Activation of NF-kappaB p65/c-Rel dimer is associated with neuroprotection elicited by mGlu5 receptor agonists against MPP(+) toxicity in SK-N-SH cells.
Nuclear factor-kappaB (NF-kappaB) is a transcriptional regulator of neuron survival eliciting diverse effects according to the specific composition of its active dimer. While p50/p65 mediates neurodegenerative events, c-Rel-containing dimers promote cell survival. Stimulation of metabotropic glutamate receptors type 5 (mGlu5) reduces neuron vulnerability to amyloid-beta through activation of anti-apoptotic, c-Rel-dependent transcription of Bcl-X(L) pathway. We here evaluated the protective activity of mGlu5 agonists in dopaminergic SK-N-SH cells exposed to 1-methyl-4-phenylpyridinium (MPP(+)), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causing parkinsonism in experimental animals. MPP(+) produced a concentration-dependent cell loss. Activation of mGlu5 receptors by CHPG (1 mM) and 3HPG (50 microM) abolished the toxic effect produced by 3 microM MPP(+). The neuroprotection was associated with activation of NF-kappaB p65/c-Rel dimer and reduction of p50/p65. These effects were prevented by the mGlu5 receptor antagonist MPEP (5 microM). It is suggested that mGlu5 receptor agonists through activation of a c-Rel-dependent anti-apoptotic pathway can rescue dopaminergic cell from mitochondrial toxicity.
Sarnico
I
I
Division of Pharmacology and Experimental Therapeutics, Department of Biomedical Sciences and Biotechnologies, School of Medicine, University of Brescia, Brescia, Italy.
Boroni
F
F
Benarese
M
M
Sigala
S
S
Lanzillotta
A
A
Battistin
L
L
Spano
P
P
Pizzi
M
M
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000704:Analysis of Variance; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009447:Neuroblastoma; D010648:Phenylacetates / Q000494:pharmacology; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism*; D013997:Time Factors
C107349:2-chloro-5-hydroxyphenylglycine; D018690:Excitatory Amino Acid Agonists; D006540:Herbicides; D016328:NF-kappa B; D010648:Phenylacetates; D020569:Proto-Oncogene Proteins c-rel; D015655:1-Methyl-4-phenylpyridinium; D005998:Glycine