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 antiinflammatory 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 ␤-adrenergic receptor agonists and a cAMP analog, and blocked by a specific ␤2-adrenergic receptor antagonist. In primary neurons, addition of MCP-1 reduced NMDA-dependent glutamate release as well as glutamate-dependent Ca 2ϩ 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.

CXCL16 Orchestrates Adenosine A3Receptor and MCP-1/CCL2 Activity to Protect Neurons from Excitotoxic Cell Death in the CNS

“…Six hours after stimulation, astrocyte culture media were collected and analyzed by ELISA. We found a basal release of CCL2 from astrocytes, in agreement with previous data (Giullemin et al, 2003;Wittendorp et al, 2004;Madrigal et al, 2009), that increases upon CXCL16 stimulation, as shown in Figure 6B (n ϭ 7; p Ͻ 0.05). When experiments were performed with astrocytes derived from A 3 R Ϫ/Ϫ mice, CXCL16 was not able to increase the basal release of CCL2 (1660 pg/ml/mg vs 1410 pg/ml/mg).…”

“…The ability of CCL2 to preserve neuronal cell death by other insults, such as HIV-1 trans-activator protein (Tat) toxicity, has been documented (Yao et al, 2009). Moreover the hypothesis that CCL2 can act as a critical intermediate factor driving neuroprotection is consistent with the findings that, in human cortical neuronal cultures, CCL2 released by astrocytes, upon RANTES stimulation, reduces the toxic effect of NMDA and Tat (Eugenin et al, 2003), and with recent data showing that astrocyte-derived CCL2 mediates the neuroprotective effect of noradrenaline against excitotoxic and OGD damages (Madrigal et al, 2009).…”

“…It has been recently found that astrocyte-derived CCL2 represents an intermediate player in the neuroprotective effect exerted by noradrenaline against excitotoxic or OGD damage (Madrigal et al, 2009). Since we found that CXCL16 induces the release of CCL2 from astrocytes, we wanted to determine whether astrocyte-derived CCL2 is a mediator of CXCL16 neuroprotection.…”

Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine

“…In addition, other mechanisms of the neuroprotective effects of NE have been suggested. It has been shown that NE also acts on astrocytes resulting in the secretion of the neuroprotective chemokine MCP-1 (24) and that it is able to protect neurons from Aβ-induced damage involving PPARδ and GSH-synthesis (25).…”

Tissue Engineering for Tissue and Organ Regeneration

“…MSCs combined with growth factors also provided functional effects and in some cases reduced the lesion volume, the number of apoptotic cells within the ischemic lesion and stimulated host repair responses as recruitment of host progenitor cells (Esneault et al, 2008;Rahnemai-Azar et al, 2011;van Velthoven et al, 2009). Modulation of inflammatory and immune response or production of neuroprotective chemokines such as fractalkine and monocyte chemoattractant protein-1 (MCP-1) by MSCs are others mechanisms that may be involved in neuronal protection during ischemia (Re & Przedborski, 2006;Ohtaki et al, 2008;Madrigal et al, 2009;Garbayo et al, 2011). Recruitment of host progenitor cells may also contribute to MSC-induced repair processes in response to chemokines [growth-related oncogene (GRO), MCP-1] secreted by the implanted cells (Rahnemai-Azar et al, 2011;Gordon et al, 2009).…”