Glia as a therapeutic target: Selective suppression of human amyloid-β-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration

Hantamalala Ralay Ranaivo, Jeffrey M. Craft, Wenhui Hu, Ling Guo, Laura K. Wing, Linda J. Van Eldik, D. Martin Watterson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

130 Scopus citations

Abstract

A corollary of the neuroinflammation hypothesis is that selective suppression of neurotoxic products produced by excessive glial activation will result in neuroprotection. We report here that daily oral administration to mice of the brain-penetrant compound 4,6-diphenyl-3-(4-(pyrimidin-2-yl)piperazin-1- yl)pyridazine (MW01-5-188WH), a selective inhibitor of proinflammatory cytokine production by activated glia, suppressed the human amyloid-β(Aβ) 1-42-induced upregulation of interleukin-1β, tumor necrosis factor-́, and S100B in the hippocampus. Suppression of neuroinflammation was accompanied by restoration of hippocampal synaptic dysfunction markers synaptophysin and postsynaptic density-95 back toward control levels. Consistent with the neuropathophysiological improvements, MW01-5-188WH therapy attenuated deficits inYmaze behavior, a hippocampal-linked task. Oral MW01-5-188WH therapy begun 3 weeks after initiation of intracerebroventricular infusion of human Aβ decreased the numbers of activated astrocytes and microglia and the cytokine levels in the hippocampus without modifying amyloid plaque burden or altering peripheral tissue cytokine upregulation in response to an in vivo inflammatory challenge. The results provide a novel integrative chemical biology proof in support of the neuroinflammation hypothesis of disease progression, demonstrate that neurodegeneration can be attenuated independently of plaque modulation by targeting innate brain proinflammatory cytokine responses, and indicate the feasibility of developing efficacious, safe, and selective therapies for neurodegenerative disorders by targeting key glial activation pathways.

Original languageEnglish (US)
Pages (from-to)662-670
Number of pages9
JournalJournal of Neuroscience
Volume26
Issue number2
DOIs
StatePublished - Jan 11 2006

Keywords

  • Alzheimer's disease
  • Behavior
  • Cytokines
  • Glia
  • Neurodegeneration
  • Neuroinflammation

ASJC Scopus subject areas

  • Neuroscience(all)

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