Astrocyte-derived MCP-1 mediates neuroprotective effects of noradrenaline.
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.
Madrigal
Jose L M
JL
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Leza
Juan C
JC
Polak
Paul
P
Kalinin
Sergey
S
Feinstein
Douglas L
DL
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
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