title: Hyperosmolar sodium chloride is toxic to cultured neurons and causes reduction of glucose metabolism and ATP levels, an increase in glutamate uptake, and a reduction in cytosolic calcium.
abstract: Elevation of serum sodium, hypernatremia, which may occur during dehydration or treatment with sodium chloride, may cause brain dysfunction and damage, but toxic mechanisms are poorly understood. We found that exposure to excess NaCl, 10-100mmol/L, for 20h caused cell death in cultured cerebellar granule cells (neurons). Toxicity was due to Na(+), since substituting excess Na(+) with choline reduced cell death to control levels, whereas gluconate instead of excess Cl(-) did not. Prior to cell death from hyperosmolar NaCl, glucose consumption and lactate formation were reduced, and intracellular aspartate levels were elevated, consistent with reduced glycolysis or glucose uptake. Concomitantly, the level of ATP became reduced. Pyruvate, 10mmol/L, reduced NaCl-induced cell death. The extracellular levels of glutamate, taurine, and GABA were concentration-dependently reduced by excess NaCl; high-affinity glutamate uptake increased. High extracellular [Na(+)] caused reduction in intracellular free [Ca(2+)], but a similar effect was seen with mannitol, which was not neurotoxic. We suggest that inhibition of glucose metabolism with ensuing loss of ATP is a neurotoxic mechanism of hyperosmolar sodium, whereas increased uptake of extracellular neuroactive amino acids and reduced intracellular [Ca(2+)] may, if they occur in vivo, contribute to the cerebral dysfunction and delirium described in hypernatremia.
authors.affiliation: Norwegian Defence Research Establishment, Kjeller, Norway; Oslo and Akershus University College of Applied Sciences, Oslo, Norway.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Morland
authors.affiliation: Norwegian Defence Research Establishment, Kjeller, Norway.
authors.forename: Mi Nguyen
authors.initials: MN
authors.lastname: Pettersen
authors.affiliation: Norwegian Defence Research Establishment, Kjeller, Norway; Department of Complex Neurology and Neurohabilitation, Oslo University Hospital and The University of Oslo, Oslo, Norway. Electronic address: bjornar.hassel@ffi.no.
authors.forename: Bjørnar
authors.initials: B
authors.lastname: Hassel
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003600:Cytosol / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D012462:Saline Solution, Hypertonic / Q000633:toxicity*; D014316:Tritium / Q000378:metabolism
chemical_list: D000596:Amino Acids; D012462:Saline Solution, Hypertonic; D014316:Tritium; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D005947:Glucose; D002118:Calcium
keywords: Calcium; Dehydration; Delirium; Hyperosmolarity; Neurotoxicity; Sodium