L -Ornithine- L -aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure

Abstract

Brain edema sufficient to cause intracranial hypertension and brain herniation remains a major cause of mortality in acute liver failure (ALF). Studies in experimental animal models of ALF suggest a role for ammonia in the pathogenesis of both encephalopathy and brain edema in this condition. As part of a series of studies to evaluate the therapeutic efficacy of ammonia-lowering agents, groups of rats with ALF caused by hepatic devascularization were treated with L-ornithine-L-aspartate (OA), an agent shown previously to be effective in reducing blood ammonia concentrations in both experimental and human chronic liver failure. Treatment of rats in ALF with infusions of OA (0.33 g/kg/h, intravenously) resulted in normalization of plasma ammonia concentrations and in a significant delay in onset of severe encephalopathy. More importantly, brain water content was significantly reduced in OA-treated rats with ALF. These protective effects of OA were accompanied by increased plasma concentrations of several amino acids including glutamate, ␥-aminobutyric acid (GABA), taurine, and alanine, as well as the branched-chain amino acids, leucine, isoleucine, and valine. Increased availability of glutamate following OA treatment provides the substrate for the major ammonia-removal mechanism (glutamine synthetase). Plasma (but not cerebrospinal fluid) glutamine concentrations were increased 2-fold (P F .02) in OAtreated rats, consistent with increased muscle glutamine synthesis. Direct measurement of glutamine synthetase activities revealed a 2-fold increase following OA treatment. These findings demonstrate a significant ammonia-lowering effect of OA together with a protective effect on the development of encephalopathy and brain edema in this model of ALF. (HEPATOLOGY 1999;30:636-640.)Brain swelling culminating in increased intracranial pressure and subsequent brain herniation remains the major cause of death in acute liver failure (ALF). Although the pathogenesis of brain edema in ALF has not been fully elucidated, there is a growing body of evidence to suggest that ammonia (either directly or indirectly) plays a predominant role. In experimental animal models of ALF resulting from hepatectomy, 1 hepatic devascularization, 2,3 or toxic liver injury, 4 brain edema is a consistent finding, and brain ammonia frequently reaches millimolar concentrations. Exposure of various brain preparations to millimolar concentrations of ammonia in vitro results in significant cell swelling. 5,6 Furthermore, precipitous increases in blood ammonia concentrations are associated with brain edema in conditions such as Reye' s syndrome 7 and urea cycle enzymopathies. 8 L-Ornithine-L-aspartate (OA) has been proven to be effective in lowering blood ammonia concentrations in both experimental and human chronic liver failure. 9-11 A recent randomized, clinical trial of OA treatment revealed significant reductions in blood ammonia in cirrhotic patients concomitant with a significant improvement of neuropsychiatric symptoms. 10 In view of these findin...

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“…Similar results have been described in vitro following the exposure of cultured astrocytes to ammonia (Norenberg et al, 1991). Furthermore, prevention of brain edema in rats with ALF has been shown with ammonia-lowering strategies (Cordoba et al, 1999;Rose et al, 1999Rose et al, , 2000. Unrelated to ammonia, swelling-induced glutamate release was demonstrated in cortical astrocytes exposed to a hypo-osmotic medium (Kimelberg et al, 1990).…”

“…It has been suggested that ammonia plays an important role in the pathogenesis of brain edema (astrocytic swelling) in ALF. Increased brain water content has been described in both normal (Takahashi et al, 1991) and in portacaval shunted (Blei et al, 1994) rats infused with ammonia as well as in rats with liver devascularization (Rose et al, 1999). Similar results have been described in vitro following the exposure of cultured astrocytes to ammonia (Norenberg et al, 1991).…”

“…In experimental animal models of ALF, brain ammonia levels may reach concentrations as high as 5 mM (Swain et al, 1992a), concentrations known to result in deleterious effects, by both direct and indirect mechanisms, on cerebral metabolism and neurotransmission. The importance of ammonia in ALF is emphasized and demonstrated in studies where ammonia-lowering strategies were shown to be beneficial in the prevention of brain edema and severe HE in rats with ALF (Cordoba et al, 1999;Rose et al, 1999Rose et al, , 2000. In the present review article, "ammonia" will be used to represent the sum of ammonium ions (NH4) and ammonia (NH3) unless a distinction is made.…”

Management in Acute Liver Failure

“…49 In rat model of acute liver failure (ALF), LOLA has been shown to prevent brain edema and hepatic encephalopathy which was accompanied by up regulation of muscle glutamine synthase activity and plasma glutamine levels were also raised indicating that LOLA in ALF may be beneficial. 50 A randomized placebo controlled double blind trial of LOLA in patients with ALF was recently published. 51 However LOLA therapy was not associated with decrease in ammonia levels or improvement in encephalopathy or survival (Figure 2).…”

Medical Therapy of Brain Edema in Fulminant Hepatic Failure

“…An infusion of ornithine-aspartate to rats with ischemic FHF reduced hyperammonemia and prevented the development of brain edema while resulting in a post-translational increase in glutamine synthetase activity in muscle. 22,23 Clinical trials with this agent, commercially available in Europe, should be performed cautiously, because the nitrogenous load could result in worsening of the clinical picture if human muscle does not respond in a similar fashion.…”