Background: Excessive accumulation of ammonia in the brain is a causative factor of an
array of neurological manifestations of hyperammonemic encephalopathies (“hyperammonemias”,
HA) among which hepatic encephalopathy (HE) is a major epidemiologic and therapeutic challenge.
While ammonia neurotoxicity is symptomatically and mechanistically very complex, there is a consensus
with regard to the leading role in its pathogenesis of: i) astrocytes being the primary cellular target
of ammonia toxicity; ii) alterations of glutamate (Glu)-dependent neurotransmission (over-excitation
followed by inhibition of glutamatergic tone) being the cornerstone of its neurophysiological manifestations;
and iii) brain edema, an often lethal consequence of astrocytic swelling, being among other
factors caused by the retention of glutamine (Gln) in these cells.
Objective: This article critically evaluates the present literature attempting to relate manifestations of
HA to changes in astrocytic Glu and Gln transport as observed in different in vivo and in vitro HA
and/or HE models. Emphasis is put on two disproportions in the state of the art: i) the paucity of available
data regarding ammonia-dependent changes in Glu transport activity vs the relative abundance of
information on the expression of astrocytic Glu transporters (GLT-1/EAAT2 and GLAST/EAAT1); ii)
the just emerging still not very conclusive knowledge on the response of astrocytic Gln transporters
SN1 and SN2.
Conclusion: The review on the above issues is complemented by own recent data which fill some of
the many gaps in the knowledge. A brief account is included on the roles of heteromeric cell membrane
Glu/arginine (Arg) exchanger y+LAT2 and on the mitochondrial Gln transport.
Keywords: Ammonia, hepatic encephalopathy, glutamate transport, glutamine transport, GLT-1, GLAST, SN1, SN2.
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