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Systems biology approaches for toxicology
William Slikker1, Merle G Paule, Linnzi K M Wright
1National Center for Toxicological Research, U S Food and Drug Administration, Jefferson, Arkansas 72079-9502, USA. william.slikker@fda.hhs.gov
Journal of Applied Toxicology : JAT
|February 1, 2007
Summary
Systems biology aids understanding of neurodegeneration. Blocking N-methyl-D-aspartate (NMDA) receptors in developing brains with agents like ketamine increases vulnerability to excitotoxicity, but this can be mitigated.
Area of Science:
- Systems biology and toxicology
- Neuroscience
- Developmental toxicology
Background:
- Systems biology integrates gene/protein expression data with toxicological outcomes.
- Developing brains are vulnerable to neurotoxic insults.
- N-methyl-D-aspartate (NMDA) receptor antagonists, like ketamine, disrupt normal brain development.
Purpose of the Study:
- To explore the value of systems biology in understanding neurodegeneration in the developing brain.
- To investigate the mechanisms of NMDA antagonist-induced neurotoxicity.
- To develop and validate biological models for NMDA antagonist neurotoxicity.
Main Methods:
- Developing a biological model of NMDA receptor antagonist exposure in the developing brain.
- Utilizing antisense oligonucleotides to target NMDA receptor NR1 subunit mRNA.
- Investigating the role of apoptosis and NF-kappaB translocation in ketamine neurotoxicity.
- Analyzing preliminary gene expression data.
Main Results:
- Ketamine exposure leads to NMDA receptor upregulation, increasing excitotoxic vulnerability.
- Blocking NMDA receptor upregulation with antisense oligonucleotides significantly reduced ketamine-induced cell death.
- Ketamine-induced neurotoxicity involves apoptosis and is prevented by inhibiting NF-kappaB translocation.
- Biological models confirmed pathways underlying NMDA antagonist-induced cell death.
Conclusions:
- Systems biology provides a framework for modeling complex toxicological processes.
- NMDA receptor antagonists can induce neurodevelopmental toxicity through excitotoxicity.
- Targeting NMDA receptor pathways offers potential therapeutic strategies for NMDA antagonist neurotoxicity.
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