Neurobiology of ammonia

Felipo, Vicente

doi:10.2217/fmeb2013.13.204

Cited by 56 publications

(92 citation statements)

References 43 publications

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“…Ammonia intoxication impairs vital central nervous system (CNS) functions such as energy metabolism [14], hemodynamics [15] and neurotransmission [16]. As an outcome of the balance between its ionic and gaseous forms, ammonia readily passes the blood-brain barrier (BBB) and accumulates in the brain [16].…”

Section: Introductionmentioning

confidence: 99%

“…As an outcome of the balance between its ionic and gaseous forms, ammonia readily passes the blood-brain barrier (BBB) and accumulates in the brain [16]. Elevated arterial ammonia levels correlate closely with brain ammonia uptake; ammonia within the brain is then detoxified by astrocytes by glutamine synthetase (GS), resulting in the accrual of glutamine [17].…”

Section: Introductionmentioning

confidence: 99%

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Role of Bioflavonoid Quercetin on Expression of Urea Cycle Enzymes, Astrocytic and Inflammatory Markers in Hyperammonemic Rats

et al. 2016

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This study evaluates the role of quercetin on the expression of urea cycle enzymes, astrocytic, neuronal and inflammatory markers in hyperammonemic rats. Hyperammonemia (provoked by intraperitonial injections of (ammonium chloride-100 mg/kg b.w for 56 days), showed diminished expression of urea cycle enzymes [carbamyl phosphate synthetase-1 (CPS-1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS) and arginase (ARG)] in liver and decreased expression of neuronal and astrocytic markers-glutamine synthase (GS) and phosphate activated glutaminase (PAG) in brain and increased expression of brain inflammatory markers such as interleukin 6 (IL6), inducible nitric oxide synthase (iNOS) and nuclear transcription factor kappa B (NF-jB) (by western blot analysis) and exhibited downregulated expression of soluble guanylate cyclase (sGC), glial fibrillary acidic protein (GFAP) in brain and ASS in liver investigated (by RT-PCR). Oral treatment of quercetin (50 mg/kg b.w) to hyperammonemic rats (1) increased the expression of urea cycle enzymes (CPS-1, OTC, ASS and ARG), neuronal and astrocytic markers (GS and PAG) (2) decreased the expression of IL6, iNOS and NF-jB and (3) upregulated mRNA expression of SGC, GFAP and ASS. Our results specify that quercetin's antihyperammonemic effects could be through its, anti-inflammatory, neuroprotective and hepatoprotective effects.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of Bioflavonoid Quercetin on Expression of Urea Cycle Enzymes, Astrocytic and Inflammatory Markers in Hyperammonemic Rats

et al. 2016

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“…Ammonia is considered a major pathogenic factor in the development of HE [9]. The brain solely relies on the amidation of glutamate catalyzed by the enzyme glutamine synthetase (GS) to detoxify ammonia.…”

Section: Introductionmentioning

confidence: 99%

Increased brain lactate is central to the development of brain edema in rats with chronic liver disease

Bosoi

Zwingmann

Marin

et al. 2014

Journal of Hepatology

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The pathogenesis of brain edema in patients with chronic liver disease (CLD) and minimal hepatic encephalopathy (HE) remains undefined. This study evaluated the role of brain lactate, glutamine and organic osmolytes, including myo-inositol and taurine, in the development of brain edema in a rat model of cirrhosis.Six-week bile-duct ligated (BDL) rats were injected with (13)C-glucose and de novo synthesis of lactate, and glutamine in the brain was quantified using (13)C nuclear magnetic resonance spectroscopy (NMR). Total brain lactate, glutamine, and osmolytes were measured using (1)H NMR or high performance liquid chromatography. To further define the interplay between lactate, glutamine and brain edema, BDL rats were treated with AST-120 (engineered activated carbon microspheres) and dichloroacetate (DCA: lactate synthesis inhibitor).Significant increases in de novo synthesis of lactate (1.6-fold, p<0.001) and glutamine (2.2-fold, p<0.01) were demonstrated in the brains of BDL rats vs. SHAM-operated controls. Moreover, a decrease in cerebral myo-inositol (p<0.001), with no change in taurine, was found in the presence of brain edema in BDL rats vs. controls. BDL rats treated with either AST-120 or DCA showed attenuation in brain edema and brain lactate. These two treatments did not lead to similar reductions in brain glutamine.Increased brain lactate, and not glutamine, is a primary player in the pathogenesis of brain edema in CLD. In addition, alterations in the osmoregulatory response may also be contributing factors. Our results suggest that inhibiting lactate synthesis is a new potential target for the treatment of HE.Canadian Institutes of Health Research. CB:Fonds de recherche du Québec – Sant

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“…And as described earlier [33,49,50], these rats were considered to representative of a true CLF led HA model of neuroinflammation/excitotoxicity. Using these HA rats, we examined the expression profiles of TNF-α, NFκB and apoptotic factors in the cortex and cerebellum.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Normalizes Hyperammonemia Induced Pro-Inflammatory and Pro-Apoptotic Conditions in Rat Brain

Khanna¹,

Trigun²

2016

IJCAM

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Research ArticleInt J Complement Alt Med 2016, 4(2): 00115 IntroductionAmmonia neurotoxicity is considered responsible for development of a serious nervous system disorder called hepatic encephalopathy (HE). This situation arises mainly due to liver dysfunction led hyperammonemia (HA). HE is characterized by the neuropsychiatric manifestations related to motor dysfunction, memory impairment, and deranged sleep-awake cycle [1,2]. Since HE affects the quality of life of the patients, it is important to develop effective therapeutic strategy against HE. This necessitates understanding the neuro-chemistry of HA pathogenesis.Since ammonia crosses the blood brain barrier easily, prolonged HA condition, a common situation during chronic liver failure (CLF), is likely to maintain increased ammonia concentration in brain [3,4]. The information, mainly derived from the cell culture system and from animal models with acute HE, suggest that the increased brain ammonia level mainly drives astrocytes to undergo significant morpho-pathological changes and also over activates glutamate-NMDA receptor (N-Methyl-D-Aspartate Receptor) pathway in the post-synaptic neurons [1,[5][6][7]. Moreover, NMDAR inhibition could not be translated into prevention of ammonia neurotoxicity, mainly because threshold glutamate-NMDAR activation is necessary for normal neurological functions including higher order brain functions and normal synaptic activity.During recent past, "TNF theory" (Tumor necrosis factor) of HE pathogenesis could draw much attention due to a close association between the level of TNF-α and ammonia in the brain of CLF patients with HE [8]. Later studies have also emphasized significant involvement of TNF-α and other cytokines in HE to the extent that these cytokines could be used as markers for encephalopathy grading [4,[9][10][11][12][13].It is now evident that the microglia and astroglia cells in brain synthesize TNF-α to regulate higher order brain functions and astrocyte induced synaptic strengthening [14][15][16][17]. However, when produced in higher amounts during neuropathology, they are known to potentiate glutamate induced cytotoxicity by inhibiting glutamate transport to the glial cells from the synaptic cleft [12,[16][17][18][19]. Even development of MHE has been described to be dependent more on enhanced inflammatory markers than the severity of CLF or HA in the CLF patients [20]. Moreover, some findings from in vitro studies suggest that resveratrol treatment could prevent ammonia toxicity in astroglial cells by normalizing ROS/RNS level [12,21,22]. Thus, hinting towards a significant role of resveratrol in ameliorating ammonia toxicity. However, the mechanism by which resveratrol does so is unclear.Resveratrol (3, 3, 4'-trihydroxy-Trans stilbene), a natural polyphenol, is found in a number of dietary sources such as grapes, berries, and red wine [23][24][25]. It acts as an effective cardioprotector, AbstractChronic liver failure (CLF) led hyperammonemia (HA) is known to develop a metabolic brain disorder known a...

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Neurobiology of ammonia

Cited by 56 publications

References 43 publications

Role of Bioflavonoid Quercetin on Expression of Urea Cycle Enzymes, Astrocytic and Inflammatory Markers in Hyperammonemic Rats

Role of Bioflavonoid Quercetin on Expression of Urea Cycle Enzymes, Astrocytic and Inflammatory Markers in Hyperammonemic Rats

Increased brain lactate is central to the development of brain edema in rats with chronic liver disease

Resveratrol Normalizes Hyperammonemia Induced Pro-Inflammatory and Pro-Apoptotic Conditions in Rat Brain

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