Hypertonicity promotes survival of corticospinal motoneurons via mitogen-activated protein kinase p38 signaling.
Extracellular hypertonicity can induce the phosphorylation of mitogen-activated protein kinases (MAPKs). Of these, both extracellular signal-regulated kinases (ERKs) and the stress-activated kinase p38 have been implicated in neuronal cell survival. Resuscitation with hypertonic saline decreases secondary brain injury after trauma, as well as neuronal damage, after ischemia. Since hypertonicity has been shown to support somatic cell survival, we investigated if hypertonicity can also prevent neuronal cell death via MAPK signaling. Death of postnatal rat corticospinal motoneurons (CSMNs) was induced by serum deprivation, and survival in both isotonic and hypertonic media was assessed after 20 h. Addition of NaCl (4-250 mM) to isotonic medium significantly and dose dependently protected CSMN in enriched cultures, increasing cell survival by up to 70% over that in isotonic medium. This response was not restricted to NaCl; addition of KCl, choline chloride, and sucrose had similar effects on cell survival. In addition, hypertonicity supported the survival of pure CSMN populations, albeit with lower potency. In cortical cell suspensions, hypertonic NaCl (20-100 mM) increased basal phosphorylation of p38 and ERK. The activation of both MAPKs, which was induced by 40 mM NaCl, was transient. Cultivation of CSMNs in media containing the specific p38 inhibitor SB203580 abolished the protective effect of hypertonic NaCl, indicating a central role for p38. We therefore conclude that hypertonicity can prevent neuronal cell death via MAPK signaling.
Junger
Heidi
H
Department of Anesthesiology, University of California San Diego, La Jolla, California 92093-0818, USA. ajunger@ucsd.edu
Edelman
David B
DB
Junger
Wolfgang G
WG
D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002794:Choline / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006982:Hypertonic Solutions / Q000494:pharmacology* / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000201:enzymology; D011712:Pyramidal Tracts / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000494:pharmacology; D013395:Sucrose / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D006982:Hypertonic Solutions; D018696:Neuroprotective Agents; D012965:Sodium Chloride; D013395:Sucrose; D011189:Potassium Chloride; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002794:Choline