Modulator effects of interleukin-1β and tumor necrosis factor-α on AMPA-induced excitotoxicity in mouse organotypic hippocampal slice cultures

Liliana Bernardino, Sara Xapelli, Ana P. Silva, Birthe Jakobsen, Frantz R. Poulsen, Catarina R. Oliveira, Annamaria Vezzani, João O. Malva, Jens Zimmer

Research output: Contribution to journalArticle

164 Citations (Scopus)

Abstract

The inflammatory cytokines interleukin-1β and tumor necrosis factor-α (TNF-α) have been identified as mediators of several forms of neurodegeneration in the brain. However, they can produce either deleterious or beneficial effects on neuronal function. We investigated the effects of these cytokines on neuronal death caused by exposure of mouse organotypic hippocampal slice cultures to toxic concentrations of AMPA. Either potentiation of excitotoxicity or neuroprotection was observed, depending on the concentration of the cytokines and the timing of exposure. A relatively high concentration of mouse recombinant TNF-α (10 ng/ml) enhanced excitotoxicity when the cultures were simultaneously exposed to AMPA and to this cytokine. Decreasing the concentration of TNF-α to 1 ng/ml resulted in neuroprotection against AMPA-induced neuronal death independently on the application protocol. By using TNF-α receptor (TNFR) knock-out mice, we demonstrated that the potentiation of AMPA-induced toxicity by TNF-α involves TNF receptor-1, whereas the neuroprotective effect is mediated by TNF receptor-2. AMPA exposure was associated with activation and proliferation of microglia as assessed by macrophage antigen-1 and bromodeoxyuridine immunohistochemistry, suggesting a functional recruitment of cytokine-producing cells at sites of neurodegeneration. Together, these findings are relevant for understanding the role of proinflammatory cytokines and microglia activation in acute and chronic excitotoxic conditions.

Original languageEnglish
Pages (from-to)6734-6744
Number of pages11
JournalJournal of Neuroscience
Volume25
Issue number29
DOIs
Publication statusPublished - Jul 20 2005

Fingerprint

alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Interleukin-1
Tumor Necrosis Factor-alpha
Cytokines
Tumor Necrosis Factor Receptors
Microglia
Macrophage-1 Antigen
Poisons
Neuroprotective Agents
Bromodeoxyuridine
Knockout Mice
Immunohistochemistry
Brain

Keywords

  • Cytokines
  • Glutamate
  • Inflammation
  • Microglia
  • Neurodegeneration
  • Neuroprotection

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Modulator effects of interleukin-1β and tumor necrosis factor-α on AMPA-induced excitotoxicity in mouse organotypic hippocampal slice cultures. / Bernardino, Liliana; Xapelli, Sara; Silva, Ana P.; Jakobsen, Birthe; Poulsen, Frantz R.; Oliveira, Catarina R.; Vezzani, Annamaria; Malva, João O.; Zimmer, Jens.

In: Journal of Neuroscience, Vol. 25, No. 29, 20.07.2005, p. 6734-6744.

Research output: Contribution to journalArticle

Bernardino, Liliana ; Xapelli, Sara ; Silva, Ana P. ; Jakobsen, Birthe ; Poulsen, Frantz R. ; Oliveira, Catarina R. ; Vezzani, Annamaria ; Malva, João O. ; Zimmer, Jens. / Modulator effects of interleukin-1β and tumor necrosis factor-α on AMPA-induced excitotoxicity in mouse organotypic hippocampal slice cultures. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 29. pp. 6734-6744.
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