Brain edema in acute liver failure: inhibition by L-histidine

Abstract

Brain edema and the associated increase in intracranial pressure are potentially lethal complications of acute liver failure (ALF). Astrocyte swelling (cytotoxic edema) represents a significant component of the brain edema in ALF, and elevated blood and brain ammonia levels have been strongly implicated in its formation. We earlier showed in cultured astrocytes that oxidative stress (OS) and the mitochondrial permeability transition (mPT) play major roles in the mechanism of ammonia-induced astrocyte swelling. Glutamine, a byproduct of ammonia metabolism, has also been shown to induce OS, the mPT, and astrocyte swelling. Such effects of glutamine were suggested to be mediated by its hydrolysis in mitochondria, potentially yielding high levels of ammonia in this organelle and leading to OS and the mPT. L-histidine, an inhibitor of mitochondrial glutamine transport, was recently shown to mitigate OS, mPT, and cell swelling in cultured astrocytes treated with ammonia. The present study examined whether L-histidine similarly abolishes OS, the mPT, and brain edema in a rat model of ALF. Treatment of rats with thioacetamide caused a significant degree of brain edema, which was associated with induction of OS and the mPT. These changes were completely abolished by L-histidine, supporting a key role of mitochondrial glutamine transport and hydrolysis in the mechanism of the brain edema associated with ALF.

Figure 1

Brain ammonia (A) and glutamine (B) levels in ALF rat. Values were mean ± SEM of triplicate measurements in samples obtained from four separate animals in each experimental group. *P < 0.01 versus control (C). TAA indicates thioacetamide; Hist, L-histidine (100 mg/kg, i.p).

Figure 2

Brain glutamine synthetase activity in ALF rat. Values were mean ± SEM of triplicate measurements in samples obtained from four separate animals in each experimental group. *P < 0.01 versus control (C). There was no statistical difference between TAA versus TAA+ Hist.

Figure 3

Brain PAG activity in ALF rat. Values were mean ± SEM of triplicate measurements in samples obtained from four separate animals in each experimental group.

Figure 4

Effect of L-histidine in hemeoxygenase (HO-1) protein expression in rats with ALF. The density of protein bands are expressed as mean ± SEM percentage values of triplicate measurements in samples obtained from four separate animals in each experimental group. *P < 0.05 versus control; **P < 0.01 versus TAA.

Figure 5

Effect of L-histidine on the mPT in mitochondria from brains of rats with TAA-induced ALF. Values represent the ratio of DPM/unit citrate synthase/DPM/mg homogenate. This ratio was obtained by first normalizing the DPM of [³H]−2-DG-6P in the mitochondrial fraction per unit citrate synthase (a mitochondrial marker), and then divided by [³H]−2-DG-6P DPM values from brain homogenates which were normalized to mg protein. Values in each experimental group represent mean ± SEM (n = 9). *P < 0.05 versus control; **P < 0.01 versus TAA.

Figure 6

Effect of L-histidine on brain edema in ALF. Values in each experimental group represent percent brain water content of cortical sections (weighing ≈10 mg) obtained from nine rats in each experiments.