Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis

Abstract

Two mechanisms may account for brain edema in fulminant hepatic failure: the osmotic effects of brain glutamine, a product of ammonia detoxification, and a change of cerebral blood flow (CBF). We have shown brain edema, a marked increase in brain glutamine, and a selective rise in CBF in rats after portacaval anastomosis receiving an ammonia infusion. In this study, we inhibited the activity of glutamine synthetase with methionine-sulfoximine (MSO) and examined ammonia levels, brain water and CBF. A major complication of fulminant hepatic failure (FHF) is the development of brain edema and intracranial hypertension, a leading cause of death in this syndrome. 1 The pathogenesis of the increase in brain water in the setting of a failing liver remains controversial. Over a decade of research in this area, 2 main theories have emerged. In the first, the accumulation of glutamine in glial cells would account for the development of brain edema. 2 Glutamine is the product of detoxification of ammonia, a reaction localized to astrocytes in view of the selective localization of glutamine synthetase to this cell. 3 Glial swelling is a prominent neuropathological feature of experimental 4 and human FHF. 5 Inhibition of glutamine synthesis with methionine-sulfoximine (MSO) prevents the development of ammonia-induced brain edema in normal rats, 6 decreases astrocyte swelling, 7 and ameliorates brain edema in rats after portacaval anastomosis receiving an ammonia infusion. 8 A second view emphasizes a pathogenic role for disturbances in the cerebral circulation. 9 A high cerebral blood flow (CBF) is noted in patients with FHF who develop brain edema. 10,11 In addition, failure of cerebrovascular autoregulation to changes in arterial pressure is also prominent in these subjects. 12 The possibility that this increase in CBF may be linked to brain edema is further supported by reports of selective abnormalities of the blood-brain barrier, a controversial observation in experimental models of FHF. 13,14 The rat after portacaval anastomosis receiving a continuous intravenous ammonia infusion is a well-standardized, controlled paradigm of brain edema, in which cerebral swelling occurs in the absence of acute liver failure. In this preparation, we have recently reported the simultaneous presence of a marked increase in brain glutamine and a selective 3-fold increase in cerebral perfusion at the time of an increase in brain water and intracranial pressure. 15 Furthermore, mild hypothermia (35°C, 33°C) prevented the development of brain edema in spite of a similar increase in brain glutamine as the normothermic animals. The main effect of hypothermia was to prevent the rise in CBF seen in the edematous, normothermic rats.If MSO ameliorates brain edema in this model by inhibiting glutamine synthesis and hypothermia also prevents brain swelling by normalizing CBF, it is of interest to determine the effects of MSO on cerebral perfusion. Normalization of CBF with MSO would suggest that the 2 postulated mechanisms of brain edema may in fac...

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

“…It has been shown that pre-treatment of cultured astrocytes with the irreversible GS inhibitor, methionine sulfoximine (MSO), result in an attenuation in the increase in ammonia-induced glutamine and swelling (Norenberg and Bender, 1994). Similar results have been observed following ammonia-infusion in portacaval shunted rats pre-treated with MSO (Master et al, 1999 andWillard-Mack et al, 1996). However, following ammonia-lowering treatments, which are beneficial in attenuating brain edema and the onset of coma in animal models of ALF, a decrease in high cerebral glutamine levels was not observed Zwingmann et al, 2004).…”

Worsening of cerebral hyperemia by the administration of terlipressin in acute liver failure with severe encephalopathy

“…Studies in portacaval shunted rats administered an ammonia load have demonstrated a rise in CBF that paralleled the increase in ICP and correlated directly with brain water content. 25,26 Cerebral hyperemia is of crucial importance in the development of increased ICP in ALF. Normal cerebral vascular resistance is essential for the maintenance of cerebral autoregulation.…”

“…Reactive vasodilatation or vasoconstriction ensures constant cerebral perfusion. 27 When methods are introduced to control the rise in CBF, such as methionine-sulfoximine (an inhibitor of glutamine synthase) 25 and mild hypothermia, 28 ammonia-induced cerebral edema is prevented. It also has been shown that the cerebral vasoconstrictor indomethacin blunts the rise in CBF in portacaval shunted rats receiving an ammonia load and that the consequent reduction in CBF leads to a disproportionate reduction of ammonia uptake by the brain, which may reduce brain edema.…”

Brain Alanine Formation as an Ammonia-Scavenging Pathway during Hyperammonemia: Effects of Glutamine Synthetase Inhibition in Rats and Astrocyte—Neuron Co-Cultures

“…[7][8][9] In vivo studies have shown that administration of methionine sulfoximine (MSO), which specifically inhibits GS, ameliorates astrocyte swelling and brain edema observed during acute hyperammonemia. [10][11][12][13] A decreased ammonia fixation by GS may lead either to a stimulation of an alternative ammoniascavenging pathway or to a corresponding, increased ammonia concentration. A study using neuronal-astrocytic co-cultures provided evidence for a high incorporation of ammonia nitrogen in both alanine and glutamine, 14 suggesting that ammonia might be metabolized not only via GS catalyzed formation of glutamine but also by the concerted action of glutamate dehydrogenase (GDH) and alanine aminotransferase (ALAT) leading to trapping of ammonia in alanine, as illustrated in Figure 1.…”