Norepinephrine and nitric oxide promote cell survival signaling in hippocampal neurons.
Nitric oxide (NO), physical exercise and/or antidepressant drugs, through the increased release of norepinephrine and brain-derived neurotrophic factor (BDNF), have been shown to exert profound protective, pro-survival effects on neurons otherwise compromised by injury, disease, prolonged stress, and subsequent depression in vivo. We sought, therefore, to evaluate such survival and neuroprotection in hippocampal neurons in culture, which, in an analogous model of in vivo cellular stress, was deprived of several vital nutrients. We assessed pro-survival outcomes following the application of norepinephrine or the noradrenergic partial agonist, clonidine, a general nitric oxide synthase inhibitor and NO donor, using a cell survival assay and quantitative Western blotting of the survival signaling molecules, BDNF, P-CREB, P-Akt, and P-MAPK in hippocampal neuronal lysates. We demonstrate that norepinephrine, clonidine, the NO donor and various combinations of these drugs increased cell survival and the immunoreactivity of the four survival signaling molecules in the face of nutrient deprivation stress, whereas the NO synthase inhibitor, and each of several survival signaling pathway inhibitors all decreased cell survival even below that of controls without nutrient supplementation. These results demonstrate that conditions that make cells vulnerable to environmental/toxic insult can be offset by norepinephrine and its related drugs or by NO donors and exacerbated by drugs that specifically inhibit a key survival signaling pathway. These results indicate that pharmacological intervention can promote neuroprotection and survival signaling in the face of nutrient withdrawal, but that this may require that several pathways remain intact.
Department of Biological Sciences, California State University, Los Angeles, 5151 State University Dr., Los Angeles, CA 90032, USA.
Neha J
NJ
Patel
Michael J
MJ
Chen
Amelia A
AA
Russo-Neustadt
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D003000:Clonidine / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005502:Food; D006624:Hippocampus / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology*; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013312:Stress, Physiological
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D003000:Clonidine; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine