PMID- 17097633
OWN - NLM
STAT- MEDLINE
DCOM- 20070124
LR  - 20131121
IS  - 0014-2999 (Print)
IS  - 0014-2999 (Linking)
VI  - 553
IP  - 1-3
DP  - 2006 Dec 28
TI  - MEK inhibition exacerbates ischemic calcium imbalance and neuronal cell death in 
      rat cortical cultures.
PG  - 18-27
AB  - Interruption in the brain's blood supply leads to an ischemic condition, which is 
      characterised by a depletion of energy phosphates and related failure of ionic 
      pumps, increased extracellular potassium, neuronal depolarisation and release of 
      excitatory amino acids, e.g. glutamate. The subsequent activation of 
      N-methyl-d-aspartate glutamate receptors triggers a wide range of intracellular 
      signals, including the mitogen-activated protein kinase (MAPK) pathway. 
      Activation and inhibition of the MAPK/extracellular regulated kinases (ERK) 
      pathway are both reported to be neuroprotective in conditions associated with 
      excitotoxic injury. The present study was designed to explore the involvement of 
      this signalling pathway in cultured rat cortical neurons subjected to 
      chemically-induced ischemia obtained by coupling the mitochondrial toxin 
      3-nitropropionic acid with glucose deprivation. Loss of neuronal viability, 
      reduced neuronal energy state (ATP level and mitochondrial membrane potential) 
      and increased cytoplasmic mitochondrial calcium were all observed. The NMDA 
      antagonist MK-801 counteracted these effects, suggesting a glutamate-dependent 
      ischemic cell death. Addition of U0126, a selective inhibitor of MAPK kinase, 
      exacerbated this neuronal cell death. However, non-significant changes in 
      activated cAMP response element-binding protein were seen. The rise in 
      cytoplasmic calcium under ischemic conditions was associated with neuronal cell 
      swelling. Both swelling and increase in cytoplasmic calcium were exacerbated and 
      prevented by U0126 and MK-801, respectively. These data suggest that in this 
      ischemic model the MAPK/ERK pathway might exert a regulatory effect on calcium 
      entry independent from gene expression.
FAU - Franceschini, Davide
AU  - Franceschini D
AD  - Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline 
      Research and Development Limited, New Frontiers Science Park, Third Avenue, 
      Harlow CM19 5AW, UK. davide.franceschini@unipd.it
FAU - Giusti, Pietro
AU  - Giusti P
FAU - Skaper, Stephen D
AU  - Skaper SD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060908
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Receptors, Glutamate)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - IY9XDZ35W2 (Glucose)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Blotting, Western
MH  - Brain Ischemia/*pathology
MH  - Calcium/*metabolism
MH  - Cell Death/physiology
MH  - Cell Survival/physiology
MH  - Cells, Cultured
MH  - Cerebral Cortex/metabolism/*pathology
MH  - Cyclic AMP Response Element-Binding Protein/metabolism
MH  - Electron Transport/physiology
MH  - Energy Metabolism/physiology
MH  - Extracellular Signal-Regulated MAP Kinases/*antagonists & inhibitors
MH  - Female
MH  - Glucose/deficiency
MH  - L-Lactate Dehydrogenase/metabolism
MH  - Membrane Potentials/physiology
MH  - Mitochondrial Membranes/physiology
MH  - Neurons/*physiology
MH  - Phosphorylation
MH  - Pregnancy
MH  - Rats
MH  - Receptors, Glutamate/physiology
MH  - Receptors, N-Methyl-D-Aspartate/physiology
EDAT- 2006/11/14 09:00
MHDA- 2007/01/25 09:00
CRDT- 2006/11/14 09:00
PHST- 2005/12/27 00:00 [received]
PHST- 2006/08/28 00:00 [revised]
PHST- 2006/08/29 00:00 [accepted]
PHST- 2006/11/14 09:00 [pubmed]
PHST- 2007/01/25 09:00 [medline]
PHST- 2006/11/14 09:00 [entrez]
AID - S0014-2999(06)00929-0 [pii]
AID - 10.1016/j.ejphar.2006.08.043 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2006 Dec 28;553(1-3):18-27. doi: 10.1016/j.ejphar.2006.08.043. 
      Epub 2006 Sep 8.