Aminopyridazines inhibit beta-amyloid-induced glial activation and neuronal damage in vivo.
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 (Abeta)-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 Abeta1-42, decreased the number of activated astrocytes and microglia and the levels of proinflammatory cytokines interleukin-1beta, tumor necrosis factor-alpha 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 Abeta-induced neuroinflammation in vivo, with resultant attenuation of neuronal damage.
Craft
Jeffrey M
JM
Drug Discovery Program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Watterson
D Martin
DM
Frautschy
Sally A
SA
Van Eldik
Linda J
LJ
D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D000631:Aminopyridines / Q000008:administration & dosage*; D016229:Amyloid beta-Peptides; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D007263:Infusions, Parenteral; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects* / Q000473:pathology*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D016896:Treatment Outcome
D000631:Aminopyridines; D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents