Journal of Molecular Neuroscience

, Volume 24, Issue 1, pp 115–122 | Cite as

Aminopyridazines attenuate hippocampus-dependent behavioral deficits induced by human β-amyloid in a murine model of neuroinflammation

  • Jeffrey M. Craft
  • Linda J. Van Eldik
  • Magdalena Zasadzki
  • Wenhui Hu
  • D. Martin Watterson
Neuroinflammation

Abstract

The importance of glial cell-driven neuroinflammation in the pathogenesis and progression of Alzheimer’s disease (AD) led us to initiate a drug discovery effort targeting the neuroinflammatory cycle that is characteristic of AD. We used our synthetic chemistry platform focused on bioavailable aminopyridazines as a new chemotype for AD drug discovery to develop novel, selective suppressors of key inflammatory and oxidative pathways in glia. We found that MW01-070C, an aminopyridazine that works via mechanisms distinct from NSAIDs and p38 MAPK inhibitors, attenuates β-amyloid (Aβ)-induced neuroinflammation and neuronal dysfunction in a dose-dependent manner, and prevents Aβ-induced behavioral impairment. In vivo data were obtained with a murine model that uses intraventricular infusion of human Aβ1–42 peptide and replicates many of the hallmarks of AD pathology, including neuroinflammation, neuronal and synaptic degeneration, and amyloid deposition. The quantifiable endpoint pathology is robust, reproducible, and rapid in onset. Our results provide a proof of concept that targeting neuroinflammation with aminopyridazines is a viable AD drug discovery approach that has the potential to modulate disease progression and document the utility of this mouse model for preclinical screening of compounds targeting AD-relevant neuroinflammation and neuronal death.

Index Entries

Neuroinflammation pyridazines cytokines drug discovery glia Alzheimer’s disease animal model behavior 

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Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • Jeffrey M. Craft
    • 1
    • 2
  • Linda J. Van Eldik
    • 1
    • 2
  • Magdalena Zasadzki
    • 1
    • 3
  • Wenhui Hu
    • 1
    • 2
    • 3
  • D. Martin Watterson
    • 1
    • 3
  1. 1.Drug Discovery ProgramNorthwestern University Feinberg School of MedicineChicago
  2. 2.Department of Cell and Molecular BiologyNorthwestern University Feinberg School of MedicineChicago
  3. 3.Department of Molecular Pharmacology and Biological ChemistryNorthwestern University Feinberg School of MedicineChicago

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