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-beta (Abeta) 1-42-induced upregulation of interleukin-1beta, tumor necrosis factor-alpha, 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 in Y maze behavior, a hippocampal-linked task. Oral MW01-5-188WH therapy begun 3 weeks after initiation of intracerebroventricular infusion of human Abeta 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Amyloid beta-Peptides / administration & dosage
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Amyloid beta-Peptides / antagonists & inhibitors
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Amyloid beta-Peptides / toxicity*
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
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Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
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Anti-Inflammatory Agents, Non-Steroidal / toxicity
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Astrocytes / drug effects*
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Astrocytes / metabolism
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Biological Availability
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Brain / drug effects*
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Brain / metabolism
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Chemical and Drug Induced Liver Injury / etiology
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Cytokines / biosynthesis*
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Cytokines / genetics
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Depression, Chemical
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Drug Evaluation, Preclinical
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Female
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Gene Expression Regulation / drug effects
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Hippocampus / drug effects*
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Hippocampus / metabolism
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Hippocampus / physiology
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Humans
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Infusions, Parenteral
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Interleukin-1 / biosynthesis
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Interleukin-1 / genetics
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Lipopolysaccharides / pharmacology
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Maze Learning / drug effects
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Mice
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Mice, Inbred C57BL
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Microglia / drug effects*
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Microglia / metabolism
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Microsomes, Liver / metabolism
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Nerve Degeneration / prevention & control*
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Nerve Growth Factors / biosynthesis
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Nerve Growth Factors / genetics
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Neuroprotective Agents / administration & dosage
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Neuroprotective Agents / pharmacokinetics
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Neuroprotective Agents / therapeutic use*
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Neuroprotective Agents / toxicity
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Peptide Fragments / administration & dosage
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Peptide Fragments / antagonists & inhibitors
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Peptide Fragments / toxicity*
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Piperazines / administration & dosage
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Piperazines / pharmacokinetics
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Piperazines / therapeutic use*
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Piperazines / toxicity
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Plaque, Amyloid / pathology
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Pyridazines / administration & dosage
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Pyridazines / pharmacokinetics
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Pyridazines / therapeutic use*
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Pyridazines / toxicity
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Rats
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S100 Calcium Binding Protein beta Subunit
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S100 Proteins / biosynthesis
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S100 Proteins / genetics
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Single-Blind Method
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
Substances
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4,6-diphenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)pyridazine
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Amyloid beta-Peptides
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Anti-Inflammatory Agents, Non-Steroidal
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Cytokines
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Interleukin-1
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Lipopolysaccharides
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Nerve Growth Factors
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Neuroprotective Agents
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Peptide Fragments
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Piperazines
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Pyridazines
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S100 Calcium Binding Protein beta Subunit
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S100 Proteins
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S100B protein, human
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S100b protein, mouse
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S100b protein, rat
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Tumor Necrosis Factor-alpha
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amyloid beta-protein (1-42)