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The Journal of Neuroscience, January 7, 2009, 29(1):263-267; doi:10.1523/JNEUROSCI.4926-08.2009

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Brief Communications
Astrocyte-Derived MCP-1 Mediates Neuroprotective Effects of Noradrenaline

Jose L. M. Madrigal,^3,4 Juan C. Leza,^3,4 Paul Polak,^1,2 Sergey Kalinin,^1,2 and Douglas L. Feinstein^1,2

¹Department of Anesthesiology, University of Illinois, Chicago, Illinois 60612, ²Jesse Brown Veteran's Affairs Hospital, Chicago, Illinois 60612, ³Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain, and ⁴Centro de Investigación Biomédica en Red en Salud Mental, 28040 Madrid, Spain

Correspondence should be addressed to Douglas L. Feinstein, 835 South Wolcott Street, MC 513, Room E719, University of Illinois, Chicago, IL 60612. Email: dlfeins{at}uic.edu

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 β-adrenergic receptor agonists and a cAMP analog, and blocked by a specific β2-adrenergic receptor antagonist. In primary neurons, addition of MCP-1 reduced NMDA-dependent glutamate release as well as glutamate-dependent Ca²⁺ 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.

Key words: chemokines; glia; cAMP; glutamate; NMDA; ischemia

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Received Oct. 13, 2008; revised Nov. 14, 2008; accepted Dec. 1, 2008.

Correspondence should be addressed to Douglas L. Feinstein, 835 South Wolcott Street, MC 513, Room E719, University of Illinois, Chicago, IL 60612. Email: dlfeins{at}uic.edu

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