. 1 Both authors contributed equally. 2 Supported by the Danish Medical Research Council.…”

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Aquaporin 4 as a NH3 Channel

Assentoft

Kaptan

Schneider

et al. 2016

Journal of Biological Chemistry

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Ammonia is a biologically potent molecule, and the regulation of ammonia levels in the mammalian body is, therefore, strictly controlled. The molecular paths of ammonia permeation across plasma membranes remain ill-defined, but the structural similarity of water and NH 3 has pointed to the aquaporins as putative NH 3 -permeable pores. Accordingly, a range of aquaporins from mammals, plants, fungi, and protozoans demonstrates ammonia permeability. Aquaporin 4 (AQP4) is highly expressed at perivascular glia end-feet in the mammalian brain and may, with this prominent localization at the bloodbrain-interface, participate in the exchange of ammonia, which is required to sustain the glutamate-glutamine cycle. Here we observe that AQP4-expressing Xenopus oocytes display a reflection coefficient <1 for NH 4 Cl at pH 8.0, at which pH an increased amount of the ammonia occurs in the form of NH 3 . Taken together with an NH 4 Cl-mediated intracellular alkalization (or lesser acidification) of AQP4-expressing oocytes, these data suggest that NH 3 is able to permeate the pore of AQP4. Exposure to NH 4 Cl increased the membrane currents to a similar extent in uninjected oocytes and in oocytes expressing AQP4, indicating that the ionic NH 4 ؉ did not permeate AQP4.Molecular dynamics simulations revealed partial pore permeation events of NH 3 but not of NH 4 ؉ and a reduced energy barrier for NH 3 permeation through AQP4 compared with that of a cholesterol-containing lipid bilayer, suggesting AQP4 as a favored transmembrane route for NH 3 . Our data propose that AQP4 belongs to the growing list of NH 3 -permeable water channels.

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“…The subsequent depolarization of neuronal GABA reverse potential (E GABA ) impairs cortical inhibitory system and can lead to local excitotoxicity that has clinical manifestations in HE [33]. On the other hand, hyperammonaemia causes activation of the astrocytic peripheral-type benzodiazepine receptors [34], which is associated with increase in production of neurosteroids by mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Modern view on hepatic encephalopathy: basic terms and concepts of pathogenesis

Shulyatnikova

Shavrin

2017

Patologìâ

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Background. The problem of acute and chronic forms of hepatic encephalopathy (HE) is not clearly identified among modern problems of hepatology and neuroscience in Ukraine. Despite the significant contribution to the development of lethal complications in patients with liver pathology and long history of the study of this issue, there is still no unified opinion on the links of HE pathogenesis.The aim of this review is to conduct a comprehensive analysis of current data on the spreading and mechanisms of development of HE.HE is a complex of potentially reversible neurocognitive disorders in patients with chronic or acute hepatic failure (ALF). HE is more often a complication of liver cirrhosis and is the second most frequent cause of hospitalization of such patients after ascites. When decompensating liver failure in acute or chronic hepatic pathology in patients severe forms of HE develop, accompanied by a progressive increase in intracranial pressure and the development of coma, which often ends lethal due to poor corrigibility of intracranial hypertension while maintaining hepatogenic neurointoxication. HE is considered as the end result of the accumulation of a number of neurotoxic substances in the brain, among which are ammonia, mercaptans, short chain fatty acids, false neurotransmitters, gamma-aminobutyric acid, manganese. The most popular among the reasons for the development of HE is the neurotoxic theory of ammonia. Ammonia is subjected to detoxification in the liver, turning into urea, a smaller fraction with the participation of glutamine synthetase is used in the synthesis of glutamine in muscles, liver and astrocytes of brain. In case of hepatic dysfunction and/or portosystemic shunting, the concentration of ammonia in blood increases up to 10 times and the main load for its detoxification is shifted to myocytes and astroglia. In ALF glutamine overload of astrocytes occurs with a change in intracellular osmolarity and subsequent edema of astroglia, which is accompanied by the development of cytotoxic edema of the brain. In this case, in astrocytes damaging of mitochondrial respiratory chain occurs and mitochondrial insufficiency develops, as well as processes of nitrosative-oxidative stress and oxidation of astrocytic and neuronal RNA, disruption of gene expression, synthesis of neuro-and gliotransmitters and synaptic plasticity. The increased influx of aromatic amino acids into brain leads to the synthesis of false neurotransmitters, which worsens serotoninergic, GABA-ergic, dopaminergic and glutamatergic neurotransmission. Damage to the components of the blood-brain barrier leads to aggravation of the water imbalance, penetration of hematogenous cytokines, endotoxins and other products of systemic inflammatory reaction into the cerebral parenchyma and development of neuroinflammation, which makes an important contribution to the further progression of cerebral edema.Conclusions: despite a comprehensive study of the problem, many open questions remain in the pathogenesis of HE. Special attention ...

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Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering

Cited by 219 publications

References 53 publications

Toxic levels of ammonia in human brain abscess

Toxic levels of ammonia in human brain abscess

Aquaporin 4 as a NH3 Channel

Modern view on hepatic encephalopathy: basic terms and concepts of pathogenesis

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