Glutamine, Myo –Inositol, and Organic Brain Osmolytes After Portocaval Anastomosis in the Rat: Implications for Ammonia–Induced Brain Edema

Abstract

and mechanisms that lead to the decrease of cerebral myoBrain myo-inositol, an organic osmolyte, is decreased inositol are poorly understood. in cirrhotic patients with hepatic encephalopathy but myo-Inositol is a six-carbon polyol that participates in the appears unchanged in fulminant hepatic failure. An ossynthesis of intracellular signaling compounds of the phosmoregulatory response to the increase in brain glutaphatidylinositol group 5 and is a main organic osmolyte in mine may explain the decrease in brain myo-inositol; if the regulatory volume response to osmotic stress. 6 Besides this is the case, organic osmolytes may account for difhepatic encephalopathy, a decrease in brain myo-inositol has ferences in the development of brain edema seen in been noted in affective disorders 7 and in chronic hyponaacute or chronic liver failure. The response of myo-inositremia. 8 In the latter, the decrease of myo-inositol is accompatol and nine other organic osmolytes to the increase in nied by a reduction of other organic osmolytes, including glubrain glutamine at different time intervals after portacatamine, as part of the process of cellular regulatory volume val anastomosis (PCA) in the rat was studied. Organic decrease. This response is elicited by the osmotic gradient osmolytes were measured in brain tissue and cerebrobetween the intracellular and extracellular compartments. spinal fluid. Water in cerebral cortex was measured after During regulatory volume decrease, brain cells lose inorganic ammonia infusion with the gravimetric method. Six ions as well as organic osmolytes, such as amino acids, meweeks after PCA, despite an increase in brain glutamine thylamines, and inositols, to avoid cell swelling. ), the content of total organic osmo-vere neurophysiological consequences, the unique physical lytes did not increase (PCA, 44.1 { 3; sham, 43 { 4) be-and chemical properties of organic osmolytes allow cells to cause of a decrease of other osmolytes (myo-inositol, 54%; withstand large changes in their concentration without detriurea, 39%; taurine, 33%; and glutamate, 8%). Brain myo-mental effects to cellular structure and function.6 In hyponainositol was lower at 3 weeks (3.4 { 0.5 kg wt 01 ) than at tremia, up to one fourth of the osmotic response is dependent 1 day after PCA (4.7 { 0.5 kg wt 01). An ammonia infusion on organic osmolytes. 10 resulted in brain edema at both time points. In conclu-In hepatic encephalopathy, the decrease in brain myo-inosion, the reduction in brain myo-inositol in PCA rats is sitol could occur as a compensatory response to the osmotic accompanied by the decrease of other organic osmo-gradient induced by the accumulation of glutamine in astrolytes, supporting the view that changes in myo-inositol cytes. If this is the case, other organic osmolytes should also reflect an osmoregulatory response. The decrease in decrease in response to the increase in glutamine. In patients brain myo-inositol is more marked as time elapses after with fulminant hepatic failure (FHF), the accumulation o...

Brain lactate by magnetic resonance spectroscopy during fulminant hepatic failure in the dog

“…37 Evidence in support of glutamine serving as an organic osmolyte was obtained in hyperammonemic animals 38 or animals after total hepatectomy 39 or portocaval anastomosis. 13 In our study of drug-induced FHF, the concentration of brain glutamine increased to 8.3 mmol/L (see Fig. 4), which is within 100% variation of the basal concentration of brain glutamine.…”

“…Therefore, both ICP and brain lactate were assumed to reflect the extent of cerebral edema during acute liver failure. Because other brain metabolites, such as glutamine and glutamate, may contribute to the formation of cerebral edema, [9][10][11][12][13] concentrations of glutamine and glutamate were also determined by MRS in this study.…”

Hypothermia in Acute Liver Failure

“…Ammonia removal in the brain is solely accomplished by the production of glutamine through the astrocyte-specific enzyme glutamine synthetase. It has been pro-posed that ammonia-induced brain edema in ALF involves alterations in astrocytic in-tracellular osmolarity resulting from glutamine accumulation (Cordoba et al, 1996). This is supported by studies demonstrating the administration of the glutamine synthetase inhibition, methionine sulfoximine, reduces ammonia-induced brain edema both in vitro (Norenberg and Bender, 1994) and in vivo (Chodobski et al, 1986;Takahashi et al, 1991).…”

Keeping cool in acute liver failure: Rationale for the use of mild hypothermia

“…These observations challenge the notion of glutamine as the major determinant of brain edema in ALF. Glutamine, however, is not the only organic osmolyte or solute altered in ALF; increases of glucose, alanine and lactate and decreases of glutamate, aspartate, myo-inositol and taurine have also been noted [90], [91], [92] and [93]. Increases of brain lactate and alanine correlate better than glutamine with the grade of encephalopathy and brain edema in hepatic devascularized rats [91] and [92].…”

“…Since the brain cannot synthesize urea, detoxification of ammonia relies almost entirely on glutamine synthetase localized in astrocytes [88]. An increase of brain glutamine is a major feature in hyperammonemia or ALF [87], [89], [90], [91], [92], [93] and [94], and inhibition of glutamine synthesis attenuates ammonia-induced brain edema [87] and [89]. The osmotic effects of glutamine may partly explain the selective astrocytic swelling in ALF.…”