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The Journal of Neuroscience, July 20, 2005, 25(29):6734-6744; doi:10.1523/JNEUROSCI.1510-05.2005

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Neurobiology of Disease
Modulator Effects of Interleukin-1 and Tumor Necrosis Factor- on AMPA-Induced Excitotoxicity in Mouse Organotypic Hippocampal Slice Cultures

Liliana Bernardino,² Sara Xapelli,² Ana P. Silva,² Birthe Jakobsen,¹ Frantz R. Poulsen,¹ Catarina R. Oliveira,² Annamaria Vezzani,³ João O. Malva,² and Jens Zimmer¹

¹Anatomy and Neurobiology, Institute of Medical Biology, University of Southern Denmark, DK-5000 Odense C, Denmark, ²Center for Neuroscience and Cell Biology, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal, and ³Laboratory of Experimental Neurology, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, 20157 Milano, Italy

The inflammatory cytokines interleukin-1 and tumor necrosis factor- (TNF-) 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- (10 ng/ml) enhanced excitotoxicity when the cultures were simultaneously exposed to AMPA and to this cytokine. Decreasing the concentration of TNF- to 1 ng/ml resulted in neuroprotection against AMPA-induced neuronal death independently on the application protocol. By using TNF- receptor (TNFR) knock-out mice, we demonstrated that the potentiation of AMPA-induced toxicity by TNF- 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.

Key words: glutamate; cytokines; inflammation; neuroprotection; neurodegeneration; microglia

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Received Dec 21, 2004; revised May 31, 2005; accepted May 31, 2005.

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