Lactate Contributes to Ammonia-Mediated Astroglial Dysfunction During Hyperammonemia

Abstract

Even though ammonia is considered to underlie nervous system symptoms of dysfunction during hyperammonemia, lactate, which increases as a metabolic consequence of high ammonia levels, might also be a contributing factor. The data presented here show that NH4Cl (5 mM) mediates astroglial cell swelling, and that treatment with NH4Cl or lactate (25 mM) causes rearrangements of actin filaments and reduces astroglial glutamate uptake capacity. Co-application with BaCl2, which blocks astroglial uptake of NH4+, prevents NH4Cl-mediated cell swelling and rearrangement of actin filaments, but does not reduce NH4Cl-induced glutamate uptake capacity inhibition. Neither NH4Cl nor lactate affected glutamate uptake or protein expression in microglial cultures, indicating that astroglial cells are more susceptible to the neurotoxic affects of ammonia. Our results suggest that ammonium underlies brain edema, but that lactate can contribute to some of the cellular dysfunctions associated with elevated cerebral levels of ammonia.

Naloxone and Ouabain in Ultralow Concentrations Restore Na+/K+-ATPase and Cytoskeleton in Lipopolysaccharide-treated Astrocytes

“…Others have seen morphological changes induced by LPS in cultured astrocytes (48,49). In line with earlier published data, the present findings confirm that there is a connection between rearrangement of actin filaments and changes in astrocytic morphology and cell volume (46,47).…”

“…We found that the actin filaments were disorganized after many h of LPS exposure. The actin filaments, which are normally organized in stress fibers, changed into ring structures after 1 h of treatment and were disrupted and disorganized at 24 h. We have observed similar patterns previously when astrocytes were exposed to ethanol, ammonium chloride, or lactate (46,47). Others have seen morphological changes induced by LPS in cultured astrocytes (48,49).…”

Ammonia triggers exocytotic release of L‐glutamate from cultured rat astrocytes

“…In line with previous studies (Andersson et al, 2009;Rose et al, 2005;Schliess et al, 2002), NH 4 Cl (5 mmol/ L) induced a transient increase of [Ca 21 ] i in astrocytes, as assessed by Fluo-4 fluorescence (Fig. 10A,B).…”

The liver–brain axis in liver failure: neuroinflammation and encephalopathy

“…A study in cultured microglial cells revealed that this cell preparation is less susceptible to substantial morphological or functional modifications than astroglial cells when exposed to toxic concentrations of ammonia. 23 Moreover, although a subsequent study provided evidence for activation of microglial cultures after exposure to ammonia, 22 in neither study did exposure to ammonia have any marked effect on the release of proinflammatory cytokines by these cells. In an ex vivo study, feeding of ammonium salts to healthy rodents resulted in microglial activation together with increased brain levels of Il-1β.…”

“…Brain lactate concentrations of 10-12 mM have been reported at coma stages of encephalopathy in liver failure; [27][28][29] concentrations of this magnitude resulted in substantially increased TNF and IL-6 release from cultures of microglial cells. 23 Accumulation of lactate in the brain has been attributed to an inhibitory effect of ammonia on the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase 32 and/or activation of the glycolytic enzyme p hosphofructokinase 1. 33…”