Interleukin-1 beta attenuates excitatory amino acid-induced neurodegeneration in vitro: involvement of nerve growth factor.

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Abstract

Certain cytokines have been reported to exert neurotrophic actions in vivo and in vitro. In the present study, we investigated the possible neuroprotective actions of the cytokine human recombinant interleukin-1 beta (hrIL-1 beta) against excitatory amino acid (EAA)-induced neurodegeneration in cultured primary cortical neurons. Brief (15 min) exposure of cultures to submaximal concentrations of glutamate, NMDA, AMPA, or kainate caused extensive neuronal death (approximately 70% of all neurons). Neuronal damage induced by the EAAs was significantly reduced (up to 70%) by pretreatment with 500 ng/ml (6.5 x 10(3) U/ml) hrIL-1 beta for 24 hr. The neuroprotective effect of hrIL-1 beta was reversed by coapplication of an IL-1 receptor antagonist (IL-1ra, 50 micrograms/ml). Neuroprotective actions of hrIL-1 beta were also reduced by administration of a neutralizing monoclonal antibody to NGF (65% inhibition). In concordance, the neurotoxic actions of EAAs were significantly reduced (by 40%) after pretreatment with NGF (100 ng/ml for 48 hr). Furthermore, an additive neuroprotective effect of approximately 75% was observed when cultures were exposed to a combination of hrIL-1 beta and NGF. In contrast, exposure of cultures to high concentrations hrIL-1 beta alone (100 micrograms/ml, 1.3 x 10(6) U/ml) for periods up to 72 hr resulted in neurotoxicity, which was reversed by IL-1ra (1 mg/ml). These findings suggest that hrIL-1 beta can limit EAA-induced neuronal damage. These effects appear to be may be mediated, at least in part, via NGF. These findings may be relevant to the understanding of neurodegenerative diseases.

Keyword(s)

Analysis of Variance; Animals; Cells, Cultured; Comparative Study; Dose-Response Relationship, Drug; Fetus; Human; Kinetics; Rats; Rats, Sprague-Dawley; Support, Non-U.S. Gov't; cytology: Neurons; drug effects: Cell Death; drug effects: Nerve Degeneration; immunology: Nerve Growth Factors; pharmacology: Antibodies, Monoclonal; pharmacology: Excitatory Amino Acids; pharmacology: Glutamic Acid; pharmacology: Interleukin-1; pharmacology: Kainic Acid; pharmacology: N-Methylaspartate; pharmacology: Neurotoxins; pharmacology: Recombinant Proteins; pharmacology: Sialoglycoproteins; pharmacology: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; physiology: Cerebral Cortex

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