Neurotoxic effects of tumor necrosis factor alpha in primary human neuronal cultures are mediated by activation of the glutamate AM PA receptor subtype: Implications for AIDS neuropathogenesis

Harris A. Gelbard*, Kirk A. Dzenko, David Di Loreto, Coca del Cerro, Manuel del Cerro, Leon C. Epstein

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

144 Scopus citations

Abstract

Human immunodeficiency virus type 1 (HIV) infection of the central nervous system is characterized by neuronal loss in discrete areas of the central nervous system. We have previously demonstrated that HIV-infected monocytes in culture with astroglial cells produce high levels (≥ 200 pg/ml) of the cytokine tumor necrosis factor-alpha (TNFα). We now demonstrate that TNFα (≥ 200 pg/ml) is neurotoxic to cultured primary human fetal cortical neurons at both light and electron microscopic levels. Subtoxic doses of TNFα (50 pg/ml) are neurotoxic in combination with the glutamate (±)-α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) subtype receptor agonist AMPA (100 μA/). The neurotoxic effects of TNFα (200 μg/ml) are blocked in part by the AMPA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (10 μM/). This suggests that TNFα may exert neurotoxic effects on human neurons by indirect activation of AMPA receptors, which may be important in the pathogenesis and treatment of HIV-mediated encephalopathy.

Original languageEnglish (US)
Pages (from-to)417-422
Number of pages6
JournalDevelopmental Neuroscience
Volume15
Issue number6
DOIs
StatePublished - Jan 1 1993

Keywords

  • (±)-α-Amino-3-hydroxy-5-methyl-isoxazole-4-proprionic acid
  • 6-Cyano-7-nitroquinoxaline-2, 3-dione
  • Central nervous system
  • Cytokine
  • Human immunodeficiency virus
  • Non-N-methyl-D-aspartate receptor
  • Tumor necrosis factor-alpha

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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