Roles of Glutamate and Glutamine Transport in Ammonia Neurotoxicity: State of the Art and Question Marks

Author(s): Katarzyna Dabrowska*, Katarzyna Skowronska, Mariusz Popek, Marta Obara-Michlewska, Jan Albrecht, Magdalena Zielinska*

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Volume 18 , Issue 4 , 2018

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Graphical Abstract:


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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Article Details

Year: 2018
Page: [306 - 315]
Pages: 10
DOI: 10.2174/1871520618666171219124427
Price: $65

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