S100B potently activates p65/c-Rel transcriptional complexes in hippocampal neurons: Clinical implications for the role of S100B in excitotoxic brain injury.
Increased serum levels of S100B are positively correlated with multiple forms of CNS damage, such as stroke, CNS trauma and neurodegenerative diseases, but also in psychiatric disorders. However, it is currently not known whether increased serum levels of S100B reflect a neuroregenerative or neurodegenerative response. Since glutamate receptor overactivation (excitotoxicity) may contribute to neuronal pathology in psychiatric disorders, we investigated the effect of S100B on N-methyl-d-aspartate (NMDA)-induced neuronal cell death. Here we demonstrate that very low concentrations of S100B significantly protect primary rat hippocampal neurons against NMDA toxicity by activation of transcription factors of the Rel/nuclear factor kappaB (NF-kappaB) family. Further experiments suggest that i) S100B activated expression of the receptor of advanced glycation products (RAGE) gene in neurons and ii) S100B induced a unique composition of the active NF-kappaB complex consisting of the p65 and c-Rel subunits suggesting a novel mechanism for NF-kappaB activation involved in S100B-mediated neuroprotection. Our data suggest that S100B secreted during the glial response to brain injury potently activates p65/c-Rel in a RAGE-dependent manner and may exert neuroprotective and neuroregenerative effects in psychiatric disorders.
Center for Neurology and Neurosurgery, Experimental Neurosurgery, Johann Wolfgang Goethe University Clinics, D-60590 Frankfurt, Germany. koegel@em.uni-frankfurt.de
D
D
Kögel
M
M
Peters
H-G
HG
König
S M A
SM
Hashemi
N T
NT
Bui
V
V
Arolt
M
M
Rothermundt
J H M
JH
Prehn
D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009414:Nerve Growth Factors; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins; D020569:Proto-Oncogene Proteins c-rel / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000502:physiology
D002352:Carrier Proteins; D018690:Excitatory Amino Acid Agonists; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D029543:Nucleocytoplasmic Transport Proteins; D020569:Proto-Oncogene Proteins c-rel; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579158:S100b protein, rat; C063447:p65 oncofetal mRNA transport protein, rat