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Microglia as a Surrogate Biosensor to Determine Nanoparticle Neurotoxicity
Published on: October 25, 2016
A network pharmacology and in silico approach to target NEU1-mediated microglial activation in neuroinflammation:
Sami I Alzarea1, Omar Awad Alsaidan2, Sumera Qasim1
1Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, 72341, Al-Jouf, Saudi Arabia.
Background:
Neuroinflammation is a critical driver of neurodegenerative diseases such as Alzheimer's and Parkinson's. Activation of microglia through Toll-like receptor 4 (TLR4) signaling contributes to neuronal dysfunction. Neuraminidase 1 (NEU1) enhances TLR4 activation via desialylation, amplifying inflammatory cascades. This study investigates the therapeutic potential of NEU1 inhibition using Osthole (OST), identified through integrated network pharmacology and in silico modeling, with subsequent in vivo validation.
Methods:
NEU1 inhibitors were predicted using network pharmacology, followed by analysis of NEU1-related neuroinflammatory pathways via protein-protein interaction (PPI) networks, Gene Ontology (GO), and KEGG enrichment. OST, the top-ranked candidate, was evaluated in an LPS-induced neuroinflammation mouse model through behavioral assessments (Locomotor Activity, Y-Maze, Morris Water Maze). qPCR was used to quantify NEU1, CD11b, and cytokines (TNF-α, IL-1β, IL-6) in the hippocampus and prefrontal cortex. Molecular docking and molecular dynamics (MD) simulations were performed to assess OST-NEU1 binding and interaction stability.
Results:
OST significantly improved spatial memory in LPS-treated mice, reduced escape latency, and enhanced Y-maze performance. It downregulated NEU1 and CD11b expression, attenuating microglial activation, and suppressed pro-inflammatory cytokine expression. Docking showed a strong binding affinity of OST to NEU1 (-17 kcal/mol), with stable interactions confirmed by MD simulations (low RMSD and residue fluctuations).
Conclusion:
NEU1 inhibition via OST reduces neuroinflammation and cognitive deficits in vivo. Computational modeling supports OST's stable and specific binding to NEU1, highlighting its potential as a lead compound against neuroinflammation in neurodegenerative disorders.
