The vitamin-E analog trolox and the NMDA antagonist MK-801 protect pyramidal neurons in hippocampal slice cultures from IL-1beta-induced neurodegeneration.
The neurotoxic effect of the pro-inflammatory cytokine interleukin (IL)-1beta was studied in monolayer cultures, obtained using roller-drum incubation of hippocampal slices from neonatal Sprague Dawley rats. Following exposure to recombinant rat IL-1beta for four days, a concentration dependent loss was observed in the number of NMDAR1 receptor subunit immunoreactive pyramidal neurons in the cultures, reaching significance at 10 ng/ml rIL-1beta. Also incubation with recombinant mouse IL-1beta caused a loss of pyramidal neurons, with a significant effect at a concentration of 30 pg/ml. The vitamin E analog trolox (30 microM) was found to exert a protective effect against the rIL-1beta induced neuronal degeneration. A neuroprotective action against rIL-1beta was also found after co-incubation with the NMDA antagonist dizocilpine (MK-801; 30 microM), while no protection was found with the GABAA mimetic clomethiazole. Hence, the pro-inflammatory cytokine IL-1beta is neurotoxic to hippocampal pyramidal neurons when studied in an in vitro system with advanced phenotypic characteristics. The neuroprotective effects exerted by trolox and MK-801 suggest that free radicals and NMDA receptor-mediated processes are involved in IL-1beta -induced neurodegeneration.
Radesäter
Ann-Cathrin
AC
Bioscience, Local Discovery Research Area CNS and Pain Control, AstraZeneca, SE-151 85 Södertälje, Sweden.
Johansson
Sara
S
Oberg
Caroline
C
Luthman
Johan
J
D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D002719:Chlormethiazole / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018757:GABA Modulators / Q000494:pharmacology; D006624:Hippocampus / Q000473:pathology*; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000633:toxicity*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D017966:Pyramidal Cells / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects
D000975:Antioxidants; D002839:Chromans; D018690:Excitatory Amino Acid Agonists; D018757:GABA Modulators; D007375:Interleukin-1; D018696:Neuroprotective Agents; D011963:Receptors, GABA-A; D002719:Chlormethiazole; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid