PMID- 23752092
OWN - NLM
STAT- MEDLINE
DCOM- 20140813
LR  - 20130906
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Linking)
VI  - 73
DP  - 2013 Oct
TI  - Monocyte Chemoattractant Protein-1 upregulates GABA-induced current: evidence of 
      modified GABAA subunit composition in cortical neurons from the G93A mouse model 
      of Amyotrophic Lateral Sclerosis.
PG  - 247-60
LID - S0028-3908(13)00259-1 [pii]
LID - 10.1016/j.neuropharm.2013.05.045 [doi]
AB  - Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that affects 
      upper and lower motor neurons. Previous evidence has indicated that excitotoxic 
      cell death in ALS may remarkably depend on Cl(-) ion influx through the GABA(A) 
      receptors. In this study we have analysed the effect of Monocyte Chemoattractant 
      Protein-1 (MCP-1), a chemokine expressed to a higher level in ALS patients, on 
      GABAA receptors in cultured cortical neurons from a genetic model of ALS (G93A) 
      and compared with wild type SOD1 (SOD1) and their corresponding non transgenic 
      littermates (Control). By performing electrophysiological experiments we have 
      observed that, in cortical neurons MCP-1 (2-150 ng/ml) induced an enhancement of 
      GABA-evoked currents that was significantly higher in G93A neurons compared to 
      controls. The effect of MCP-1 was not dependent on the activation of its receptor 
      CCR2, while it was blocked by flumazenil, the antagonist of benzodiazepine sites. 
      Analysis of GABAA receptor subunit composition has indicated an altered subunit 
      expression level in G93A cortical neurons compared to controls. Instead, in 
      cultured spinal neurons MCP-1 induced a significant reduction of GABA-evoked 
      currents, also through the benzodiazepine sites, indicating a region-specific 
      mechanism of action. However, no differences were observed in the current 
      reduction between the three neuronal populations. These findings provide the 
      first evidence that MCP-1, acting on benzodiazepine sites, can modulate the 
      GABA-evoked currents, depending on the subunit composition of GABA(A) receptor. 
      In cortical neurons MCP-1 upmodulates the GABA-evoked current and this effect is 
      exacerbated in the mutated neurons. It is reasonable to assume that the higher 
      Cl(-) influx through GABA(A) receptors in the presence of MCP-1 in mutated 
      cortical neurons may induce an excitotoxicity acceleration. Agents able to block 
      the MCP-1 production may then prove useful for ALS treatment.
CI  - Copyright (c) 2013 Elsevier Ltd. All rights reserved.
FAU - Caioli, Silvia
AU  - Caioli S
AD  - IRCCS Fondazione S. Lucia, Via del Fosso di Fiorano, 64, 00143 Rome, Italy.
FAU - Pieri, Massimo
AU  - Pieri M
FAU - Antonini, Alessia
AU  - Antonini A
FAU - Guglielmotti, Angelo
AU  - Guglielmotti A
FAU - Severini, Cinzia
AU  - Severini C
FAU - Zona, Cristina
AU  - Zona C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130608
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (GABA-A Receptor Antagonists)
RN  - 0 (Protein Subunits)
RN  - 0 (Receptors, GABA-A)
RN  - 40P7XK9392 (Flumazenil)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
SB  - IM
MH  - Amyotrophic Lateral Sclerosis/genetics/*metabolism
MH  - Animals
MH  - Cells, Cultured
MH  - Cerebral Cortex/drug effects/physiology
MH  - Chemokine CCL2/antagonists & inhibitors/*pharmacology
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Flumazenil/pharmacology
MH  - GABA-A Receptor Antagonists/pharmacology
MH  - Humans
MH  - Male
MH  - Membrane Potentials/drug effects/physiology
MH  - Mice
MH  - Mice, Transgenic
MH  - Neurons/drug effects/physiology
MH  - Protein Subunits/metabolism
MH  - Receptors, GABA-A/*metabolism
MH  - Spinal Cord/drug effects/physiology
MH  - gamma-Aminobutyric Acid/pharmacology
OTO - NOTNLM
OT  - ALS
OT  - Electrophysiology
OT  - GABA receptor modulator
OT  - GABA-induced current
OT  - Immunosystem
OT  - Neurodegeneration
EDAT- 2013/06/12 06:00
MHDA- 2014/08/15 06:00
CRDT- 2013/06/12 06:00
PHST- 2013/02/04 00:00 [received]
PHST- 2013/05/06 00:00 [revised]
PHST- 2013/05/27 00:00 [accepted]
PHST- 2013/06/12 06:00 [entrez]
PHST- 2013/06/12 06:00 [pubmed]
PHST- 2014/08/15 06:00 [medline]
AID - S0028-3908(13)00259-1 [pii]
AID - 10.1016/j.neuropharm.2013.05.045 [doi]
PST - ppublish
SO  - Neuropharmacology. 2013 Oct;73:247-60. doi: 10.1016/j.neuropharm.2013.05.045. 
      Epub 2013 Jun 8.