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Isoflurane neurotoxicity is mediated by p75NTR-RhoA activation and actin depolymerization
Brian P Lemkuil1, Brian P Head, Matthew L Pearn
1Department of Anesthesiology and Veterans Affairs San Diego Healthcare System, University of California, San Diego, La Jolla, California 92161-5085, USA. ppatel@ucsd.edu
Anesthesiology
|December 21, 2010
Summary
Isoflurane harms developing brains by activating RhoA and depolymerizing actin. Inhibiting RhoA or stabilizing the cytoskeleton protects neurons from this neurotoxicity.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Isoflurane neurotoxicity in developing brains is not fully understood.
- p75 neurotrophin receptor activation and subsequent RhoA signaling are implicated.
- RhoA's role in actin depolymerization suggests a potential mechanism for neurotoxicity.
Purpose of the Study:
- To investigate if inhibiting RhoA or preventing cytoskeletal depolymerization can mitigate isoflurane-induced neurotoxicity.
- To test the efficacy of p75 neurotrophin receptor inhibition and cytoskeletal stabilization.
Main Methods:
- Primary neuron and hippocampal slice cultures from neonatal mice were exposed to isoflurane.
- Cultures were pretreated with TAT-Pep5 (p75 inhibitor) or jasplakinolide (cytoskeletal stabilizer).
- RhoA activation, cytoskeletal changes (drebrin, phalloidin), and apoptosis (caspase-3) were assessed.
Main Results:
- Isoflurane increased RhoA activation and induced cytoskeletal depolymerization and apoptosis in neurons.
- TAT-Pep5 reduced RhoA activation and protected against cytoskeletal loss and apoptosis.
- Jasplakinolide also prevented isoflurane-induced cytoskeletal depolymerization and apoptosis.
Conclusions:
- Isoflurane exposure triggers RhoA activation, leading to cytoskeletal breakdown and neuronal apoptosis.
- Targeting RhoA signaling or actin stabilization offers a promising strategy to prevent isoflurane neurotoxicity in developing brains.
