Mechanisms of Ammonia-Induced Astrocyte Swelling

Norenberg, Michael D.; Rao, Kakulavarapu V. Rama; Jayakumar, Arumugam R.

doi:10.1007/s11011-005-7911-7

Cited by 164 publications

(132 citation statements)

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“…A high-protein diet would cause hyperammonemia, and ammonia has been reported to cause deterioration of mitochondria through the production of reactive oxygen species (1,29), and it has been known to provoke central and peripheral fatigue (14) and would alter energy consumption. Fumarate, which is a degradation product of protein and amino acids, has been reported to cause impairment of muscle contractility (21) and fatigue (20).…”

Section: Discussionmentioning

confidence: 99%

Dietary protein decreases exercise endurance through rapamycin-sensitive suppression of muscle mitochondria

Mitsuishi

Miyashita

Muraki

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Mitsuishi M, Miyashita K, Muraki A, Tamaki M, Tanaka K, Itoh H. Dietary protein decreases exercise endurance through rapamycin-sensitive suppression of muscle mitochondria. Am J Physiol Endocrinol Metab 305: E776 -E784, 2013. First published July 23, 2013; doi:10.1152/ajpendo.00145.2013.-Loss of physical performance is linked not only to decreased activity in daily life but also to increased onset of cardiovascular diseases and mortality. A highprotein diet is recommended for aged individuals in order to preserve muscle mass; however, the regulation of muscle mitochondria by dietary protein has not been clarified. We investigated the long-term effects of a high-protein diet on muscle properties, focusing especially on muscle mitochondria. Mice were fed a high-protein diet from the age of 8 wk and examined for mitochondrial properties and exercise endurance at the ages of 20 and 50 wk. Compared with normal chow, a high-protein diet significantly decreased the amount of muscle mitochondria, mitochondrial activity, and running distance at 50 wk, although it increased muscle mass and grip power. Inhibition of TORC1-dependent signal pathways by rapamycin from 8 wk suppressed the decline in mitochondria and exercise endurance observed when mice were fed the high-protein diet in association with preserved AMPK activity. Collectively, these findings suggest a role for dietary protein as a suppressor of muscle mitochondria and indicate that the age-associated decline in exercise endurance might be accelerated by excessive dietary protein through rapamycin-sensitive suppression of muscle mitochondria. skeletal muscle mass; muscle mitochondria; physical performance; exercise endurance; TORC1; AMPK; rapamycin MAINTENANCE OF PHYSICAL PERFORMANCE is essential for a healthy life, especially among the elderly. The loss of muscle mass associated with aging, termed sarcopenia, is known to predict a wide range of diseases and morbidity. Sarcopenic individuals suffer from increased risk of falls and fractures and, as a result, a 1.5 to 4.6-fold higher risk of loss of independence compared with those with a normal volume of muscle mass (19,35). Moreover, inactive individuals are at higher risk of coronary heart diseases and all-cause mortality (4,5,7,22,33,38), and the relative risk for coronary heart diseases is reported to be similar between inactivity and smoking, hypertension, or dyslipidemia (16).The age-associated change in muscle is not limited to a decrease in muscle volume; the amount of muscle mitochondria decreases with aging (30, 37). Because skeletal muscle consumes 40% of total energy intake and plays a vital role in whole body energy homeostasis (12, 47), the age-associated reduction in mitochondrial amount and function in skeletal muscle is likely to contribute to an age-associated decline in physical activity, and the development of obesity and diabetes in the elderly, through dysregulation of energy homeostasis (31, 32, 34). Unlike obesity or osteoporosis, however, muscle aging is not recognized as a pathological ...

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Section: Discussionmentioning

confidence: 99%

Dietary protein decreases exercise endurance through rapamycin-sensitive suppression of muscle mitochondria

Mitsuishi

Miyashita

Muraki

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Section: Nih Public Accessmentioning

confidence: 99%

“…Furthermore, aquaporin (AQP) 4, the most abundant water channel in the CNS is present on the astrocytes (Vizuete et al, 1999;Rao et al, 2003) and plays a crucial role in brain edema formation observed after CNS insults or in disease (Manley et al, 2004;Badaut et al, 2002;Alexander et al, 2003). Edema could lead to increased intracranial pressure, resulting in brain herniation and finally death (Norenberg et al, 2005).Septic encephalopathy although common and devastating, the role of the different mechanisms behind this occurrence, still remains unclear. Although cytokines such as TNF-α are key mediators of sepsis (Lucas et al, 1997), knowledge as to their effects in brain is still being investigated, in the setting of endotoxemia.…”

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confidence: 99%

TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1

Alexander

Jacob

Cunningham

et al. 2008

Neurochemistry International

198

141

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In this study, we demonstrate that mice deficient in TNFR1 (TNFR1 -/-) were resistant to LPSinduced encephalopathy. Systemic administration of lipopolysaccharide (LPS) induces a widespread inflammatory response similar to that observed in sepsis. Following LPS administration TNFR1 -/-mice had less caspase-dependent apoptosis in brain cells and fewer neutrophils infiltrating the brain (p<0.039), compared to control C57Bl6 (TNFR1 +/+ ) mice. TNFR1-dependent increase in aquaporin (AQP)-4 mRNA and protein expression was observed with a concomitant increase in water content, in brain (18% increase in C57Bl6 mice treated with LPS vs those treated with saline), similar to cerebral edema observed in sepsis. Furthermore, absence of TNFR1 partially but significantly reduced the activation of astrocytes, as shown by immunofluorescence and markedly inhibited iNOS mRNA expression (p<0.01).Septic Encephalopathy is a devastating complication of sepsis. Although, considerable work has been done to identify the mechanism causing the pathological alterations in this setting, the culprit still remains an enigma. Our results demonstrate for the first time that endotoxemia leads to inflammation in brain, with alteration in blood-brain barrier, up-regulation of AQP4 and associated edema, neutrophil infiltration, astrocytosis, as well as apoptotic cellular death, all of which appear to be mediated by TNF-α signaling through TNFR1. KeywordsRodent; Septic Encephalopathy; Lipopolysaccharide; Apoptosis; Aquaporin 4 Neuroimmunology Sepsis is a condition characterized by uncontrolled infection and affects many organs including brain (Green et al., 2004), with an attendant high mortality rate. Administration of bacterial endotoxin (LPS), a cell wall component of gram-negative bacteria, to mice cause pathogenesis, mimicking what occurs in clinical sepsis (Gardenfors et al., 2002;Radzivil et al., 1990). Septic encephalopathy could be due to multiple factors including inflammatory cells and their mediators, reduced cerebral blood flow, disruption of the blood-brain barrier (BBB), cerebral edema and inflammation (Papadopoulos et al., 2000). One of the mediators of inflammation that play a key role in sepsis, tumor necrosis factor (TNF-α), is increased in circulation following LPS administration (Tsao et al., 2001;Merrill and Benveniste, 1996). Serum TNF-α is an acute phase response and does not correlate with the alterations in brain, Address correspondence and reprint requests to Dr. Jessy J. Alexander, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC5100, Chicago, IL 60637. jalexand@medicine.bsd.uchicago.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered w...

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“…This is accomplished in the astrocyte via glutamine synthetase (GS). Glutamine is osmotically active and can cause astrocytic swelling leading to cytotoxic oedema (Batshaw et al 1986;Bender and Norenberg 1996;Norenberg 1996;Norenberg et al 2005). Studies in which the GS inhibitor methionine sulfoximine is administered demonstrate reduced ammonia-induced brain oedema in both in vivo (Takahashi et al 1991) and in vitro models (Blei et al 1994;Norenberg and Bender 1994;Takahashi et al 1991).…”

Section: Pathogenic Mechanisms Of Acute Hyperammonaemiamentioning

confidence: 99%

Neurological implications of urea cycle disorders

Gropman

Summar

Leonard³

2007

J of Inher Metab Disea

191

152

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SummaryThe urea cycle disorders constitute a group of rare congenital disorders caused by a deficiency of the enzymes or transport proteins required to remove ammonia from the body. Via a series of biochemical steps, nitrogen, the waste product of protein metabolism, is removed from the blood and converted into urea. A consequence of these disorders is hyperammonaemia, resulting in central nervous system dysfunction with mental status changes, brain oedema, seizures, coma, and potentially death. Both acute and chronic hyperammonaemia result in alterations of neurotransmitter systems. In acute hyperammonaemia, activation of the NMDA receptor leads to excitotoxic cell death, changes in energy metabolism and alterations in protein expression of the astrocyte that affect volume regulation and contribute to oedema. Neuropathological evaluation demonstrates alterations in the astrocyte morphology. Imaging studies, in particular 1 H MRS, can reveal markers of impaired metabolism such as elevations of glutamine and reduction of myoinositol. In contrast, chronic hyperammonaemia leads to adaptive responses in the NMDA receptor and impairments in the glutamate-nitric oxide-cGMP pathway, leading to alterations in cognition and learning. Therapy of acute hyperammonaemia has relied on ammonia-lowering agents but in recent years there has been considerable interest in neuroprotective strategies. Recent studies have suggested restoration of learning abilities by pharmacological manipulation of brain cGMP with phosphodiesterase inhibitors. Thus, both strategies are intriguing areas for potential investigation in human urea cycle disorders.

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Mechanisms of Ammonia-Induced Astrocyte Swelling

Cited by 164 publications

References 159 publications

Dietary protein decreases exercise endurance through rapamycin-sensitive suppression of muscle mitochondria

Dietary protein decreases exercise endurance through rapamycin-sensitive suppression of muscle mitochondria

TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1

Neurological implications of urea cycle disorders

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