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

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


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.

Original languageEnglish
Pages (from-to)115-122
Number of pages8
JournalJournal of Molecular Neuroscience
Issue number1
StatePublished - Aug 2004

Bibliographical note

Funding Information:
These studies were supported in part by grants from the Institute for the Study of Aging, the Alzheimer’s Association, and NIH grants AG13939, AG20243, AG21184, AG00260, and NS47586.


  • Alzheimer's disease
  • Animal model
  • Behavior
  • Cytokines
  • Drug discovery
  • Glia
  • Neuroinflammation
  • Pyridazines

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience


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