title: Lipoic acid protects C6 cells against ammonia exposure through Na⁺-K⁺-Cl⁻ co-transporter and PKC pathway.
abstract: Astrocytes play an essential role in the central nervous system (CNS) homeostasis. They providing metabolic support and protecting against oxidative stress and glutamatergic excitotoxicity. Glutamate uptake, an electrogenic function, is driven by cation gradients and the Na⁺-K⁺-Cl⁻ co-transporter (NKCC1) carries these ions into and out of the cell. Elevated concentrations of ammonia in the brain lead to cerebral dysfunction. Ammonia toxicity can be mediated by an excitotoxic mechanism, oxidative stress and ion discharged. Astrocytes also convert excess ammonia and glutamate into glutamine, via glutamine synthetase (GS). Lipoic acid (LA) is a modulator of the cellular redox status potentially beneficial in neurodegenerative diseases. In this study, we investigated the effect of LA on glial parameters, in C6 cells exposed to ammonia. Ammonia increased S100B secretion and decreased glutamate uptake, GS activity and glutathione (GSH) content. LA was able to prevent these effects. LA exerts its protective effect on glutamate uptake and S100B secretion via mechanisms dependent of NKCC1 and PKC. These findings show that LA is able to modulate glial function impairments by ammonia in vitro, indicating a potential therapeutic agent to improve glutamatergic metabolism and oxidative stress against hyperammonemia.
authors.affiliation: Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Larissa Daniele
authors.initials: LD
authors.lastname: Bobermin
authors.forename: Diogo Onofre
authors.initials: DO
authors.lastname: Souza
authors.forename: Carlos-Alberto
authors.initials: CA
authors.lastname: Gonçalves
authors.forename: André
authors.initials: A
authors.lastname: Quincozes-Santos
mesh_terms: D000641:Ammonia / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000633:toxicity; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D005978:Glutathione / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018696:Neuroprotective Agents / Q000819:agonists / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D064568:S100 Calcium Binding Protein beta Subunit / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D064506:Solute Carrier Family 12, Member 2 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D008063:Thioctic Acid / Q000819:agonists / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D064568:S100 Calcium Binding Protein beta Subunit; C579158:S100b protein, rat; C578879:Slc12a2 protein, rat; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064506:Solute Carrier Family 12, Member 2; D018698:Glutamic Acid; D008063:Thioctic Acid; D000641:Ammonia; D011493:Protein Kinase C; D005974:Glutamate-Ammonia Ligase; D005978:Glutathione
keywords: Ammonia; C6 astroglial cells; Glutamatergic metabolism; Lipoic acid; NKCC1; S100B secretion