title: Astrocyte-derived MCP-1 mediates neuroprotective effects of noradrenaline.
abstract: The neurotransmitter noradrenaline (NA) can provide neuroprotection against insults including inflammatory stimuli and excitotoxicity, which may involve paracrine effects of neighboring glial cells. Astrocytes express and secrete a variety of inflammatory and anti-inflammatory molecules; however, the effects of NA on astrocyte chemokine expression have not been well characterized. In primary astrocytes, NA increased expression of chemokine CCL2 (MCP-1) at the mRNA and protein levels. NA increased activation of an MCP-1 promoter driving luciferase expression, which was replicated by beta-adrenergic receptor agonists and a cAMP analog, and blocked by a specific beta2-adrenergic receptor antagonist. In primary neurons, addition of MCP-1 reduced NMDA-dependent glutamate release as well as glutamate-dependent Ca(2+) entry. Similarly, conditioned media from NA-treated astrocytes reduced glutamate release, an effect that was blocked by neutralizing antibody to MCP-1, whereas MCP-1 dose-dependently reduced neuronal damage attributable to NMDA or to glutamate. MCP-1 significantly reduced lactate dehydrogenase release from neurons after oxygen-glucose deprivation (OGD) and prevented the loss of ATP levels that occurred after OGD or treatment with glutamate. Incubation of neurons with astrocytes separated by a membrane to prevent physical contact showed that NA induced astrocyte release of sufficient MCP-1 to reduce neuronal damage attributable to OGD. These findings indicate that the neuroprotective effects of NA are mediated, at least in part, by induction and release of astrocyte MCP-1.
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors.forename: Jose L M
authors.initials: JL
authors.lastname: Madrigal
authors.forename: Juan C
authors.initials: JC
authors.lastname: Leza
authors.forename: Paul
authors.initials: P
authors.lastname: Polak
authors.forename: Sergey
authors.initials: S
authors.lastname: Kalinin
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism*; D018920:Coculture Techniques / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D000860:Hypoxia / Q000188:drug therapy; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D017628:Microglia / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection / Q000379:methods
chemical_list: D000319:Adrenergic beta-Antagonists; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018696:Neuroprotective Agents; D011412:Propanolamines; D012333:RNA, Messenger; D018698:Glutamic Acid; C026777:ICI 118551; D016202:N-Methylaspartate; D000255:Adenosine Triphosphate; D011433:Propranolol; D007770:L-Lactate Dehydrogenase; D005947:Glucose; D002118:Calcium; D009638:Norepinephrine