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Neuropharmacology. 2013 Dec;75:337-46. doi: 10.1016/j.neuropharm.2013.07.037. Epub 2013 Aug 16.

CCL5-glutamate interaction in central nervous system: Early and acute presynaptic defects in EAE mice.

Author information

1
Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genoa, Viale Cembrano 4, Genoa 16148, Italy.
2
Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, Genoa 16163, Italy.
3
Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Largo Daneo 3, Genoa 16132, Italy.
4
Laboratory of Oncology, Istituto Giannina Gaslini, Largo G. Gaslini 5, Genoa 16147, Italy.
5
Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Largo Daneo 3, Genoa 16132, Italy; Center of Excellence for Biomedical Research, University of Genoa, Viale Benedetto XV, Genoa 16132, Italy.
6
Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genoa, Viale Cembrano 4, Genoa 16148, Italy; Center of Excellence for Biomedical Research, University of Genoa, Viale Benedetto XV, Genoa 16132, Italy. Electronic address: pittalug@pharmatox.unige.it.

Abstract

We investigated the CCL5-glutamate interaction in the cortex and in the spinal cord from mice with Experimental Autoimmune Encephalomyelitis (EAE) at 13 and 21/30 days post immunization (d.p.i.), representing the onset and the peak of the disease, respectively. An early reduction of the KCl-evoked glutamate release was observed in cortical terminals from EAE mice at 13 d.p.i., persisting until 21/30 d.p.i. A concomitant reduction of the depolarization-evoked cyclic adenosine monophosphate (cAMP), but not of the inositol 1,4,5-trisphosphate (IP3) cortical production also occurred at 13 d.p.i, that still was detectable at the acute stage of disease (21 dp.i.). Inasmuch, the CCL5-mediated inhibition of glutamate exocytosis observed in control mice turned to facilitation in EAE mouse cortex at 13 d.p.i., then becoming undetectable at 21/30 d.p.i. Differently, glutamate exocytosis, as well as IP3 and cAMP productions were unaltered in spinal cord synaptosomes from EAE mice at 13 d.p.i., but significantly increased at 21/30 d.p.i., while the presynaptic CCL5-mediated facilitation of glutamate exocytosis observed in control mice remained unchanged. In both CNS regions, the presynaptic defects were parallelled by increased CCL5 availability. Inasmuch, the presynaptic defects so far described in EAE mice were reminiscent of the effects acute CCL5 exerts in control conditions. Based on these observations we propose that increased CCL5 bioavailability could have a role in determining the abovedescribed impaired presynaptic impairments in both CNS regions. These presynaptic defects could be relevant to the onset of early cognitive impairments and acute neuroinflammation and demyelinating processes observed in multiple sclerosis patients.

KEYWORDS:

4′-6′-diaminidino-2-phenylindole; AC; CCL5; CD45; CNS; CSF; Cortex; DAPI; EAE; EAE mice; Experimental Autoimmune Encephalomyelitis; Glutamate release; HE; IP(3); LFB; Luxol Fast Blue; MOG; MS; PLC; Regulated upon activation normal T cells expressed and secreted, Tris-buffered saline; Spinal cord; Tris; Tris-(hydroxymethyl)-amino methane; [(3)H]D-ASP; [(3)H]d-aspartate; adenylyl cyclase; cAMP; central nervous systems; cerebrospinal fluid; cluster of differentiation 45; cyclic adenosine monophosphate; d.p.i.; days post immunization; f.c.; final concentration; haematoxylin eosin; inositol-1,4,5-trisphosphate; multiple sclerosis; myelin oligodendrocyte glycoprotein; n.s.; not significant; phospholipase C

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