Glutamine

Abstract

Mechanisms involved in hepatic encephalopathy still remain to be defined. Nonetheless, it is well recognized that ammonia is a major factor in its pathogenesis, and that the astrocyte represents a major target of its CNS toxicity. In vivo and in vitro studies have shown that ammonia evokes oxidative/nitrosative stress, mitochondrial abnormalities (the mitochondrial permeability transition, MPT) and astrocyte swelling, a major component of the brain edema associated with fulminant hepatic failure. How ammonia brings about these changes in astrocytes is not well understood. It has long been accepted that the conversion of glutamate to glutamine, catalyzed by glutamine synthetase, a cytoplasmic enzyme largely localized to astrocytes in brain, represented the principal means of cerebral ammonia detoxification. Yet, the "benign" aspect of glutamine synthesis has been questioned. This article highlights evidence that, at elevated levels, glutamine is indeed a noxious agent. We also propose a mechanism by which glutamine executes its toxic effects in astrocytes, the "Trojan horse" hypothesis. Much of the newly synthesized glutamine is subsequently metabolized in mitochondria by phosphate-activated glutaminase, yielding glutamate and ammonia. In this manner, glutamine (the Trojan horse) is transported in excess from the cytoplasm to mitochondria serving as a carrier of ammonia. We propose that it is the glutamine-derived ammonia within mitochondria that interferes with mitochondrial function giving rise to excessive production of free radicals and induction of the MPT, two phenomena known to bring about astrocyte dysfunction, including cell swelling. Future therapeutic approaches might include controlling excessive transport of newly synthesized glutamine to mitochondria and its subsequent hydrolysis. (HEPATOLOGY 2006;44:788-794.)

Astroglial Glutamate–Glutamine Shuttle Is Involved in Central Sensitization of Nociceptive Neurons in Rat Medullary Dorsal Horn

“…The lack of any observed significant effects of MSO alone, in contrast to our findings that it significantly attenuates MO-induced central sensitization, suggests that its action on astroglial GS is not evident in basal conditions but is apparent in hyperexcitable states, consistent with findings by ourselves and others that glia may not affect basal nociceptive processing but rather participate in exaggerated pain states (Watkins and Maier, 2005;Xie et al, 2007). It is also noteworthy that an excess of glutamine in the CNS is involved in ammonia neurotoxicity (e.g., hyperammonemia and hepatic encephalopathy), possibly through its detrimental effects on mitochondrial function (Albrecht and Norenberg, 2006). The dose of glutamine superfusion (250 M) used in the present study was also selected at a level below the rat's cerebral basal interstitial concentration (385 M) (Kanamori and Ross, 2004) to avoid neuronal excitation elicited by too high a dose of glutamine, and control experiments with superfusion of glutamine also resulted in no significant changes in MDH neuronal properties.…”

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

“…51 The 'Trojan horse' hypothesis has recently been proposed as an alternative theory to explain the development of astrocyte swelling and implicates an important role for both ammonia and glutamine. 52 The excess glutamine synthesized within astrocytes is transported into mitochondria where it is metabolised by phosphate-activated glutaminase (PAG) to ammonia and glutamate. Glutamine, the 'Trojan horse', thereby acts as a carrier of ammonia into mitochondria, where its accumulation can lead to oxidative stress and ultimately, astrocyte swelling.…”

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

“…Albrecht and Norenberg have proposed that the mitochondrial toxic effect of glutamine is due to its increased hydrolysis by glutaminase, resulting in ammonia liberation. This has been defined as the "Trojan horse" theory ( Albrecht and Norenberg, 2006).…”