Successful inhibition of excitotoxic neuronal damage and microglial activation after delayed application of interleukin-1 receptor antagonist.
Interleukin (IL)-1 is an important mediator of neuronal demise and glial activation after acute central nervous system lesions and is antagonized by IL-1 receptor antagonist (IL-1RA). Here we determined the time window in which IL-1RA elicits neuroprotective effects in rat organotypic hippocampal slice cultures (OHSC). OHSC were lesioned with N-methyl-D-aspartate (NMDA) and treated with IL-1RA (100 ng/ml) at different time points postinjury or were left untreated. Damaged neurons, microglial cells, and astrocytes were labelled with NeuN, propidium iodide, isolectin B(4), or glial fibrillary acidic protein (GFAP), respectively, and were analyzed by confocal laser scanning microscopy. In lesioned OHSC, the most dramatic increase in microglial cell number occurred between 8 and 16 hr postinjury, and the maximal neuronal demise was found between 16 and 24 hr postinjury. The cellular source of IL-1beta was investigated by immunohistochemistry, and IL-1beta immunoreactivity was found in few microglial cells at 4 hr postinjury and in numerous microglial cells and astrocytes at 16 hr postinjury. In both glial populations, IL-1beta immunoreactivity peaked at 24 hr postinjury. IL-1RA treatment potently suppressed neuronal damage by 55% when initiated within the first 16 hr postinjury (P < 0.05), and IL-1RA treatment initiated at 24 hr postinjury resulted in weaker but still significant neuroprotection. IL-1RA treatment also reduced the number of microglial cells significantly when initiated within 36 hr postinjury (P < 0.05). In conclusion, IL-1RA exhibits significant neuroprotective effects in this in vitro model of excitotoxic injury even after delayed application.
Vogt
Cornelia
C
Dr. Senckenbergische Anatomie, Institut für Anatomie II, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Hailer
Nils P
NP
Ghadban
Chalid
C
Korf
Horst-Werner
HW
Dehghani
Faramarz
F
D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000187:drug effects; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D018613:Microscopy, Confocal; D016202:N-Methylaspartate / Q000633:toxicity; D009410:Nerve Degeneration / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D013995:Time
D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017472:Receptors, Interleukin-1; D016202:N-Methylaspartate