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Ketamine-induced neurotoxicity and changes in gene expression in the developing rat brain
Fang Liu1, Merle G Paule, Syed Ali
1Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR 72079, USA.
Current Neuropharmacology
|September 3, 2011
Summary
High-dose ketamine (N-methyl-D-aspartate receptor antagonist) can cause apoptosis in developing rat neurons. Repeated ketamine exposure led to increased NMDA receptor expression and triggered cell death, particularly in the frontal cortex.
Area of Science:
- Neuroscience
- Pharmacology
- Developmental Biology
Background:
- Ketamine is an NMDA receptor antagonist used in pediatric and obstetric anesthesia.
- Emerging evidence suggests ketamine may induce neuronal cell death in developing organisms.
Purpose of the Study:
- To investigate the dose- and time-dependent neurotoxic effects of ketamine in developing rat pups.
- To analyze associated changes in gene expression following ketamine administration.
Main Methods:
- Postnatal day 7 rat pups received ketamine (5, 10, or 20 mg/kg) via one, three, or six subcutaneous injections.
- Brain tissues were collected for histochemical examination and RNA analysis (in situ hybridization, microarray, qRT-PCR).
Main Results:
- Six injections of 20 mg/kg ketamine significantly increased apoptotic neuronal cell death in the frontal cortex.
- Ketamine treatment led to increased NMDA receptor NR1 subunit expression.
- Gene expression analysis revealed altered apoptotic pathways and increased NMDA receptor gene expression.
Conclusions:
- Repeated high-dose ketamine exposure can induce compensatory up-regulation of NMDA receptors in developing brains.
- This up-regulation may subsequently trigger apoptosis in developing neurons, highlighting potential neurotoxic risks.
