Lactate contributes to ammonia-mediated astroglial dysfunction during hyperammonemia.
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.
Andersson
Anna K
AK
Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Guldhedsgatan 19, 1 tr, Gothenburg 41345, Sweden.
Adermark
Louise
L
Persson
Mikael
M
Westerlund
Anna
A
Olsson
Torsten
T
Hansson
Elisabeth
E
D008841:Actin Cytoskeleton / Q000648:ultrastructure; D000641:Ammonia / Q000378:metabolism*; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D048429:Cell Size; D002478:Cells, Cultured; D018920:Coculture Techniques; D027341:Excitatory Amino Acid Transporter 1 / Q000096:biosynthesis; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis; D022124:Hyperammonemia / Q000378:metabolism* / Q000473:pathology; D019344:Lactic Acid / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; C493392:Slc1a3 protein, rat; D000643:Ammonium Chloride; D019344:Lactic Acid; D000641:Ammonia; D002118:Calcium