Abstract：
:Although sigma 1 (σ(1)) receptors and mitogen-activated protein kinases (MAPKs) are known modulators of neuroprotection, a role for MAPK signaling pathways in σ receptor-mediated neuroprotection has not been investigated in detail.The present study aims to investigate the possible link between σ(1) receptors and MAPKs in neuroprotection. Primary mixed cortical and hippocampal neurons were treated with σ(1) receptor agonists PRE-084 or 4-PPBP in a time- and concentration-dependent manner; and in another set of experiments, cells were pre-incubated with σ(1) receptor antagonist BD1047 or MEK inhibitor PD98059 in a concentration-dependent manner prior to PRE-084 or 4-PPBP treatment. Levels of phosphorylated and total ERK1/2, JNK and p38-MAPK were determined with western blotting and ERK1/2 phosphorylation was confirmed with immunofluorescence. To investigate neuroprotection by σ(1) receptors, cells were pre-treated with PRE-084 or 4-PPBP and glucose-starved for various times: in the presence or absence of pre-incubated BD1047 or PD98059. Cell viability was then measured with MTT assay. Both PRE-084 and 4-PPBP caused phosphorylation of ERK1/2, but not p38-MAPK and JNK. ERK1/2 phosphorylation was inhibited by BD1047 and PD98059 in a concentration-dependent manner. Immunofluorescence confirmed the phosphorylation of ERK1/2 by PRE-084 and 4-PPBP and its inhibition by BD1047 and PD98059. Pre-treating glucose-deprived neurons with 4-PPBP, but not PRE-084; caused neuroprotection which was inhibited by BD1047 and PD98059. 4-PPBP, but not PRE-084; causes ERK1/2 phosphorylation-mediated neuroprotection. This presents a novel mechanism by σ(1) receptors in modulating neuroprotection.
journal_name
Neuropharmacologyjournal_title
Neuropharmacologyauthors
Tan F,Guio-Aguilar PL,Downes C,Zhang M,O'Donovan L,Callaway JK,Crack PJdoi
10.1016/j.neuropharm.2010.05.014subject
Has Abstractpub_date
2010-11-01 00:00:00pages
416-24issue
6eissn
0028-3908issn
1873-7064pii
S0028-3908(10)00139-5journal_volume
59pub_type
杂志文章abstract：:About 20-30% of patients with epilepsy continue to have seizures despite carefully monitored treatment with antiepileptic drugs. The mechanisms explaining why some patients' respond and others prove resistant to antiepileptic drugs are poorly understood. It has been proposed that pharmacoresistance is related to reduc...
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