Aminopyridazines inhibit β-amyloid-induced glial activation and neuronal damage in vivo

Jeffrey M. Craft, D. Martin Watterson, Sally A. Frautschy, Linda J.Van Eldik

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

Abstract

The critical role of chronic inflammation in disease progression continues to be increasingly appreciated across multiple disease areas, especially in neurodegenerative disorders such as Alzheimer's disease. We report that late intervention with a recently discovered aminopyridazine suppressor of glial activation, developed to inhibit both oxidative and inflammatory cytokine pathways, attenuates human amyloid beta (Aβ)-induced glial activation in a murine model. Peripheral administration of the aminopyridazine MW01-070C, beginning 3 weeks after the start of intracerebroventricular infusion of human Aβ1-42, decreased the number of activated astrocytes and microglia and the levels of proinflammatory cytokines interleukin-1β, tumor necrosis factor-α and S100B in the hippocampus. Inhibition of neuroinflammation correlated with a decreased neuron loss, restoration towards control levels of synaptic dysfunction biomarkers in the hippocampus, and diminished amyloid plaque deposition. The results from this in vivo chemical biology approach provide a proof of concept that targeting of key glia inflammatory cytokine pathways can suppress Aβ-induced neuroinflammation in vivo, with resultant attenuation of neuronal damage.

Original languageEnglish
Pages (from-to)1283-1292
Number of pages10
JournalNeurobiology of Aging
Volume25
Issue number10
DOIs
StatePublished - 2004

Bibliographical note

Funding Information:
These studies were supported in part by research grants from the Institute for the Study of Aging, the Alzheimer’s Association, and NIH (AG13939, AG20243, AG21184, AG10685, NS47586); NIH training grant T32 AG00260; and a research fellowship from the PhRMA Foundation. We thank Catherine Stephens, Carolyn Smith, and Magdalena Zasadzki for technical assistance, and Drs. Mark Wainwright and Anastasia Velentza for helpful discussions and advice.

Keywords

  • Alzheimer's disease
  • Aminopyridazine
  • Amyloid
  • Animal model
  • Drug discovery
  • Glia
  • Hippocampus
  • Neuroinflammation

ASJC Scopus subject areas

  • General Neuroscience
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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